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Sample records for tetrahydrocannabinol

  1. POTENTIAL CW AGENTS. TASK 3. ANALOGS OF TETRAHYDROCANNABINOL

    Science.gov (United States)

    The preparation of Adams’ most active tetrehydrocannabinol analog (Formula I, R=1,2-dimethylheptyl), and of synthetic tetrahydrocannabinol (I, R=n...beta-(3,5-dimethoxyphenyl) ethylanine. The pyrons related to tetrahydrocannabinol (II, R=n-amyl) has been reaction with aqueous ammonia to produce a high...amylphenol. An attempt will be made to condense this aminophenol with pulegone to give a nitrogen analog of tetrahydrocannabinol . The synthesis of pulegone from isopulegol has been accomplished.

  2. Delta 9-tetrahydrocannabinol produced discrimination in pigeons.

    Science.gov (United States)

    Henriksson, B G; Johansson, J O; Järbe, T U

    1975-01-01

    In an operant situation pigeons learned to peck one response key 90 min after an injection of 0.25mg/kg delta9-tetrahydrocannabinol (delta9-THC) and another key when trained nondrugged. When tested with doses of delta9-THC lwer than the training dose the birds disciminated 0.20 mg/kg of the drug from the nondrugged state but not 0.15 mg/kg or lower doses. The animals were able to discriminate the drug state from the nondrugged 180 min but not 360 min after the injection At a shorter interval (45 min) both drug and nondrug responding appeared. Cannabinol and cannabidiol (4.0 - 8.0 mg/kg) did not elicit any drug responses, nor did pentobarbital, ditran or amphetamine. Tests with LSD resulted in both drug and nondrug responding. When administering noncannabinoid drugs in combination with delta9-THC 0.15 mg/kg the birds responded at the key associated with the drug state, suggesting interactional effects.

  3. Tetrahydrocannabinol interactions with phencyclidine and methaqualone

    Energy Technology Data Exchange (ETDEWEB)

    Lame, M.W.

    1983-01-01

    To determine the effects of ..delta../sup 9/-tetrahydrocannabinol (THC) on the pharmacokinetics and metabolism of phencyclidine (PCP) or methaqualone (MTQ), both in vivo and in vitro studies were conducted using Sprague Dawley rats. In the in vivo studies, plasma levels of /sup 3/H-PCP.HCl equivalents were significantly altered by the administration of THC, with the test curve elevated and parallel to the control. Tissue data followed the same pattern as plasma. The urinary, fecal, and biliary excretion of /sup 3/H-PCP.HCl equivalents for the most part did not show significant perturbation with the coadministration of THC. With respect of MTQ, plasma studies indicated that THC could significantly elevate /sup 14/C-MTQ equivalents for the first 4.5 hours, reduce these levels from approximately 6.5 to 16.5 hours, and again elevate the levels above controls for the period from 19.5 to 22.5 hours. All significant changes in tissue levels mirrored plasma value differences seen between test and control animals. Biliary excretion data indicated that THC showed a trend towards altering the active excretion of /sup 14/C-MTQ equivalents. In vitro microsomal metabolism studies indicated that THC production of phenylcyclohexylamine, 1-(1-phenyl-4-hydroxycyclohexyl)piperidine, and 1-(1-phenylcyclohexyl)-4-hydroxypiperidine. Similar studies conducted with MTQ revealed that THC at the 0.05, 0.025, and 0.0125 mM levels also inhibited the metabolism of this compound.

  4. Excretion of Δ9-Tetrahydrocannabinol in Sweat

    Science.gov (United States)

    Huestis, Marilyn A.; Scheidweiler, Karl B.; Saito, Takeshi; Fortner, Neil; Abraham, Tsadik; Gustafson, Richard A.; Smith, Michael L.

    2008-01-01

    Sweat testing is a noninvasive technique for monitoring drug exposure over a 7-day period in treatment, criminal justice, and employment settings. We evaluated Δ9-tetrahydrocannabinol (THC) excretion in 11 daily cannabis users after cessation of drug use. PharmChek® sweat patches worn for 7 days were analyzed for THC by gas chromatography-mass spectrometry (GC/MS). The limit of quantification (LOQ) for the method was 0.4 ng THC/patch. Sweat patches worn the first week of continuously monitored abstinence had THC above the United States Substance Abuse Mental Health Services Administration’s proposed cutoff concentration for federal workplace testing of 1 ng THC/patch. Mean ± S.E.M. THC concentrations were 3.85 ± 0.86 ng THC/patch. Eight of 11 subjects had negative patches the second week and one produced THC positive patches for four weeks of monitored abstinence. We also tested daily and weekly sweat patches from 7 subjects who were administered oral doses of up to 14.8 mg THC/day for five consecutive days. In this oral THC administration study, no daily or weekly patches had THC above the LOQ; concurrent plasma THC concentrations were all less than 6.1 μg/L. In conclusion, using proposed federal cutoff concentrations, most daily cannabis users will have a positive sweat patch in the first week after ceasing drug use and a negative patch after subsequent weeks, although patches may remain positive for four weeks or more. Oral ingestion of up to 14.8 mg THC daily does not produce a THC positive sweat patch test. PMID:17481836

  5. Detection of Δ9-tetrahydrocannabinol in exhaled breath collected from cannabis users.

    Science.gov (United States)

    Beck, Olof; Sandqvist, Sören; Dubbelboer, Ilse; Franck, Johan

    2011-10-01

    Exhaled breath has recently been proposed as a new possible matrix for drugs of abuse testing. A key drug is cannabis, and the present study was aimed at investigating the possibility of detecting tetrahydrocannabinol and tetrahydrocannabinol carboxylic acid in exhaled breath after cannabis smoking. Exhaled breath was sampled from 10 regular cannabis users and 8 controls by directing the exhaled breath by suction through an Empore C(18) disk. The disk was extracted with hexane/ethyl acetate, and the resulting extract was evaporated to dryness and redissolved in 100 μL hexane/ethyl acetate. A 3-μL aliquot was injected onto the LC-MS-MS system and analyzed using positive electrospray ionization and selected reaction monitoring. In samples collected 1-12 h after cannabis smoking, tetrahydrocannabinol was detected in all 10 subjects. The rate of excretion was between 9.0 and 77.3 pg/min. Identification of tetrahydrocannabinol was based on correct retention time relative to tetrahydrocannabinol-d(3) and correct product ion ratio. In three samples, peaks were observed for tetrahydrocannabinol carboxylic acid, but these did not fulfill identification criteria. Neither tetrahydrocannabinol or tetrahydrocannabinol carboxylic acid was detected in the controls. These results confirm older reports that tetrahydrocannabinol is present in exhaled breath following cannabis smoking and extend the detection time from minutes to hours. The results further support the idea that exhaled breath is a promising matrix for drugs-of-abuse testing.

  6. Delta(9)-tetrahydrocannabinol, 11-hydroxy-delta(9)-tetrahydrocannabinol and 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol in human plasma after controlled oral administration of cannabinoids.

    Science.gov (United States)

    Goodwin, Robert S; Gustafson, Richard A; Barnes, Allan; Nebro, Wesenyalsh; Moolchan, Eric T; Huestis, Marilyn A

    2006-08-01

    A clinical study to investigate the pharmacokinetics and pharmacodynamics of oral tetrahydrocannabinol was performed. This randomized, double-blind, placebo-controlled, within-subject, inpatient study compared the effects of THC-containing hemp oils in liquid and capsule form to dronabinol (synthetic THC) in doses used for appetite stimulation. The National Institute on Drug Abuse Institutional Review Board approved the protocol and each participant provided informed consent. Detection times and concentrations of THC, 11-hydroxy-Delta-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Delta-tetrahydrocannabinol (THCCOOH) in plasma were determined by gas chromatography-mass spectrometry [limits of quantification (LOQ)=0.5, 0.5, and 1.0 ng/mL, respectively] after oral THC administration. Six volunteers ingested liquid hemp oil (0.39 and 14.8 mg THC/d), hemp oil in capsules (0.47 mg THC/d), dronabinol capsules (7.5 mg THC/d), and placebo. Plasma specimens were collected during and after each dosing condition. THC and 11-OH-THC concentrations were low and never exceeded 6.1 ng/mL. Analytes were detectable 1.5 hour after initiating dosing with the 7.5 mg THC/d regimen and 4.5 hour after starting the 14.8 mg THC/d sessions. THCCOOH was detected 1.5 hour after the first dose, except for the 0.47 mg THC/d session, which required 4.5 hour for concentrations to reach the LOQ. THCCOOH concentrations peaked at 3.1 ng/mL during dosing with the low-dose hemp oils. Plasma THC and 11-OH-THC concentrations were negative for all participants at all doses within 15.5 hours after the last THC dose. Plasma THCCOOH persisted for at least 39.5 hours after the end of dosing and at much higher concentrations (up to 43.0 ng/mL). This study demonstrated that subjects who used high THC content hemp oil (347 mug/mL) as a dietary supplement had THC and metabolites in plasma in quantities comparable to those of patients using dronabinol for appetite stimulation. There was a significant

  7. Hashish. Importance of the phenolic hydroxyl group in tetrahydrocannabinols.

    Science.gov (United States)

    Uliss, D B; Dalzell, H C; Handrick, G R; Howes, J F; Razdan, R K

    1975-02-01

    Optically active delta-3- and delta-8-tetrahydrocannabinols (THC's), cannabidiol and racemic delta-9-cis-THC, and their corresponding analogs (1b yields 4b) in which the positions of the phenolic hydroxyl group and the n-C5 side chain have been interchanged are compared in selected pharmacological tests in mice. the results indicate that the phenolic hydroxyl group in the 1 position in THC's is very important for eliciting activity and that cannabidiol and delta-9-cis-THC possess weak CNS depressant properties.

  8. A drug discovery case history of 'delta-9-tetrahydrocannabinol, cannabidiol'.

    Science.gov (United States)

    Tanasescu, Radu; Rog, David; Constantinescu, Cris S

    2011-04-01

    Although the Cannabis sativa herb has been known for its therapeutic benefit for centuries, the interest in the clinical potential of cannabinoid-based drugs escalated after the discovery of the endocannabinoid system. The understanding of their actions at the molecular level indicates that the therapeutic applications of cannabinoids (plant-derived or synthetic) may be diverse. Several drugs containing cannabinoids are currently used in the therapy of emesis, pain and spasticity. This drug discovery case history reviews the preclinical and clinical development of Sativex ('delta-9-tetrahydrocannabinol, cannabidiol'; nabiximols). Sativex is the first licensed phytocannabinoid-based drug approved, or in the process of approval, as therapy for indications such as MS-associated spasticity or chronic pain. Sativex contains a combination of two cannabinoids in approximately equal quantities (δ-9-tetrahydrocannabinol and cannabidiol) and is administered via an oromucosal pump spray, aiming at minimising psychotropic side effects and first pass effect. Pivotal clinical safety and efficacy data that led to Sativex's approval are discussed, as well as issues that have arisen with its clinical usage. Although pleiotrophic effects of cannabinoids may raise complex issues beyond their symptomatic effects, standardised pharmaceutical cannabinoids may constitute a useful addition to the pharmacotherapeutic armamentarium in chronic conditions insufficiently alleviated by existing drugs.

  9. Understanding the Molecular Aspects of Tetrahydrocannabinol and Cannabidiol as Antioxidants

    Directory of Open Access Journals (Sweden)

    Káthia M. Honório

    2013-10-01

    Full Text Available An antioxidant mechanism of tetrahydrocannabinol (THC and cannabidiol (CBD were compared with a simplified model of α-tocopherol, butylhydroxytoluene and hydroxytoluene in order to understand the antioxidant nature of THC and CBD molecules using DFT. The following electronic properties were evaluated: frontier orbitals nature, ionization potential, O-H bond dissociation energy (BDEOH, stabilization energy, and spin density distribution. An important factor that shows an influence in the antioxidant property of THC is the electron abstraction at the phenol position. Our data indicate that the decrease of the HOMO values and the highest ionization potential values are related to phenol, ether, and alkyl moieties. On the other hand, BDEOH in molecules with the cyclohexenyl group at ortho position of phenol are formed from lower energies than the molecules with an ether group at the meta position. In the light of our results, the properties calculated here predict that THC has a sightly higher antioxidant potential than CBD.

  10. The effects of Δ9-tetrahydrocannabinol on the dopamine system

    Science.gov (United States)

    Bloomfield, Michael A P; Ashok, Abhishekh H; Volkow, Nora D; Howes, Oliver D

    2016-01-01

    Preface Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, is a pressing concern to global mental health. Patterns of use are changing drastically due to legalisation, availability of synthetic analogues (‘spice’), cannavaping and aggrandizements in the purported therapeutic effects of cannabis. Many of THC’s reinforcing effects are mediated by the dopamine system. Due to complex cannabinoid-dopamine interactions there is conflicting evidence from human and animal research fields. Acute THC causes increased dopamine release and neuron activity, whilst long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of the drug. PMID:27853201

  11. Topical delta 9-tetrahydrocannabinol and aqueous dynamics in glaucoma.

    Science.gov (United States)

    Merritt, J C; Perry, D D; Russell, D N; Jones, B F

    1981-01-01

    Systemic delta 9-tetrahydrocannabinol (THC), administered either by smoking marihuana or as synthetic THC in soft gelatin capsules, lowers ocular tension in various glaucomas, but at the expense of significant decreases in systolic blood pressure. Topical THC in light mineral oil vehicles, though effective in laboratory animals, was not shown effective in 0.05 and 0.1% topical solutions when administered to six subjects with primary open-angle glaucoma in a randomized, balanced, double-masked protocol. Light mineral oil, which has an affinity for corneal epithelium, is an optimum vehicle for administering drugs whose mechanisms of action are systemic rather than local within the eye. Further glaucoma research should therefore proceed with marihuanas containing insignificant levels of THC (less than 0.4%) and with various local delivery systems of the ocular-active cannabinoid found in Cannabis sativa.

  12. Metabolomics of Δ9-tetrahydrocannabinol: implications in toxicity.

    Science.gov (United States)

    Dinis-Oliveira, Ricardo Jorge

    2016-01-01

    Cannabis sativa is the most commonly used recreational drug, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) being the main addictive compound. Biotransformation of cannabinoids is an important field of xenobiochemistry and toxicology and the study of the metabolism can lead to the discovery of new compounds, unknown metabolites with unique structures and new therapeutic effects. The pharmacokinetics of Δ(9)-THC is dependent on multiple factors such as physical/chemical form, route of administration, genetics, and concurrent consumption of alcohol. This review aims to discuss metabolomics of Δ(9)-THC, namely by presenting all known metabolites of Δ(9)-THC described both in vitro and in vivo, and their roles in the Δ(9)-THC-mediated toxic effects. Since medicinal use is increasing, metabolomics of Δ(9)-THC will also be discussed in order to uncover potential active metabolites that can be made available for this purpose.

  13. The effects of Δ9-tetrahydrocannabinol on the dopamine system.

    Science.gov (United States)

    Bloomfield, Michael A P; Ashok, Abhishekh H; Volkow, Nora D; Howes, Oliver D

    2016-11-17

    The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid-dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.

  14. A critical review of the occurrence, detection, and treatment of Δ9-tetrahydrocannabinol in aquatic environments

    National Research Council Canada - National Science Library

    Gagnon, Graham A; Mackie, Allison L; Park, Yu Ri

    The main psychoactive compound in marijuana, Δ 9 -tetrahydrocannabinol (THC), and its metabolites are emerging organic contaminants that have been detected in waste and surface waters around the globe...

  15. Controlled release tablet formulation containing natural Δ(9)-tetrahydrocannabinol.

    Science.gov (United States)

    Punyamurthula, Nagendra S; Hingorani, Tushar; Adelli, Goutham; Gul, Waseem; ElSohly, Mahmoud A; Repka, Michael A; Majumdar, Soumyajit

    2016-01-01

    Cannabinoids are increasingly being used in the treatment of chemotherapy-induced nausea and vomiting (CINV) because of their action on the cannabinoid receptors, CB1 and CB2. The currently marketed capsule formulations (sesame oil based and crystalline powder) are required to be administered frequently to maintain therapeutic levels, which leads to non-compliance. In the present study, oral controlled release tablet formulations of Δ(9)-tetrahydrocannabinol (THC) were prepared using the lipids Precirol® and Compritol®. Release profiles using THC-lipid matrices and/or with the lipids in the external phase (blend) were evaluated. The effect of directly compressible diluents lactose mixture (Ludipress®), dicalcium phosphate anhydrous (Emcompress®) and microcrystalline cellulose (Avicel® 102) on tablet characteristics and in vitro drug release was also investigated. Further, in vitro THC release in the presence of a lipase inhibitor, Pluronic® F68, was also studied. A 24 h zero-order THC release profile was obtained with a combination of Precirol® and Compritol® in the compression blend. Addition of Pluronic® F68 did not alter THC release in vitro. These optimized tablets were chemically and physically stable for 3 months, the last time point tested, at 25 °C/60% RH. The overall results demonstrate the feasibility of preparing oral THC tablets for once a day administration which can improve CINV management.

  16. On the pharmacological properties of Delta9-tetrahydrocannabinol (THC).

    Science.gov (United States)

    Costa, Barbara

    2007-08-01

    Cannabis is one of the first plants used as medicine, and the notion that it has potentially valuable therapeutic properties is a matter of current debate. The isolation of its main constituent, Delta9-tetrahydrocannabinol (THC), and the discovery of the endocannabinoid system (cannabinoid receptors CB1 and CB2 and their endogenous ligands) made possible studies concerning the pharmacological activity of cannabinoids. This paper reviews some of the most-important findings in the field of THC pharmacology. Clinical trials, anecdotal reports, and experiments employing animal models strongly support the idea that THC and its derivatives exhibit a wide variety of therapeutic applications. However, the psychotropic effects observed in laboratory animals and the adverse reactions reported during human trials, as well as the risk of tolerance development and potential dependence, limit the application of THC in therapy. Nowadays, researchers focus on other therapeutic strategies by which the endocannabinoid system might be modulated to clinical advantage (inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism). However, emerging evidence highlights the beneficial effects of the whole cannabis extract over those observed with single components, indicating cannabis-based medicines as new perspective to revisit the pharmacology of this plant.

  17. Cannabis sativa (Hemp) Seeds, Δ9-Tetrahydrocannabinol, and Potential Overdose.

    Science.gov (United States)

    Yang, Yi; Lewis, Melissa M; Bello, Angelica M; Wasilewski, Ewa; Clarke, Hance A; Kotra, Lakshmi P

    2017-01-01

    Introduction:Cannabis sativa (hemp) seeds are popular for their high nutrient content, and strict regulations are in place to limit the amount of potentially harmful phytocannabinoids, especially Δ9-tetrahydrocannabinol (Δ9-THC). In Canada, this limit is 10 μg of Δ9-THC per gram of hemp seeds (10 ppm), and other jurisdictions in the world follow similar guidelines. Materials and Methods: We investigated three different brands of consumer-grade hemp seeds using four different procedures to extract phytocannabinoids, and quantified total Δ9-THC and cannabidiol (CBD). Discussion: We discovered that Δ9-THC concentrations in these hemp seeds could be as high as 1250% of the legal limit, and the amount of phytocannabinoids depended on the extraction procedure employed, Soxhlet extraction being the most efficient across all three brands of seeds. Δ9-THC and CBD exhibited significant variations in their estimated concentrations even from the same brand, reflecting the inhomogeneous nature of seeds and variability due to the extraction method, but almost in all cases, Δ9-THC concentrations were higher than the legal limit. These quantities of total Δ9-THC may reach as high as 3.8 mg per gram of hemp seeds, if one were consuming a 30-g daily recommended amount of hemp seeds, and is a cause for concern for potential toxicity. It is not clear if these high quantities of Δ9-THC are due to contamination of the seeds, or any other reason. Conclusion: Careful consideration of the extraction method is very important for the measurement of cannabinoids in hemp seeds.

  18. Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants

    Science.gov (United States)

    Hampson, A. J.; Grimaldi, M.; Axelrod, J.; Wink, D.

    1998-01-01

    The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Glutamate toxicity was reduced by both cannabidiol, a nonpsychoactive constituent of marijuana, and the psychotropic cannabinoid (−)Δ9-tetrahydrocannabinol (THC). Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-d-aspartate receptors, 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid receptors, or kainate receptors. N-methyl-d-aspartate receptor-induced toxicity has been shown to be calcium dependent; this study demonstrates that 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid/kainate receptor-type neurotoxicity is also calcium-dependent, partly mediated by voltage sensitive calcium channels. The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or α-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia. PMID:9653176

  19. Decarboxylation of Δ 9-tetrahydrocannabinol: Kinetics and molecular modeling

    Science.gov (United States)

    Perrotin-Brunel, Helene; Buijs, Wim; van Spronsen, Jaap; van Roosmalen, Maaike J. E.; Peters, Cor J.; Verpoorte, Rob; Witkamp, Geert-Jan

    2011-02-01

    Efficient tetrahydrocannabinol (Δ 9-THC) production from cannabis is important for its medical application and as basis for the development of production routes of other drugs from plants. This work presents one of the steps of Δ 9-THC production from cannabis plant material, the decarboxylation reaction, transforming the Δ 9-THC-acid naturally present in the plant into the psychoactive Δ 9-THC. Results of experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ mol -1 and a pre-exponential factor of 3.7 × 10 8 s -1. Using molecular modeling, two options were identified for an acid catalyzed β-keto acid type mechanism for the decarboxylation of Δ 9-THC-acid. Each of these mechanisms might play a role, depending on the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction. Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill, and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier and the pre-exponential factor of the decarboxylation of Δ 9-THC-acid. Evidence for this was found by performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carboxylic acids supporting this hypothesis. The presented approach is important for the development of a sustainable production of Δ 9-THC from the plant.

  20. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial.

    Science.gov (United States)

    van den Elsen, Geke A H; Ahmed, Amir I A; Verkes, Robbert-Jan; Kramers, Cees; Feuth, Ton; Rosenberg, Paul B; van der Marck, Marjolein A; Olde Rikkert, Marcel G M

    2015-06-09

    To study the efficacy and safety of low-dose oral tetrahydrocannabinol (THC) in the treatment of dementia-related neuropsychiatric symptoms (NPS). This is a randomized, double-blind, placebo-controlled study. Patients with dementia and clinically relevant NPS were randomly assigned to receive THC 1.5 mg or matched placebo (1:1) 3 times daily for 3 weeks. Primary outcome was change in Neuropsychiatric Inventory (NPI), assessed at baseline and after 14 and 21 days. Analyses were based on intention-to-treat. Twenty-four patients received THC and 26 received placebo. NPS were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant (mean difference NPItotal: 3.2, 95% confidence interval [CI] -3.6 to 10.0), nor were changes in scores for agitation (Cohen-Mansfield Agitation Inventory 4.6, 95% CI -3.0 to 12.2), quality of life (Quality of Life-Alzheimer's Disease -0.5, 95% CI -2.6 to 1.6), or activities of daily living (Barthel Index 0.6, 95% CI -0.8 to 1.9). The number of patients experiencing mild or moderate adverse events was similar (THC, n = 16; placebo, n = 14, p = 0.36). No effects on vital signs, weight, or episodic memory were observed. Oral THC of 4.5 mg daily showed no benefit in NPS, but was well-tolerated, which adds valuable knowledge to the scarce evidence on THC in dementia. The benign adverse event profile of this dosage allows study of whether higher doses are efficacious and equally well-tolerated. This study provides Class I evidence that for patients with dementia-related NPS, low-dose THC does not significantly reduce NPS at 21 days, though it is well-tolerated. © 2015 American Academy of Neurology.

  1. Development of fluoroimmunoassay methods for delta-9-tetrahydrocannabinol

    Energy Technology Data Exchange (ETDEWEB)

    Mason, A.P.

    1986-01-01

    Heterogeneous, competitive, labelled-ligand solid-phase primary antibody fluoroimmunoassay methods for the detection of THC in blood and plasma were proposed, and the required assay components were produced and characterized. These components included polyclonal rabbit antisera and monoclonal antibodies reactive with tetrahydrocannabinols, solid-phase immunoglobin reagents, a fluoroligand, and protein conjugates of THC for immunization and immunoassay response amplification. The stereoselective rabbit anti-THC antiserum F-444-12 was found to have a high binding titer, a high affinity (K/sub D/ = 3.4 x 10/sup -/exclamation/sup 1/ M for 5'-iodo/sup -125/I-..delta../sup 2/-THC), and high specificity versus a large number of cannabinoid compounds. Immobilization of the immunoglobulin fraction of the antiserum on hydrophilic polyacrylamide microspheres resulted in only a four fold increase in K/sub D/, and a two fold increase in the concentration of binding sites required for the production of equivalent binding titers. Specificity for small ligands was not affected, but the binding of THC-protein conjugates was reduced in potency. Two monoclonal hybridoma cell lines were produced that secrete monoclonal antibodies which bind the radioligand. The fluoroligand was synthesized from 5'-carboxy-..delta../sup 2/-THC and FITC using a diamimoethane linkage structure. While the compound had the fluorescence properties of FTIC, it was bound to the antiserum F-144-12 with a cross-reactive potency 1.4x greater than the radioligand, and 10x greater than THC.

  2. Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

    Science.gov (United States)

    Castelli, M Paola; Madeddu, Camilla; Casti, Alberto; Casu, Angelo; Casti, Paola; Scherma, Maria; Fattore, Liana; Fadda, Paola; Ennas, M Grazia

    2014-01-01

    Methamphetamine (METH) is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS), production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC) and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart) were pre- or post-treated with Δ9-THC (1 or 3 mg/kg) and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP). Results showed that, as compared to corresponding controls (i) METH-induced nNOS overexpression in the caudate-putamen (CPu) was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals); (ii) METH-induced GFAP-immunoreactivity (IR) was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50%) and by pre-treatment with 3 mg/kg Δ9-THC (-53%); (iii) METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC) by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals). The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our

  3. Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

    Directory of Open Access Journals (Sweden)

    M Paola Castelli

    Full Text Available Methamphetamine (METH is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS, production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart were pre- or post-treated with Δ9-THC (1 or 3 mg/kg and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP. Results showed that, as compared to corresponding controls (i METH-induced nNOS overexpression in the caudate-putamen (CPu was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals; (ii METH-induced GFAP-immunoreactivity (IR was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50% and by pre-treatment with 3 mg/kg Δ9-THC (-53%; (iii METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals. The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our

  4. delta 1-Tetrahydrocannabinol-induced circling behavior in rats : a possible measure of psychotomimetic activity?

    NARCIS (Netherlands)

    Nir, I; Veldhuis, H D; van Ree, J M

    1984-01-01

    Relatively high dosages of delta 1-tetrahydrocannabinol (delta 1-THC) markedly suppressed almost all normally occurring behavioral elements in rats as observed in both a small and a large open field. This effect persisted following repeated treatment and testing for 3 consecutive days. The

  5. Delta(9)-tetrahydrocannabinol activates [Ca2+], increases partly sensitive to capacitative store refilling

    NARCIS (Netherlands)

    Filipeanu, CM; deZeeuw, D; Nelemans, SA

    1997-01-01

    Delta(9)-Tetrahydrocannabinol induces [Ca2+](i) increases in DDT1MF-2 smooth muscle cells. Both Ca2+ entry and release from intracellular Ca2+ stores were concentration dependently activated. The Ca2+ entry component contributed most to the increases in [Ca2+](i). Stimulation with

  6. Effects of tetrahydrocannabinol on balance and gait in patients with dementia: A randomised controlled crossover trial

    NARCIS (Netherlands)

    Elsen, G.A.H. van den; Tobben, L.; Ahmed, A.I.A.; Verkes, R.J.; Kramers, C.; Marijnissen, R.M.; Olde Rikkert, M.G.M.; Marck, M.A. van der

    2017-01-01

    Oral tetrahydrocannabinol (THC) is currently studied for its possible efficacy on dementia-related neuropsychiatric symptoms (NPS), but might lead to increased risk of falling. This was a randomised, double-blind, crossover study to evaluate the effects of THC on mobility in dementia patients.

  7. Distribution of \\0x03949-Tetrahydrocannabinol and 11-Nor-9-Carboxy-\\0x03949-Tetrahydrocannabinol acid in postmortem biological fluids and tissues from pilots fatally injured in aviation accidents.

    Science.gov (United States)

    2013-12-01

    Despite a long history of research on the pharmacology of 9-tetrahydrocannabinol (THC), the primary active cannabinoid in marijuana, little is known of its distribution in postmortem fluids and tissues. This study presents postmortem fluid and tiss...

  8. Synthesis of [13C4]-labeled ∆9-tetrahydrocannabinol and 11-nor-9-carboxy-∆9-tetrahydrocannabinol as internal standards for reducing ion suppressing/alteration effects in LC/MS-MS quantification.

    Science.gov (United States)

    Karlsen, Morten; Liu, Huiling; Johansen, Jon Eigill; Hoff, Bård Helge

    2014-09-01

    (-)-∆9-Tetrahydrocannabinol is the principal psychoactive component of the cannabis plant and also the active ingredient in some prescribed drugs. To detect and control misuse and monitor administration in clinical settings, reference samples of the native drugs and their metabolites are needed. The accuracy of liquid chromatography/mass spectrometric quantification of drugs in biological samples depends among others on ion suppressing/alteration effects. Especially, 13C-labeled drug analogues are useful for minimzing such interferences. Thus, to provide internal standards for more accurate quantification and for identification purpose, synthesis of [13C4]-∆9-tetrahydro-cannabinol and [13C4]-11-nor-9-carboxy-∆9-tetrahydrocannabinol was developed via [13C4]-olivetol. Starting from [13C4]-olivetol the synthesis of [13C4]-11-nor-9-carboxy-∆9-tetrahydrocannabinol was shortened from three to two steps by employing nitromethane as a co-solvent in condensation with (+)-apoverbenone.

  9. Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15

    NARCIS (Netherlands)

    Niesink, Raymond J. M.; Rigter, Sander; Koeter, Maarten W.; Brunt, Tibor M.

    2015-01-01

    Between 2000 and 2005 the average percentage of Δ(9) -tetrahydrocannabinol (THC) in marijuana as sold in Dutch coffeeshops has increased substantially; the potency of domestic products (Nederwiet and Nederhasj) has particularly increased. In contrast with imported marijuana, Nederwiet hardly

  10. Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content.

    OpenAIRE

    Pickens, J. T.

    1981-01-01

    1. The oral sedative potencies of cannabis herb, crude ethanolic and petroleum-ether fractions, were assayed against delta'-trans-tetrahydrocannabinol (THC) administered orally to mice, by measuring spontaneous motor activity over 30 min periods, at selected times, up to 6 h. 2. The THC contents of the extracts were determined chemically by gas-liquid chromatography analysis and the B/C ratio (biological activity divided by chemical activity) calculated for each. The B/C values for cannabis h...

  11. Psychoactive drugs and false memory: comparison of dextroamphetamine and delta-9-tetrahydrocannabinol on false recognition

    OpenAIRE

    Ballard, Michael E.; Gallo, David A.; de Wit, Harriet

    2011-01-01

    Rationale Several psychoactive drugs are known to influence episodic memory. However, these drugs’ effects on false memory, or the tendency to incorrectly remember nonstudied information, remain poorly understood. Objectives Here, we examined the effects of two commonly used psychoactive drugs, one with memory-enhancing properties (dextroamphetamine; AMP), and another with memory-impairing properties (Δ9-tetrahydrocannabinol; THC), on false memory using the Deese/Roediger–McDermott (DRM) illu...

  12. Enrichment and identification of Δ9-Tetrahydrocannabinolic acid synthase from Pichia pastoris culture supernatants

    Directory of Open Access Journals (Sweden)

    Kerstin Lange

    2015-09-01

    Full Text Available This data article refers to the report Δ9-Tetrahydrocannabinolic acid synthase (THCAS production in Pichia pastoris enables chemical synthesis of cannabinoids (Lange et. al. 2015 [2]. THCAS was produced on a 2 L lab scale using recombinant P. pastoris KM71 KE1. Enrichment of THCAS as a technically pure enzyme was realized using dialysis and cationic exchange chromatography. nLC-ESI-MS/MS analysis identified THCAS in different fractions obtained by cationic exchange chromatography.

  13. Influence of delta9-tetrahydrocannabinol and cannabidiol on photically evoked after-discharge potentials.

    Science.gov (United States)

    Turkanis, S A; Chiu, P; Borys, H K; Karler, R

    1977-04-29

    Two cannabinoids, delta9-tetrahydrocannabinol and cannabidiol, and several reference drugs were compared relative to their effects in a recently developed anticonvulsant test system, the after-discharge potentials of the visually evoked response; the potentials were recorded electrophysiologically from electrodes permanently mounted over the visual cortices of conscious rats. In anticonvulsant doses, trimethadione and ethosuximide produced an extensive depression of after-discharge activity, whereas diphenylhydantoin and cannabidiol exerted no such effect. In contrast, anticonvulsant doses of delta9-tetrahydrocannabinol and subconvulsant doses of pentylenetetrazol markedly increased after-discharge activity, which may represent a manifestation of their central nervous system excitatory properties. The data from the present study support our previously published ovservations from several other anticonvulsant tests that indicate the anticonvulsant characteristics of cannabidiol resemble those of diphenylhydantoin rather than those of trimethadione and that the central excitatory properties of delta9-tetrahydrocannabinol distinguish it from cannabidiol. The results consistently suggest that the cannabinoids will be effective against grand mal but not absence seizures.

  14. Simultaneous and sensitive LC-MS/MS determination of tetrahydrocannabinol and metabolites in human plasma.

    Science.gov (United States)

    Ferreirós, N; Labocha, S; Walter, C; Lötsch, J; Geisslinger, G

    2013-02-01

    Cannabis is not only a widely used illicit drug but also a substance which can be used in pharmacological therapy because of its analgesic, antiemetic, and antispasmodic properties. A very rapid and sensitive method for determination of ∆(9)-tetrahydrocannabinol (THC), the principal active component of cannabis, and two of its phase I metabolites in plasma has been developed and validated. After solid-phase extraction of plasma (0.2 mL), the clean extracts were analyzed by tandem mass spectrometry after a 5-min liquid chromatographic separation. The linear calibration ranges were from 0.05 to 30 ng mL(-1) for THC and 11-nor-∆(9)-carboxy-tetrahydrocannabinol (THC-COOH) and from 0.2 to 30 ng mL(-1) for ∆(9)-(11-OH)-tetrahydrocannabinol (11-OH-THC). Imprecision and inaccuracy were always below 7 and 12 % (expressed as relative standard deviation and relative error), respectively. The method has been successfully applied to determination of the three analytes in plasma obtained from healthy volunteers after oral administration of 20 mg dronabinol.

  15. Simultaneous determination of Δ9-tetrahydrocannabinol, cannabidiol, cannabinol and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid in hair using liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Dulaurent, S; Gaulier, J M; Imbert, L; Morla, A; Lachâtre, G

    2014-03-01

    For several years, hair analyses have become a powerful tool to investigate past exposure towards xenobiotics. In the case of illicit drugs and more precisely of cannabis exposure, four compounds are usually investigated: Δ(9)-tetrahydrocannabinol (THC), the main active compound of cannabis, one of its metabolites [11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH)] and two cannabinoids (cannabinol and cannabidiol). Up until now, the hair determination of the carboxylic metabolite of THC, which has been described as the only marker allowing distinguishing consumption and passive exposure, has been performed using a gas chromatography-tandem mass spectrometry method. The aim of this study was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantitative determination of the four markers. The sample preparation was based on an alkaline hydrolysis of hair samples followed by a liquid-liquid extraction of compounds in acidic conditions using a hexane/ethyl acetate mixture. The method was validated and the results were satisfactory: intra- and inter-assay accuracies below 9% and relative standard deviation below 15% for the four compounds. Moreover, the limit of quantification for THC-COOH, the most challenging compound, was validated at 0.2 pg/mg. This concentration is in accordance with the recommendations made by a scientific society which specializes in hair testing. It makes it possible to distinguish the kind of exposure to cannabis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Analysis of tetrahydrocannabinol and its metabolite, 11-nor-Δ⁹-tetrahydrocannabinol-9-carboxylic acid, in oral fluid using liquid chromatography with tandem mass spectrometry.

    Science.gov (United States)

    Coulter, Cynthia; Garnier, Margaux; Moore, Christine

    2012-07-01

    This paper describes the determination of tetrahydrocannabinol (THC) and its metabolite, 11-nor-Δ⁹-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in oral fluid using solid-phase extraction and liquid chromatography with tandem mass spectral detection (LC-MS-MS) and its application to proficiency specimens. The method employs collection of oral fluid with the Quantisal™ device, base hydrolysis, solid-phase extraction and LC-MS-MS in positive ion electrospray mode. Because the concentration of the metabolite in oral fluid is quite low, extremely sensitive analytical methods are necessary. The requisite sensitivity was achieved by a simple, rapid derivatization of the compound after extraction. The derivatization conditions did not affect parent THC. The method was fully validated using standard parameters including linearity, sensitivity, accuracy, intra-day and inter-day imprecision, drug recovery from the collection pad, limit of quantitation, limit of detection and matrix effects. The procedure was applied to oral fluid proficiency specimens previously analyzed to assess the stability of THC-COOH.

  17. Distribution of ∆(9)-Tetrahydrocannabinol and 11-Nor-9-Carboxy-∆(9)-Tetrahydrocannabinol Acid in Postmortem Biological Fluids and Tissues From Pilots Fatally Injured in Aviation Accidents.

    Science.gov (United States)

    Kemp, Philip M; Cardona, Patrick S; Chaturvedi, Arvind K; Soper, John W

    2015-07-01

    Little is known of the postmortem distribution of ∆(9)-tetrahydrocannabinol (THC) and its major metabolite, 11-nor-9-carboxy-∆(9)-tetrahydrocannabinol (THCCOOH). Data from 55 pilots involved in fatal aviation accidents are presented in this study. Gas chromatography/mass spectrometry analysis obtained mean THC concentrations in blood from multiple sites, liver, lung, and kidney of 15.6 ng/mL, 92.4 ng/g, 766.0 ng/g, 44.1 ng/g and mean THCCOOH concentrations of 35.9 ng/mL, 322.4 ng/g, 42.6 ng/g, 138.5 ng/g, respectively. Heart THC concentrations (two cases) were 184.4 and 759.3 ng/g, and corresponding THCCOOH measured 11.0 and 95.9 ng/g, respectively. Muscle concentrations for THC (two cases) were 16.6 and 2.5 ng/g; corresponding THCCOOH, "confirmed positive" and 1.4 ng/g. The only brain tested in this study showed no THC detected and 2.9 ng/g THCCOOH, low concentrations that correlated with low values in other specimens from this case. This research emphasizes the need for postmortem cannabinoid testing and demonstrates the usefulness of a number of tissues, most notably lung, for these analyses. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  18. Hair analysis for Δ(9) -tetrahydrocannabinolic acid A (THCA-A) and Δ(9) -tetrahydrocannabinol (THC) after handling cannabis plant material.

    Science.gov (United States)

    Moosmann, Bjoern; Roth, Nadine; Auwärter, Volker

    2016-01-01

    A previous study has shown that Δ(9) -tetrahydrocannabinolic acid A (THCA-A), the non-psychoactive precursor of Δ(9) -tetrahydrocannabinol (THC) in the cannabis plant does not get incorporated in relevant amounts into the hair through the bloodstream after repeated oral intake. However, THCA-A can be measured in forensic hair samples in concentrations often exceeding the detected THC concentrations. To investigate whether the handling of cannabis plant material prior to consumption is a contributing factor for THC-positive hair results and also the source for THCA-A findings in hair, a study comprising ten participants was conducted. In this study, the participants rolled a marijuana joint on five consecutive days and hair samples of each participant were obtained. Urine samples were taken to exclude cannabis consumption prior to and during the study. THCA-A and THC could be detected in the hair samples from all participants taken at the end of the exposure period (concentration range: 15-1800 pg/mg for THCA-A and THC). Four weeks after the first exposure, THCA-A could still be detected in the hair samples of nine participants (concentration range: 4-57 pg/mg). Furthermore, THC could be detected in the hair samples of five participants (concentration range: THC as well as the major part of THCA-A found in routine hair analysis derives from external contamination caused by direct transfer through contaminated fingers. This finding is of particular interest in interpreting THC-positive hair results of children or partners of cannabis users, where such a transfer can occur due to close body contact. Analytical findings may be wrongly interpreted as a proof of consumption or at least passive exposure to cannabis smoke. Such misinterpretation could lead to severe consequences for the people concerned. Copyright © 2015 John Wiley & Sons, Ltd.

  19. Simplified analysis of 11-hydroxy-delta-9-tetrahydrocannabinol and 11-carboxy-delta-9-tetrahydrocannabinol in human meconium: method development and validation.

    Science.gov (United States)

    Tynon, Marykathryn; Porto, Marcellino; Logan, Barry K

    2015-01-01

    We describe the development of a sensitive analytical method for the analysis of 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-carboxy-delta-9-tetrahydrocannabinol (THCC) in meconium using a gas chromatography-mass spectrometry (GC/MS) platform. The method was validated according to protocols, which included assessment of accuracy, precision, robustness, stability in meconium and in-process stability, interference and sensitivity and specificity. The method consists of a solid phase extraction with alkaline hydrolysis and derivatization of the analytes with N, O-Bis(trimethylsilyl)trifluoroacteamide, followed by GC/MS analysis using selected ion monitoring. The method uses deuterated internal standards for both analytes. Calibration curves had r(2) values >0.998, and extraction efficiency was determined to be 84.7% for THCC and 78.6% for 11-OH-THC. The detection limit for both analytes was 5 ng/g. This confirmatory method was successfully applied to 183 meconium samples that had screened positive by enzyme-linked immunosorbent assay, and 67.2% were confirmed for THCC, and 2.2% were confirmed positive for 11-OH-THC. The mean (SD) and median (range) THCC (n = 123) concentrations detected were 55.0 ng/g (±59.0) and 33.75 ng/g (5-265 ng/g), while the mean and median (range) for 11-OH-THC (n = 4) concentrations were 8.25 ng/g (±4.71) and 6.5 ng/g (5-15 ng/g). © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Delta-9-tetrahydrocannabinol depresses inward sodium current in mouse neuroblastoma cells.

    Science.gov (United States)

    Turkanis, S A; Partlow, L M; Karler, R

    1991-01-01

    Whole-cell voltage-clamp techniques were used in order to define the effects of delta-9-tetrahydrocannabinol (THC) on the voltage-gated sodium current in neuroblastoma cells. With regard to the inward sodium current, THC decreased the peak amplitude and increased both the time to peak and tau for recovery. The reversal potential was unchanged, suggesting that channel selectivity for sodium was not altered by the drug. With regard to the outward sodium current, THC had no effect on the peak amplitude, time to peak or tau for recovery. This functional alteration of the voltage-gated sodium channel may contribute to the depressant effects of the cannabinoid.

  1. Tetrahydrocannabinol vs. Prochlorperazine: the effects of two antiemetics on patients undergoing radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Ungerleider, J.T.; Andrysiak, T.A.; Fiarbanks, L.A.; Tesler, A.S.; Parker, R.G.

    1984-02-01

    The authors tested the effectiveness of orally administred delta-9-tetrahydrocannabinol (THC) as compared to prochlorperazine for the alleviation of symptoms, such as vomiting and nausea, experienced by patients receiving radiotherapy. The test subjects rated the severity of their illness, as well as the extent of their subsequent moods, their level of concentration, their amount of physical activity, and their desire for social interaction. They chose the drug they preferred and recorded its side effects. The use of THC was slightly more beneficial than the use of prochlorperazine.

  2. A cannabigerol-rich Cannabis sativa extract, devoid of [INCREMENT]9-tetrahydrocannabinol, elicits hyperphagia in rats.

    Science.gov (United States)

    Brierley, Daniel I; Samuels, James; Duncan, Marnie; Whalley, Benjamin J; Williams, Claire M

    2017-06-01

    Nonpsychoactive phytocannabinoids (pCBs) from Cannabis sativa may represent novel therapeutic options for cachexia because of their pleiotropic pharmacological activities, including appetite stimulation. We have recently shown that purified cannabigerol (CBG) is a novel appetite stimulant in rats. As standardized extracts from Cannabis chemotypes dominant in one pCB [botanical drug substances (BDSs)] often show greater efficacy and/or potency than purified pCBs, we investigated the effects of a CBG-rich BDS, devoid of psychoactive [INCREMENT]-tetrahydrocannabinol, on feeding behaviour. Following a 2 h prefeed satiation procedure, 16 male Lister-hooded rats were administered CBG-BDS (at 30-240 mg/kg) or vehicle. Food intake, meal pattern microstructure and locomotor activity were recorded over 2 h. The total food intake was increased by 120 and 240 mg/kg CBG-BDS (1.53 and 1.36 g, respectively, vs. 0.56 g in vehicle-treated animals). Latency to feeding onset was dose dependently decreased at all doses, and 120 and 240 mg/kg doses increased both the number of meals consumed and the cumulative size of the first two meals. No significant effect was observed on ambulatory activity or rearing behaviour. CBG-BDS is a novel appetite stimulant, which may have greater potency than purified CBG, despite the absence of [INCREMENT]-tetrahydrocannabinol in the extract.

  3. Crystallization of Δ{sup 1}-tetrahydrocannabinolic acid (THCA) synthase from Cannabis sativa

    Energy Technology Data Exchange (ETDEWEB)

    Shoyama, Yoshinari; Takeuchi, Ayako; Taura, Futoshi [Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Tamada, Taro; Adachi, Motoyasu; Kuroki, Ryota [Neutron Science Research Center, Japan Atomic Energy Research Institute, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195 (Japan); Shoyama, Yukihiro; Morimoto, Satoshi, E-mail: morimoto@phar.kyushu-u.ac.jp [Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2005-08-01

    Δ{sup 1}-Tetrahydrocannabinolic acid (THCA) synthase from C. sativa was crystallized. The crystal diffracted to 2.7 Å resolution with sufficient quality for further structure determination. Δ{sup 1}-Tetrahydrocannabinolic acid (THCA) synthase is a novel oxidoreductase that catalyzes the biosynthesis of the psychoactive compound THCA in Cannabis sativa (Mexican strain). In order to investigate the structure–function relationship of THCA synthase, this enzyme was overproduced in insect cells, purified and finally crystallized in 0.1 M HEPES buffer pH 7.5 containing 1.4 M sodium citrate. A single crystal suitable for X-ray diffraction measurement was obtained in 0.09 M HEPES buffer pH 7.5 containing 1.26 M sodium citrate. The crystal diffracted to 2.7 Å resolution at beamline BL41XU, SPring-8. The crystal belonged to the primitive cubic space group P432, with unit-cell parameters a = b = c = 178.2 Å. The calculated Matthews coefficient was approximately 4.1 or 2.0 Å{sup 3} Da{sup −1} assuming the presence of one or two molecules of THCA synthase in the asymmetric unit, respectively.

  4. Engineering of Δ9-tetrahydrocannabinol delivery systems based on surface modified-PLGA nanoplatforms.

    Science.gov (United States)

    Martín-Banderas, Lucía; Muñoz-Rubio, Inmaculada; Álvarez-Fuentes, Josefa; Durán-Lobato, Matilde; Arias, José L; Holgado, Ma Ángeles; Fernández-Arévalo, Mercedes

    2014-11-01

    The objective of this work is to develop a nanoplatform that can potentiate the oral administration of Δ9-tetrahidrocannabinol, a highly lipophilic active agent with very promising antiproliferative and antiemetic activities. To that aim, colloidal carriers based on the biodegradable and biocompatible poly(D,L-lactide-co-glycolide) were investigated. Such delivery systems were prepared by nanoprecipitation, and nanoparticle engineering further involved surface modification with a poly(ethylene glycol), chitosan, or poly(ethylene glycol)-chitosan shells to assure the greatest uptake by intestinal cells and to minimize protein adsorption. Characterization of the nanoplatforms included particle geometry (size and shape), electrophoretic properties (surface charge). Δ9-tetrahydrocannabinol vehiculization capabilities (loading and release), blood compatibility, and cellular uptake and cytotoxicity. Results were satisfactorily used to define the optimum engineering conditions to formulate surface modified nanoparticles for the efficient oral administration of Δ9-tetrahydrocannabinol. To the best of our knowledge, this is the first time that biocompatible polymeric nanoparticles have been formulated for Δ9-tetrahydrocannabinoldelivery. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Synthesis of [13C4]-labeled ∆9-Tetrahydrocannabinol and 11-nor-9-Carboxy-∆9-tetrahydrocannabinol as Internal Standards for Reducing Ion Suppressing/Alteration Effects in LC/MS-MS Quantification

    Directory of Open Access Journals (Sweden)

    Morten Karlsen

    2014-09-01

    Full Text Available (−-∆9-Tetrahydrocannabinol is the principal psychoactive component of the cannabis plant and also the active ingredient in some prescribed drugs. To detect and control misuse and monitor administration in clinical settings, reference samples of the native drugs and their metabolites are needed. The accuracy of liquid chromatography/mass spectrometric quantification of drugs in biological samples depends among others on ion suppressing/alteration effects. Especially, 13C-labeled drug analogues are useful for minimzing such interferences. Thus, to provide internal standards for more accurate quantification and for identification purpose, synthesis of [13C4]-∆9-tetrahydro-cannabinol and [13C4]-11-nor-9-carboxy-∆9-tetrahydrocannabinol was developed via [13C4]-olivetol. Starting from [13C4]-olivetol the synthesis of [13C4]-11-nor-9-carboxy-∆9-tetrahydrocannabinol was shortened from three to two steps by employing nitromethane as a co-solvent in condensation with (+-apoverbenone.

  6. Rimonabant-Induced Δ9-Tetrahydrocannabinol Withdrawal in Rhesus Monkeys: Discriminative Stimulus Effects and Other Withdrawal Signs

    OpenAIRE

    Stewart, Jennifer L.; McMahon, Lance R.

    2010-01-01

    Marijuana-dependent individuals report using marijuana to alleviate withdrawal, suggesting that pharmacotherapy of marijuana withdrawal could promote abstinence. To identify potential pharmacotherapies for marijuana withdrawal, this study first characterized rimonabant-induced Δ9-tetrahydrocannabinol (Δ9-THC) withdrawal in rhesus monkeys by using drug discrimination and directly observable signs. Second, drugs were examined for their capacity to modify cannabinoid withdrawal. Monkeys receivin...

  7. Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study

    NARCIS (Netherlands)

    Vries, M. de; Rijckevorsel, D.C.M. van; Vissers, K.C.P.; Wilder-Smith, O.H.G.; Goor, H. van

    2017-01-01

    BACKGROUND & AIMS: Delta-9-tetrahydrocannabinol (THC) is the most abundant cannabinoid from the plant Cannabis sativa. There is only equivocal evidence that THC has analgesic effects. We performed a phase 2 controlled trial to evaluate the analgesic efficacy, pharmacokinetics, safety, and

  8. Opposing Actions of Chronic[Deta][superscript 9] Tetrahydrocannabinol and Cannabinoid Antagonists on Hippocampal Long-Term Potentiation

    Science.gov (United States)

    Hoffman, Alexander F.; Oz, Murat; Yang, Ruiqin; Lichtman, Aron H.; Lupica, Carl R.

    2007-01-01

    Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, [Deta][superscript 9]-tetrahydrocannabinol ([Deta][superscript 9]-THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for…

  9. Spray freeze drying to produce a stable Delta(9)-tetrahydrocannabinol containing inulin-based solid dispersion powder suitable for inhalation

    NARCIS (Netherlands)

    van Drooge, Dirk-Jan; Hinrichs, Wouter L J; Dickhoff, Bastiaan H J; Elli, Marco N A; Visser, Marinella R; Zijlstra, Gerrit S; Frijlink, Henderik W

    2005-01-01

    The purpose of this study is to investigate whether spray freeze drying produces an inhalable solid dispersion powder in which Delta(9)-tetrahydrocannabinol (THC) is stabilised. Solutions of THC and inulin in a mixture of tertiary butanol (TBA) and water were spray freeze dried. Drug loads varied

  10. Evaluation of Δ9-tetrahydrocannabinol metabolites and oxidative stress in type 2 diabetic rats

    Directory of Open Access Journals (Sweden)

    Zeynep Coskun

    2016-02-01

    Full Text Available Objective(s: The object of the study is to examine the effects of Δ9-tetrahydrocannabinol (THC against oxidative stress in the blood and excretion of THC metabolites in urine of type 2 diabetic rats. Materials and Methods: The control (n=8, THC control (n=6, diabetes (n=8 and diabetes + THC (n=7 groups were created. Type 2 diabetes was induced by nicotinamide (NA, 85 mg/kg + streptozotocin (STZ, 65 mg/kg. THC was administered intraperitoneally for seven days. The glutathione (GSH level in erythrocytes and malondialdehyde (MDA level, superoxide dismutase (SOD and catalase (CAT enzyme activities in plasma were measured. THC metabolites were analyzed in urine. Results: The results showed that the erythrocyte GSH levels were significantly increased (P

  11. Acute effects of Delta-9-Tetrahydrocannabinol on performance monitoring in healthy volunteers

    Directory of Open Access Journals (Sweden)

    Desiree eSpronk

    2011-09-01

    Full Text Available Rationale: The error-related negativity (ERN is a negative event-related potential that occurs immediately after an erroneous response and is thought to reflect human performance monitoring. Delta-9-Tetrahydrocannabinol (THC administration in healthy volunteers has been linked to impaired performance monitoring in behavioral studies, but to date no studies have examined the effects of cannabinoids on the ERN. Methods: EEG data from 10 healthy volunteers was recorded during execution of a speeded choice reaction time task (Flankers task after administration of THC or placebo vapor in a double-blind randomized crossover design. Results: The findings of this study show that the ERN was significantly reduced after administration of THC. The behavioral outcomes on the Flankers task showed no indications of drug-induced impairments.Discussion: The diminished ERN reflects impairments in the process of performance monitoring. The task design was not optimized to find behavioral effects. The study shows that cannabinoids impair performance monitoring.

  12. Learning impairment by Δ(9)-tetrahydrocannabinol in adolescence is attributable to deficits in chunking.

    Science.gov (United States)

    Steel, Ryan W J; Miller, John H; Sim, Dalice A; Day, Darren John

    2011-12-01

    Cannabis is the most popular illicit drug used by adolescents. Yet, there are only a few studies that have examined the effects of cannabis use on learning and memory during this sensitive and important neurodevelopmental stage. Male adolescent Sprague-Dawley rats were treated with Δ(9)-tetrahydrocannabinol (THC, 6 mg/kg) daily for 27 days and concurrently trained in a spatial learning and memory task. The chronic effects of cannabis use were specifically examined by assessing animal behaviour during the 'postacute' period (17 h after drug exposure), when minimal acute drug burden is expected to be present. The postacute period is a good model for cannabis use patterns in human adolescents. In addition, we investigated whether the hierarchical organization of working memory (chunking) was impaired by THC-treatment. We show that THC exposure impairs adolescent learning when tested in the postacute period, and that THC impairs the ability of animals to use a chunking strategy.

  13. Synthetic delta-9-tetrahydrocannabinol (dronabinol) can improve the symptoms of schizophrenia.

    Science.gov (United States)

    Schwarcz, Glenn; Karajgi, Basawaraj; McCarthy, Richard

    2009-06-01

    We are reporting improvement of symptoms of schizophrenia in a small group of patients who received the cannabinoid agonist dronabinol (synthetic Delta-9-tetrahydrocannabinol). Before this report, cannabinoids had usually been associated with worsening of psychotic symptoms. In a heuristic, compassionate use study, we found that 4 of 6 treatment-refractory patients with severe chronic schizophrenia but who had a self-reported history of improving with marijuana abuse improved with dronabinol. This improvement seems to have been a reduction of core psychotic symptoms in 3 of the 4 responders and not just nonspecific calming. There were no clinically significant adverse effects. These results complement the recent finding that the cannabinoid blocker rimonabant does not improve schizophrenic symptoms and suggest that the role of cannabinoids in psychosis may be more complex than previously thought. They open a possible new role for cannabinoids in the treatment of schizophrenia.

  14. Effect of Delta-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans

    NARCIS (Netherlands)

    Beaumont, H.; Jensen, J.; Carlsson, A.; Ruth, M.; Lehmann, A.; Boeckxstaens, G. E.

    2009-01-01

    Background and purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-oesophageal reflux and are a potential pharmacological treatment target. We evaluated the effect of the CB(1)/CB(2) receptor agonist Delta(9)-tetrahydrocannabinol

  15. Investigation of a recently detected 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol isomer: Studies on the degradation of 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol glucuronide.

    Science.gov (United States)

    Hanisch, Stephanie; Paulke, Alexander; Toennes, Stefan W

    2016-09-10

    An isomer of the tetrahydrocannabinol (THC) metabolite 11-nor-9-carboxy-Δ(9)-THC (THCCOOH) had been detected in blood of cannabis users. The present study was initiated to elucidate whether the labile metabolite THCCOOH-glucuronide could be the precursor. THCCOOH-glucuronide was incubated in human serum and albumin (HSA) solution at various temperatures (-18, 4.5, 22 and 37°C) and pH values (pH 7.4 and 8.3) for seven days in the presence or absence of the esterase inhibitor sodium fluoride. Analysis of incubation samples was performed using LC-MS/MS. Marked degradation of THCCOOH-glucuronide was observed at 37°C. It was found that not only THCCOOH, but also the isomer is a degradation product of THCCOOH-glucuronide and its in-vivo production is assumed. Degradation to THCCOOH and the isomer occurred at alkaline pH, in the presence of fluoride-sensitive esterases and of HSA alone. To inhibit isomer formation during sample storage, refrigeration and controlling of the pH are recommended. However, THCCOOH and the isomer exhibit similar properties during incubations in serum, but differ in their interaction with HSA. The present study confirmed the nature of the isomer as degradation product of the abundant THC metabolite THCCOOH-glucuronide. Serum albumin and esterases are obviously involved. The isomer is formed not only during storage, but also under physiological conditions, suggesting that it can be considered an in-vivo metabolite. However, the chemical structure of the isomer remains unknown and further research is necessary. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Δ9-Tetrahydrocannabinol content in cannabis samples seized in Novi Sad during 2008

    Directory of Open Access Journals (Sweden)

    MAJA DJURENDIĆ-BRENESEL

    2010-07-01

    Full Text Available The three main cannabinoids Δ9-tetrahydrocannabinol (Δ9-THC, cannabidiol (CBD and cannabinol (CBN were identified and determined quantitatively using a GCD (GC-EI instrument in 280 samples of illicit herbal cannabis, seized by the Police authorities in Novi Sad, during 2008. The samples were sent to the Institute of Forensic Medicine, Clinical Center Vojvodina, for forensic chemical analysis. The cannabinoid content of the samples enabled the classification of the cannabis into three chemical phenotypes and the differentiation into drug and textile-cannabis, using the Waller classification index. This differentiation has great forensic significance in the classification of certain cases as a criminal action. The experimental results showed that the Δ9-THC content in illicitly circulated cannabis slightly decreased from January to December 2008, as did the quality of the drug-cannabis. The reasons for the quality variations could lie in the geographical origin of the cannabis plants, the conditions of plants storage, various parts of the plants in samples and the time elapsed between harvesting and chemical analysis.

  17. Automated GC-MS Determination of Δ9-Tetrahydrocannabinol, Cannabinol and Cannabidiol in Hair.

    Science.gov (United States)

    Heinl, Sonja; Lerch, Oliver; Erdmann, Freidoon

    2016-09-01

    The determination of Δ(9)-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD) in hair is a major routine task in forensic laboratories worldwide. A comprehensively automated liquid-liquid extraction (LLE) method has been developed. The automation was carried out by an x-y-z sample robot equipped with modules capable of shaking, centrifugation and solvent evaporation. It comprises digestion of hair in sodium hydroxide solution, LLE, extract evaporation, reconstitution in silylation reagent, inlet derivatization and GC-MS analysis. Method validation guidelines of the Society for Toxicological and Forensic Chemistry were fulfilled. The limit of quantification (LOQ) was 0.01 ng/mg for THC, 0.06 ng/mg for CBN and 0.03 ng/mg for CBD. This is below the required LOQ for THC (0.02 ng/mg) in medical psychological assessments in Germany. Also it is far below the required LOQ of the Society of Hair Testing of 0.1 ng/mg for THC. Four-round robin tests were passed successfully and several post- and ante-mortem samples were analyzed. To date the method is routinely employed at the Institute of Legal Medicine in Giessen, Germany. To the best of our knowledge, this is the first publication on a comprehensively automated classical LLE workflow in the field of hair analysis. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis.

    Science.gov (United States)

    Morgan, Celia J A; Freeman, Tom P; Schafer, Gráinne L; Curran, H Valerie

    2010-08-01

    Worldwide cannabis dependence is increasing, as is the concentration of Delta(9)-tetrahydrocannabinol (THC) in street cannabis. At the same time, the concentration of the second most abundant cannabinoid in street cannabis, cannabidiol (CBD), is decreasing. These two cannabinoids have opposing effects both pharmacologically and behaviorally when administered in the laboratory. No research has yet examined how the ratio of these constituents impacts on the appetitive/reinforcing effects of cannabis in humans. A total of 94 cannabis users were tested 7 days apart, once while non-intoxicated and once while acutely under the influence of their own chosen smoked cannabis on dependence-related measures. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analyzed for levels of cannabinoids. On the basis of CBD : THC ratios in the cannabis, individuals from the top and bottom tertiles were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD : THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD : THC. Those smoking higher CBD : THC strains also showed lower self-rated liking of cannabis stimuli on both test days. Our findings suggest that CBD has potential as a treatment for cannabis dependence. The acute modulation of the incentive salience of drug cues by CBD may possibly generalize to a treatment for other addictive disorders.

  19. Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market.

    Science.gov (United States)

    Gatch, Michael B; Forster, Michael J

    2015-08-01

    When synthetic cannabinoid compounds became controlled by state and federal governments, different, noncontrolled compounds began to appear as marijuana substitutes. Unlike the scheduled cannabinoids, the newer compounds have not been characterized for potency and efficacy in preclinical studies. The purpose of these experiments was to determine whether some of the more recent synthetic compounds sold as marijuana substitutes have behavioral effects similar to those of Δ-tetrahydrocannabinol (Δ-THC), the pharmacologically active compound in marijuana. The compounds UR-144, XLR-11, AKB-48 (APINACA), PB-22 (QUPIC), 5F-PB-22, and AB-FUBINACA were tested for locomotor depressant effects in male Swiss-Webster mice and subsequently for their ability to substitute for Δ-THC (3 mg/kg, intraperitoneally) in drug discrimination experiments with male Sprague-Dawley rats. UR-144, XLR-11, AKB-48, and AB-FUBINACA each decreased locomotor activity for up to 90 min, whereas PB-22 and 5F-PB-22 produced depressant effects lasting 120-150 min. Each of the compounds fully substituted for the discriminative stimulus effects of Δ-THC. These findings confirm the suggestion that these compounds have marijuana-like psychoactive effects and abuse liability.

  20. Treatment of Spasticity in Spinal Cord Injury with Dronabinol, a Tetrahydrocannabinol Derivative.

    Science.gov (United States)

    Kogel, Robert W.; Johnson, Paul B.; Chintam, Rani; Robinson, Charles J.; Nemchausky, Bernard A.

    1995-10-01

    Spinal-cord-injured patients and the medical literature have increasingly reported anecdotes regarding tetrahydrocannabinol (THC)-induced spasmolysis. These reports motivated this trial of dronabinol, a THC derivative, for the treatment of spasticity in the spinal-cord-injured population. Five made quadriplegic patients were given oral dronabinol in escalating doses from 5 mg BID to 20 mg TID in addition to their current, but ineffective, spasmolytic regime. The pendulum drop test was used to quantify spasticity (stiffness) in the knees. The Weschler Memory Scale (WMS), Profile of Mood States (POMS), and personal interviews were administered by the clinical psychologist to evaluate any changes in the subjects' cognition and/or emotional states. Spasticity was markedly improved in two of the five subjects, unchanged in a third, fluctuated in a fourth and made progressively worse in a fifth. The WMS revealed improvement in memory skills of two subjects and no change in the other. Psychological interviews and the POMS indicated decreased vigor in all subject, but otherwise demonstrated highly individualized emotional changes as indicated by increases and/or decreases in the dysphoric mood scales.

  1. Psychoactive drugs and false memory: comparison of dextroamphetamine and δ-9-tetrahydrocannabinol on false recognition.

    Science.gov (United States)

    Ballard, Michael E; Gallo, David A; de Wit, Harriet

    2012-01-01

    Several psychoactive drugs are known to influence episodic memory. However, these drugs' effects on false memory, or the tendency to incorrectly remember nonstudied information, remain poorly understood. Here, we examined the effects of two commonly used psychoactive drugs, one with memory-enhancing properties (dextroamphetamine; AMP), and another with memory-impairing properties (Δ(9)-tetrahydrocannabinol; THC), on false memory using the Deese/Roediger-McDermott (DRM) illusion. Two parallel studies were conducted in which healthy volunteers received either AMP (0, 10, and 20 mg) or THC (0, 7.5, and 15 mg) in within-subjects, randomized, double-blind designs. Participants studied DRM word lists under the influence of the drugs, and their recognition memory for the studied words was tested 2 days later, under sober conditions. As expected, AMP increased memory of studied words relative to placebo, and THC reduced memory of studied words. Although neither drug significantly affected false memory relative to placebo, AMP increased false memory relative to THC. Across participants, both drugs' effects on true memory were positively correlated with their effects on false memory. Our results indicate that AMP and THC have opposing effects on true memory, and these effects appear to correspond to similar, albeit more subtle, effects on false memory. These findings are consistent with previous research using the DRM illusion and provide further evidence that psychoactive drugs can affect the encoding processes that ultimately result in the creation of false memories.

  2. Genetic dissection of behavioural and autonomic effects of Delta(9-tetrahydrocannabinol in mice.

    Directory of Open Access Journals (Sweden)

    Krisztina Monory

    2007-10-01

    Full Text Available Marijuana and its main psychotropic ingredient Delta(9-tetrahydrocannabinol (THC exert a plethora of psychoactive effects through the activation of the neuronal cannabinoid receptor type 1 (CB1, which is expressed by different neuronal subpopulations in the central nervous system. The exact neuroanatomical substrates underlying each effect of THC are, however, not known. We tested locomotor, hypothermic, analgesic, and cataleptic effects of THC in conditional knockout mouse lines, which lack the expression of CB1 in different neuronal subpopulations, including principal brain neurons, GABAergic neurons (those that release gamma aminobutyric acid, cortical glutamatergic neurons, and neurons expressing the dopamine receptor D1, respectively. Surprisingly, mice lacking CB1 in GABAergic neurons responded to THC similarly as wild-type littermates did, whereas deletion of the receptor in all principal neurons abolished or strongly reduced the behavioural and autonomic responses to the drug. Moreover, locomotor and hypothermic effects of THC depend on cortical glutamatergic neurons, whereas the deletion of CB1 from the majority of striatal neurons and a subpopulation of cortical glutamatergic neurons blocked the cataleptic effect of the drug. These data show that several important pharmacological actions of THC do not depend on functional expression of CB1 on GABAergic interneurons, but on other neuronal populations, and pave the way to a refined interpretation of the pharmacological effects of cannabinoids on neuronal functions.

  3. Mucoadhesive tetrahydrocannabinol-loaded NLC - Formulation optimization and long-term physicochemical stability.

    Science.gov (United States)

    Hommoss, Ghaith; Pyo, Sung Min; Müller, Rainer H

    2017-08-01

    Tetrahydrocannabinol (THC) is used to treat pain in cancer patients. On the market there are mainly oral formulations. Especially to treat the problematic breakthrough pain in cancer, an easy applicable formulation with fast onset is desired. This formulation was developed as an aqueous nasal spray using nanostructured lipid carriers (NLC). The NLC were prepared with cetyl palmitate, having good miscibility with the oily THC and yielding particles with 1year physical long-term stability. To make the particles mucoadhesive, small particles with diameters of about 200nm were produced and additionally their surface positively charged using a cationic stabilizer. Optimal NLC suspensions contained 1% particles (lipid:THC ratio 7:1) stabilized with 0.05% cetylpyridinium chloride (CPC), and 2% particles with a mixture of 0.05% CPC, and 0.05% Tween® 80. The particle size remained unchanged during spraying using commercial spray bottle, and PARI BOY. A strong interaction with negatively charged mucin was shown by a sharp decrease of the positive NLC zeta potential and fast charge reversal in the mucin solution test. The solid matrix of the NLC had a stabilizing effect on THC. 91% THC remained after 6months storage at 4°C, and 79% under stress conditions at 40°C. By adding additional chemical stabilizers, and producing under protective conditions, a commercial formulation for patient seems feasible. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC) Induces Trophoblast Dysfunction.

    Science.gov (United States)

    Chang, Xinwen; Bian, Yiding; He, Qizhi; Yao, Julei; Zhu, Jingping; Wu, Jinting; Wang, Kai; Duan, Tao

    2017-01-01

    Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ9-tetrahydrocannabinol (THC), the major component of marijuana, on trophoblast function, placental development, and birth outcomes. The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC) staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3) were detected by western blot. We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction. © 2017 The Author(s). Published by S. Karger AG, Basel.

  5. A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice.

    Science.gov (United States)

    Bilkei-Gorzo, Andras; Albayram, Onder; Draffehn, Astrid; Michel, Kerstin; Piyanova, Anastasia; Oppenheimer, Hannah; Dvir-Ginzberg, Mona; Rácz, Ildiko; Ulas, Thomas; Imbeault, Sophie; Bab, Itai; Schultze, Joachim L; Zimmer, Andreas

    2017-06-01

    The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.

  6. Repeated Δ9-tetrahydrocannabinol exposure in adolescent monkeys: persistent effects selective for spatial working memory.

    Science.gov (United States)

    Verrico, Christopher D; Gu, Hong; Peterson, Melanie L; Sampson, Allan R; Lewis, David A

    2014-04-01

    Epidemiological findings suggest that, relative to adults, adolescents are more vulnerable to the adverse persistent effects of cannabis on working memory. However, the potential confounds inherent in human studies preclude direct determination of a cause-and-effect relationship between adolescent cannabis use and heightened susceptibility to persistent working memory impairments. Consequently, the authors examined the effects of repeated exposure to Δ9-tetrahydrocannabinol (THC) on performance of spatial and object working memory tasks in adolescent monkeys. Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 6 months. Performance on spatial and object memory tasks was assessed 23 or 71 hours after drug administration throughout the study. In addition, acute effects on working memory were also assessed at the beginning and end of the 6-month period. Relative to the vehicle-exposed control animals, those with repeated THC exposure had a blunted trajectory of accuracy improvements on the spatial working memory task in a delay-dependent manner. Accuracy improvements on the object working memory task did not differ between groups. Relative to the acute effects of THC on working memory at the beginning of the study, neither sensitivity nor tolerance was evident after 6 months of THC exposure. Because maturation of performance is later for spatial than for object working memory, these findings suggest that persistent effects of THC on cognitive abilities are more evident when exposure coincides with the developmental stage during which the underlying neural circuits are actively maturing.

  7. Delta9-Tetrahydrocannabinol-induced cognitive deficits are reversed by olanzapine but not haloperidol in rats.

    Science.gov (United States)

    Egashira, Nobuaki; Ishigami, Noriko; Mishima, Kenichi; Iwasaki, Katsunori; Oishi, Ryozo; Fujiwara, Michihiro

    2008-02-15

    Cannabis is the most widely used illicit substance. Delta9-Tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to induce cognitive impairment that closely resembles the impairment observed in schizophrenic patients. THC has also been known to impair spatial memory in rats tested in the eight-arm radial maze. We previously reported that microinjection of THC (20 microg/side) into the rat dorsal hippocampus impaired spatial memory and that i.p. injection of THC (6 mg/kg) decreased the extracellular levels of acetylcholine (ACh) in the dorsal hippocampus. In the present study, we compared the effects of olanzapine, an atypical antipsychotic, with those of haloperidol, a typical neuroleptic, on the impairments of spatial memory and decreased ACh levels induced by THC (6 mg/kg, i.p.) in rats. We found that olanzapine (0.1 mg/kg, i.p.) reversed the THC-induced memory deficits and decrease in extracellular ACh levels, whereas haloperidol (0.03-0.3 mg, i.p.) had no effect. These results suggest that olanzapine may improve the THC-induced impairment of spatial memory, partly by enhancing ACh release in the dorsal hippocampus. Therefore, olanzapine could attenuate the acute short-term and working memory deficits induced by cannabis.

  8. Disruption of frontal θ coherence by Δ9-tetrahydrocannabinol is associated with positive psychotic symptoms.

    Science.gov (United States)

    Morrison, Paul D; Nottage, Judith; Stone, James M; Bhattacharyya, Sagnik; Tunstall, Nigel; Brenneisen, Rudolf; Holt, David; Wilson, Daniel; Sumich, Alex; McGuire, Philip; Murray, Robin M; Kapur, Shitij; Ffytche, Dominic H

    2011-03-01

    The main ingredient in cannabis, Δ(9)-tetrahydrocannabinol (THC), can elicit acute psychotic reactions in healthy individuals and precipitate relapse in schizophrenic patients. However, the neural mechanism of this is unknown. We tested the hypothesis that THC psychopathology is related to changes in electroencephalography (EEG) power or inter-regional coherence. In a within-subjects design, participants (n=16) were given intravenous THC (1.25 mg) or placebo under double-blind conditions, during EEG recordings. Using fast-Fourier transform, EEG data were analyzed for power and coherence in the delta (1-3.5 Hz), theta (3.5-7 Hz), alpha (8-13 Hz), beta (14-25 Hz), low-gamma (30-40 Hz), and high-gamma (60-70 Hz) bands during engagement in the n-back test of working memory (WM). Compared with placebo, THC evoked positive and negative psychotic symptoms, as measured by the positive and negative syndrome scale (pimpairment. Coherence between bi-frontal electrodes in the theta band was also reduced by THC (pimpaired network dynamics with impaired communication between the right and left frontal lobes.

  9. Delta-9-tetrahydrocannabinol + cannabidiol. A reasonable option for some patients with multiple sclerosis.

    Science.gov (United States)

    2014-06-01

    Conventional drugs have only a limited impact on spasticity associated with multiple sclerosis and are rarely satisfactory. A solution for oral transmucosal delivery (spray) containing a mixture of cannabis extracts (2.7 mg of delta-9-tetrahydrocannabinol + 2.5 mg of cannabidiol per spray) has been granted marketing authorisation in France for patients who are inadequately relieved by standard treatments. Three double-blind, placebo-controlled trials in a total of about 300 patients tested this combination, in addition to ongoing treatment, for periods of 6 to 14 weeks. Individually, none of these trials showed any tangible anti-spastic efficacy, but two combined analyses showed "response rates" of about 35% with the mixture versus about 25% with placebo. In a trial with 572 patients, the 241 patients who "responded" after 4 weeks of treatment were randomised to either continue using the cannabis extract or receive placebo. Twelve weeks later, 75% of patients using the extract were still "responders", versus 51% of patients switched to placebo. The principal adverse effects of the cannabis extracts consist of neuropsychiatric disorders that resolve on treatment withdrawal. The potential for abuse increases with the dose and is tangible from 16 sprays per day. Pharmacokinetic interactions due to P-glycoprotein inhibition are likely. Treatment during pregnancy may lead to neonatal withdrawal symptoms. In practice, about 10% of patients in whom standard anti-spastic medications are unsatisfactory benefit from a specific effect of the cannabis extracts contained in this oral spray.

  10. A Novel Tetrahydrocannabinol Electrochemical Nano Immunosensor Based on Horseradish Peroxidase and Double-Layer Gold Nanoparticles

    Directory of Open Access Journals (Sweden)

    Dingqiang Lu

    2016-10-01

    Full Text Available In the current study, a novel double-layer gold nanoparticles-electrochemical immunosensor electrode immobilized with tetrahydrocannabinol (THC antibody derived from Balb/c mice was developed. To increase the fixed quantity of antibodies and electrochemical signals, an electrochemical biosensing signal amplification system was utilized with gold nanoparticles-thionine-chitosan absorbing horseradish peroxidase (HRP. In addition, a transmission electron microscope (TEM was used to characterize the nanogold solution. To evaluate the quality of the immunosensor, the amperometric I-t curve method was applied to determine the THC in PBS. The results showed that the response current had a good linear correlation with the THC concentration range from 0.01~103 ng/mL with a correlation coefficient of 0.9986. The lowest detection limit for THC was 3.3 pg/mL (S/N = 3. Moreover, it was validated with high sensitivity and reproducibility. Apparently, the immunosensor may be a very useful tool for monitoring the THC.

  11. A Novel Tetrahydrocannabinol Electrochemical Nano Immunosensor Based on Horseradish Peroxidase and Double-Layer Gold Nanoparticles.

    Science.gov (United States)

    Lu, Dingqiang; Lu, Fuping; Pang, Guangchang

    2016-10-17

    In the current study, a novel double-layer gold nanoparticles-electrochemical immunosensor electrode immobilized with tetrahydrocannabinol (THC) antibody derived from Balb/c mice was developed. To increase the fixed quantity of antibodies and electrochemical signals, an electrochemical biosensing signal amplification system was utilized with gold nanoparticles-thionine-chitosan absorbing horseradish peroxidase (HRP). In addition, a transmission electron microscope (TEM) was used to characterize the nanogold solution. To evaluate the quality of the immunosensor, the amperometric I-t curve method was applied to determine the THC in PBS. The results showed that the response current had a good linear correlation with the THC concentration range from 0.01~10³ ng/mL with a correlation coefficient of 0.9986. The lowest detection limit for THC was 3.3 pg/mL (S/N = 3). Moreover, it was validated with high sensitivity and reproducibility. Apparently, the immunosensor may be a very useful tool for monitoring the THC.

  12. Tolerability and Effects of Oral Δ9-Tetrahydrocannabinol in Older Adolescents with Marijuana Use Disorders

    Science.gov (United States)

    Gray, Kevin M.; Hart, Carl L.; Christie, Douglas K.; Upadhyaya, Himanshu P.

    2008-01-01

    Objective The tolerability and effects of oral Δ9-tetrahydrocannabinol (THC) have been previously investigated in adult marijuana abusers. However, no studies have included adolescent participants. This double-blind laboratory study investigated the tolerability and effects of oral THC in a group of older adolescents with marijuana use disorders. Methods Eight participants (ages 16–21 years), smoking an average of 5.2 days/week and 2.5 “joints”/day, completed this four-session study, during which they received one of four oral THC doses (0, 2.5, 5, 10 mg) each session. Administration of oral THC doses was counterbalanced across participants. During each session, participants completed the Digit-Symbol Substitution Task (DSST) and subjective-effect ratings at baseline and one, two, and three hours after oral THC administration. Results Oral THC (5 mg and 10 mg) increased several “positive” subjective-effect ratings (e.g., “Good Drug Effect”), while producing no significant effects on cardiovascular measures, DSST performance, or “negative” subjective-effect ratings. Conclusions These results indicate that oral THC was well tolerated and suggest further study of this medication in adolescent marijuana abusers. PMID:18627775

  13. Suppression of STAT3 Signaling by Δ9-Tetrahydrocannabinol (THC Induces Trophoblast Dysfunction

    Directory of Open Access Journals (Sweden)

    Xinwen Chang

    2017-06-01

    Full Text Available Aims: Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ9-tetrahydrocannabinol (THC, the major component of marijuana, on trophoblast function, placental development, and birth outcomes. Methods: The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3 were detected by western blot. Results: We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. Conclusion: Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction.

  14. Passive inhalation of marijuana smoke: urinalysis and room air levels of delta-9-tetrahydrocannabinol

    Energy Technology Data Exchange (ETDEWEB)

    Cone, E.J.; Johnson, R.E.; Darwin, W.D.; Yousefnejad, D.; Mell, L.D.; Paul, B.D.; Mitchell, J.

    1987-05-01

    In two separate studies, 5 drug-free male volunteers with a history of marijuana use were passively exposed to the sidestream smoke of 4 and 16 marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol (THC)) for 1 h each day for 6 consecutive days. A third study was similarly performed with 2 marijuana-naive subjects passively exposed to the smoke of 16 marijuana cigarettes. Passive smoke exposure was conducted in a small, unventilated room. Room air levels of THC and CO were monitored frequently. All urine specimens were collected and analyzed by EMIT d.a.u. assay, Abuscreen radioimmunoassay and GC/MS. The studies show that significant amounts of THC were absorbed by all subjects at the higher level of passive smoke exposure (eg., smoke from 16 marijuana cigarettes), resulting in urinary excretion of significant amounts of cannabinoid metabolites. However, it seems improbable that subjects would unknowingly tolerate the noxious smoke conditions produced by this exposure. At the lower level of passive marijuana-smoke exposure, specimens tested positive only infrequently or were negative. Room air levels of THC during passive smoke exposure appeared to be the most critical factor in determining whether a subject produced cannabinoid-positive urine specimens.

  15. (-)-Delta9-tetrahydrocannabinol antagonizes the peripheral cannabinoid receptor-mediated inhibition of adenylyl cyclase.

    Science.gov (United States)

    Bayewitch, M; Rhee, M H; Avidor-Reiss, T; Breuer, A; Mechoulam, R; Vogel, Z

    1996-04-26

    (-)-Delta9-Tetrahydrocannabinol ((-)-Delta9-THC) is the major active psychotropic component of the marijuana plant, Cannabis sativa. The membrane proteins that have been found to bind this material or its derivatives have been called the cannabinoid receptors. Two GTP-binding protein-coupled cannabinoid receptors have been cloned. CB1 or the neuronal cannabinoid receptor is found mostly in neuronal cells and tissues while CB2 or the peripheral cannabinoid receptor has been detected in spleen and in several cells of the immune system. It has previously been shown that activation of CB1 or CB2 receptors by cannabinoid agonists inhibits adenylyl cyclase activity. Utilizing Chinese hamster ovary cells and COS cells transfected with the cannabinoid receptors we report that (-)-Delta9-THC binds to both receptors with similar affinity. However, in contrast to its capacity to serve as an agonist for the CB1 receptor, (-)-Delta9-THC was only able to induce a very slight inhibition of adenylyl cyclase at the CB2 receptor. Morever, (-)-Delta9-THC antagonizes the agonist-induced inhibition of adenylyl cyclase mediated by CB2. Therefore, we conclude that (-)-Delta9-THC constitutes a weak antagonist for the CB2 receptor.

  16. Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption.

    Science.gov (United States)

    Stern, Cristina A J; Gazarini, Lucas; Vanvossen, Ana C; Zuardi, Antonio W; Galve-Roperh, Ismael; Guimaraes, Francisco S; Takahashi, Reinaldo N; Bertoglio, Leandro J

    2015-06-01

    Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  17. Cannabidiol attenuates deficits of visuospatial associative memory induced by Δ9tetrahydrocannabinol

    Science.gov (United States)

    Wright, M Jerry; Vandewater, Sophia A; Taffe, Michael A

    2013-01-01

    BACKGROUND AND PURPOSE Recent human studies suggest that recreational cannabis strains that are relatively high in cannabidiol (CBD) content produce less cognitive impairment than do strains with negligible CBD and similar Δ9tetrahydrocannabinol (THC) content. Self-selection in such studies means it is impossible to rule out additional variables which may determine both cannabis strain selection and basal cognitive performance level. Controlled laboratory studies can better determine a direct relationship. EXPERIMENTAL APPROACH In this study, adult male rhesus monkeys were assessed on visuospatial Paired Associates Learning and Self-Ordered Spatial Search memory tasks, as well as additional tests of motivation and manual dexterity. Subjects were challenged with THC (0.2, 0.5 mg·kg−1, i.m.) in randomized order and evaluated in the presence or absence of 0.5 mg·kg−1 CBD. KEY RESULTS CBD attenuated the effects of THC on paired associates learning and a bimanual motor task without affecting the detrimental effects of THC on a Self-Ordered Spatial Search task of working memory. CBD did not significantly reverse THC-induced impairment of a progressive ratio or a rotating turntable task. CONCLUSIONS AND IMPLICATIONS This study provides direct evidence that CBD can oppose the cognitive-impairing effects of THC and that it does so in a task-selective manner when administered simultaneously in a 1:1 ratio with THC. The addition of CBD to THC-containing therapeutic products may therefore help to ameliorate unwanted cognitive side-effects. LINKED ARTICLE This article is commented on by Mechoulam and Parker, pp 1363–1364 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12400 PMID:23550724

  18. Cannabidiol attenuates deficits of visuospatial associative memory induced by Δ(9) tetrahydrocannabinol.

    Science.gov (United States)

    Wright, M Jerry; Vandewater, Sophia A; Taffe, Michael A

    2013-12-01

    Recent human studies suggest that recreational cannabis strains that are relatively high in cannabidiol (CBD) content produce less cognitive impairment than do strains with negligible CBD and similar Δ(9) tetrahydrocannabinol (THC) content. Self-selection in such studies means it is impossible to rule out additional variables which may determine both cannabis strain selection and basal cognitive performance level. Controlled laboratory studies can better determine a direct relationship. In this study, adult male rhesus monkeys were assessed on visuospatial Paired Associates Learning and Self-Ordered Spatial Search memory tasks, as well as additional tests of motivation and manual dexterity. Subjects were challenged with THC (0.2, 0.5 mg·kg(-1) , i.m.) in randomized order and evaluated in the presence or absence of 0.5 mg·kg(-1) CBD. CBD attenuated the effects of THC on paired associates learning and a bimanual motor task without affecting the detrimental effects of THC on a Self-Ordered Spatial Search task of working memory. CBD did not significantly reverse THC-induced impairment of a progressive ratio or a rotating turntable task. This study provides direct evidence that CBD can oppose the cognitive-impairing effects of THC and that it does so in a task-selective manner when administered simultaneously in a 1:1 ratio with THC. The addition of CBD to THC-containing therapeutic products may therefore help to ameliorate unwanted cognitive side-effects. This article is commented on by Mechoulam and Parker, pp 1363-1364 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12400. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

  19. Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol

    Science.gov (United States)

    Vann, Robert E.; Gamage, Thomas F.; Warner, Jonathan A.; Marshall, Ericka M.; Taylor, Nathan L.; Martin, Billy R.; Wiley, Jenny L.

    2008-01-01

    Cannabis sativa (marijuana plant) contains myriad cannabinoid compounds; yet, investigative attention has focused almost exclusively on Δ9-tetrahydrocannabinol (THC), its primary psychoactive substituent. Interest in modulation of THC’s effects by these other cannabinoids [e.g., cannabidiol (CBD)] has been stimulated anew by recent approval by Canada of Sativex (a 1:1 dose ratio combination of CBD:THC) for the treatment of multiple sclerosis. The goal of this study was to determine the degree to which THC’s abuse-related effects were altered by co-administration of CBD. To this end, CBD and THC were assessed alone and in combination in a two-lever THC discrimination procedure in Long-Evans rats and in a conditioned place preference/aversion (CPP/A) model in ICR mice. CBD did not alter the discriminative stimulus effects of THC at any CBD:THC dose ratio tested. In contrast, CBD, at CBD:THC dose ratios of 1:1 and 1:10, reversed CPA produced by acute injection with 10 mg/kg THC. When administered alone, CBD did not produce effects in either procedure. These results suggest that CBD, when administered with THC at therapeutically relevant ratios, may ameliorate aversive effects (e.g., dysphoria) often associated with initial use of THC alone. While this effect may be beneficial for therapeutic usage of a CBD:THC combination medication, our discrimination results showing that CBD did not alter THC’s discriminative stimulus effects suggest that CBD:THC combination medications may also produce THC-like subjective effects at these dose ratios. PMID:18206320

  20. Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats.

    Science.gov (United States)

    Silveira, Mason M; Adams, Wendy K; Morena, Maria; Hill, Matthew N; Winstanley, Catharine A

    2017-03-01

    Acceptance of cannabis use is growing. However, prolonged use is associated with diminished psychosocial outcomes, potentially mediated by drug-induced cognitive impairments. Δ 9 -Tetrahydrocannabinol (THC) is the main psychoactive ingredient in cannabis, yet other phytocannabinoids in the plant, such as cannabidiol (CBD), have unique properties. Given that CBD can modulate the undesirable effects of THC, therapeutic agents, such as nabiximols, contain higher CBD:THC ratios than illicit marijuana. We tested the hypothesis that THC impairs a relevant cognitive function for long-term success, namely willingness to exert cognitive effort for greater rewards, and that CBD could attenuate such decision-making impairments. Male Long-Evans rats ( n = 29) performing the rat cognitive effort task (rCET) received acute THC and CBD, independently and concurrently, in addition to other cannabinoids. Rats chose between 2 options differing in reward magnitude, but also in the cognitive effort (attentional load) required to obtain them. We found that THC decreased choice of hard trials without impairing the animals' ability to accurately complete them. Strikingly, this impairment was correlated with CB1 receptor density in the medial prefrontal cortex - an area previously implicated in effortful decision-making. In contrast, CBD did not affect choice. Coadministration of 1:1 CBD:THC matching that in nabiximols modestly attenuated the deleterious effects of THC in "slacker" rats. Only male rats were investigated, and the THC/CBD coadministration experiment was carried out in a subset of individuals. These findings confirm that THC, but not CBD, selectively impairs decision-making involving cognitive effort costs. However, coadministration of CBD only partially ameliorates such THC-induced dysfunction.

  1. Interactions between Delta(9)-tetrahydrocannabinol and mu opioid receptor agonists in rhesus monkeys: discrimination and antinociception.

    Science.gov (United States)

    Li, Jun-Xu; McMahon, Lance R; Gerak, Lisa R; Becker, Ginger L; France, Charles P

    2008-08-01

    Opioid receptor agonists can enhance some effects of cannabinoid receptor agonists, and cannabinoid receptor agonists can enhance some effects of opioid receptor agonists; however, the generality of these interactions is not established. This study examined interactions between the discriminative stimulus and antinociceptive effects of mu opioid receptor agonists and Delta(9)-tetrahydrocannabinol (THC) in rhesus monkeys. Neither heroin nor morphine (intravenous (i.v.) or subcutaneous (s.c.)) altered the discriminative stimulus effects of THC in monkeys (n = 5) discriminating 0.1 mg/kg THC i.v. In contrast, THC (s.c.) markedly attenuated the discriminative stimulus effect of morphine and heroin in nondependent monkeys (n = 4) discriminating 1.78 mg/kg morphine s.c. Doses of THC that attenuated the discriminative stimulus effects of morphine in nondependent monkeys failed to modify the discriminative stimulus effects of morphine in morphine-dependent (5.6 mg/kg/12 h) monkeys (n = 4) discriminating 0.0178 mg/kg naltrexone s.c. THC also failed to modify the discriminative stimulus effects of naltrexone in morphine-dependent monkeys or the effects of midazolam in monkeys (n = 4) discriminating 0.32 mg/kg midazolam s.c. Doses of THC (s.c.) that attenuated the discriminative stimulus effects of morphine in nondependent monkeys enhanced the antinociceptive effects of morphine (s.c.) in nondependent monkeys. While mu receptor agonists did not alter the discriminative stimulus effects of THC, THC altered the effects of mu receptor agonists in a context-dependent manner. That the same doses of THC enhance, attenuate, or do not affect morphine, depending on the condition, suggests that attenuation of morphine by THC can result from perceptual masking rather than common pharmacodynamic mechanisms or pharmacokinetic interactions.

  2. Sedative activity of cannabis in relation to its delta'-trans-tetrahydrocannabinol and cannabidiol content.

    Science.gov (United States)

    Pickens, J T

    1981-04-01

    1. The oral sedative potencies of cannabis herb, crude ethanolic and petroleum-ether fractions, were assayed against delta'-trans-tetrahydrocannabinol (THC) administered orally to mice, by measuring spontaneous motor activity over 30 min periods, at selected times, up to 6 h. 2. The THC contents of the extracts were determined chemically by gas-liquid chromatography analysis and the B/C ratio (biological activity divided by chemical activity) calculated for each. The B/C values for cannabis herb, which contained THC but no CBD, was 4.47 and for ethanolic and petroleum-ether extracts, 5.26 and 4.39, respectively. 3. The sedative potency expressed as SDA50, the dose required to give 50% effect over 6 h, was 1.06 (0.98 to 1.15) mg/kg for THC; 4.72 (4.22 to 5.27) mg/kg for cannabidiol and 1.26 (1.22 to 1.80) mg/kg for chlorpromazine. 4. An infusion of cannabis herb made with boiling water was shown to have sedative activity of very low potency. 5. When the cannabinoids were completely extracted from a sample of herb with petroleum-ether the aqueous and ethanolic extracts of the marc had some sedative activity; but the 70% ethanolic fraction had none. 6. The sedative activity of THC, cannabis herb and a water soluble fraction is blocked by aspirin, a cyclo-oxygenase inhibitor, and restored by prostaglandin E2 (PGE2). 7. The sedative effect of chlorpromazine is not blocked by aspirin.

  3. Evidence based decontamination protocols for the removal of external Δ9-tetrahydrocannabinol (THC) from contaminated hair.

    Science.gov (United States)

    Duvivier, Wilco F; Peeters, Ruth J P; van Beek, Teris A; Nielen, Michel W F

    2016-02-01

    External contamination can cause false positive results in forensic hair testing for drugs of abuse and is therefore a major concern when hair evidence is used in court. Current literature about decontamination strategies is mainly focused on external cocaine contamination and no consensus on the best decontamination procedure for hair samples containing cannabinoids has been reached so far. In this study, different protocols with solvents, both organic as well as aqueous, were tested on blank and drug user hair for their performance on removing external cannabis contamination originating from either smoke or indirect contact with cannabis plant material. Smoke contamination was mimicked by exposing hair samples to smoke from a cannabis cigarette and indirect contact contamination by handling hair with cannabis contaminated gloves or hands. Δ9-tetrahydrocannabinol (THC) levels in the hair samples and wash solvents were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Aqueous surfactant solutions removed more THC contamination compared to water, but much less than organic solvents. Methanol, dichloromethane and chloroform were most efficient in removing THC contamination. Due to its lower environmental impact, methanol was chosen as the preferred decontamination solvent. After testing of different sequential wash steps on externally contaminated blank hair, three protocols performed equally well, removing all normal level and more than 99% of unrealistically high levels of external cannabis contamination. Thorough testing on cannabis users' hair, both as such and after deliberate contamination, showed that using these protocols all contamination could be washed from the hair while no incorporated THC was removed from truly positive samples. The present study provides detailed scientific evidence in support of the recommendations of the Society of Hair Testing: a protocol using a single methanol wash followed by a single aqueous

  4. Effect of Delta-9-tetrahydrocannabinol on mouse resistance to systemic Candida albicans infection.

    Directory of Open Access Journals (Sweden)

    Gideon W Blumstein

    Full Text Available Delta-9-tetrahydrocannabinol (Δ9-THC, the psychoactive component of marijuana, is known to suppress the immune responses to bacterial, viral and protozoan infections, but its effects on fungal infections have not been studied. Therefore, we investigated the effects of chronic Δ9-THC treatment on mouse resistance to systemic Candida albicans (C. albicans infection. To determine the outcome of chronic Δ9-THC treatment on primary, acute systemic candidiasis, c57BL/6 mice were given vehicle or Δ9-THC (16 mg/kg in vehicle on days 1-4, 8-11 and 15-18. On day 19, mice were infected with 5×10(5 C. albicans. We also determined the effect of chronic Δ9-THC (4-64 mg/kg treatment on mice infected with a non-lethal dose of 7.5×10(4 C. albicans on day 2, followed by a higher challenge with 5×10(5 C. albicans on day 19. Mouse resistance to the infection was assessed by survival and tissue fungal load. Serum cytokine levels were determine to evaluate the immune responses. In the acute infection, chronic Δ9-THC treatment had no effect on mouse survival or tissue fungal load when compared to vehicle treated mice. However, Δ9-THC significantly suppressed IL-12p70 and IL-12p40 as well as marginally suppressed IL-17 versus vehicle treated mice. In comparison, when mice were given a secondary yeast infection, Δ9-THC significantly decreased survival, increased tissue fungal burden and suppressed serum IFN-γ and IL-12p40 levels compared to vehicle treated mice. The data showed that chronic Δ9-THC treatment decreased the efficacy of the memory immune response to candida infection, which correlated with a decrease in IFN-γ that was only observed after the secondary candida challenge.

  5. Effects of Δ9-tetrahydrocannabinol in individuals with a familial vulnerability to alcoholism.

    Science.gov (United States)

    Ranganathan, Mohini; Sewell, R Andrew; Carbuto, Michelle; Elander, Jacqueline; Schnakenberg, Ashley; Radhakrishnan, Rajiv; Pittman, Brian; D'Souza, Deepak Cyril

    2014-06-01

    A family history (FH) of alcoholism accounts for approximately 50% of the risk of developing alcohol problems. Several lines of preclinical evidence suggest that brain cannabinoid receptor (CB1R) function may mediate the effects of alcohol and risk for developing alcoholism including the observations that reduced CB1R function decreases alcohol-related behaviors and enhanced CB1R function increases them. In this first human study, we probed CB1R function in individuals vulnerable to alcoholism with the exogenous cannabinoid Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Healthy volunteers (n = 30) participated in a three test day study during which they received 0.018 and 0.036 mg/kg of Δ(9)-THC, or placebo intravenously in a randomized, counterbalanced order under double-blind conditions. Primary outcome measures were subjective "high," perceptual alterations, and memory impairment. Secondary outcome measures consisted of stimulatory and depressant subjective effects, attention, spatial memory, executive function, Δ(9)-THC and 11-hydroxy-THC blood levels, and other subjective effects. FH was calculated using the Family Pattern Density method and was used as a continuous variable. Greater FH was correlated with greater "high" and perceptual alterations induced by Δ(9)-THC. This enhanced sensitivity with increasing FH was specific to Δ(9)-THC's rewarding effects and persisted even when FH was calculated using an alternate method. Enhanced sensitivity to the rewarding effects of Δ(9)-THC in high-FH volunteers suggests that alterations in CB1R function might contribute to alcohol misuse vulnerability.

  6. Delta-9-tetrahydrocannabinol (THC) history fails to affect THC's ability to induce place preferences in rats.

    Science.gov (United States)

    Hempel, Briana J; Wakeford, Alison G P; Clasen, Matthew M; Friar, Mary A; Riley, Anthony L

    2016-05-01

    In pre-clinical models of marijuana abuse, there is relatively limited evidence of delta-9-tetrahydrocannabinol's (THC) rewarding effects, as indexed by its general inability to induce a place preference. One explanation for this failure is that its rewarding effects are masked by its concurrently occurring aversive properties. Consistent with this explanation, THC pre-exposure, which presumably weakens its aversive effects, induces place preferences. Such demonstrations are limited to mice and given reported species differences in THC reactivity, it is unknown to what extent the same shift in affective properties would be evident in rats. The present experiment examined the effect of THC history (3.2mg/kg) on THC (1 or 3.2mg/kg) induced place preference conditioning in rats. An assessment of taste avoidance was also run to independently characterize THC's aversive effects and any changes that occurred with drug pre-exposure. These assessments were made in a combined taste avoidance/place preference procedure in which a novel saccharin solution and environment were paired with THC (0, 1 or 3.2mg/kg). THC did not induce place conditioning, and a history of THC was ineffective in increasing THC's ability to do so, despite the fact that this same history significantly attenuated the aversive effects of THC. The failure of THC to consistently induce place preferences has been argued to be a function of its concurrently occurring aversive effects masking its rewarding properties. The fact that pre-exposure to THC significantly reduced its aversive effects without impacting THC's ability to induce place preferences suggests that THC has weak rewarding effects and/or its residual aversive affects may have still masked its rewarding properties. An important area for future work will be characterizing under what conditions THC is rewarding and whether its overall reinforcing effects are impacted by the relationship between its affective properties. Copyright © 2016

  7. The psychoactive compound of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC) inhibits the human trophoblast cell turnover.

    Science.gov (United States)

    Costa, M A; Fonseca, B M; Marques, F; Teixeira, N A; Correia-da-Silva, G

    2015-08-06

    The noxious effects of cannabis consumption for fertility and pregnancy outcome are recognized for years. Its consumption during gestation is associated with alterations in foetal growth, low birth weight and preterm labor. The main psychoactive molecule of cannabis, Δ(9)-tetrahydrocannabinol (THC) impairs the production of reproductive hormones and is also able to cross the placenta barrier. However, its effect on the main placental cells, the trophoblasts, are unknown. Actually, the role of THC in cell survival/death of primary human cytotrophoblasts (CTs) and syncytiotrophoblasts (STs) and in the syncytialization process remains to be explored. Here, we show that THC has a dual effect, enhancing MTT metabolism at low concentrations, whereas higher doses decreased cell viability, on both trophoblast phenotypes, though the effects on STs were more evident. THC also diminished the generation of oxidative and nitrative stress and the oxidized form of glutathione, whereas the reduced form of this tripeptide was increased, suggesting that THC prevents ST cell death due to an antioxidant effect. Moreover, this compound enhanced the mitochondrial function of STs, as observed by the increased MTT metabolism and intracellular ATP levels. These effects were independent of cannabinoid receptors activation. Besides, THC impaired CT differentiation into STs, since it decreased the expression of biochemical and morphological biomarkers of syncytialization, through a cannabinoid receptor-dependent mechanism. Together, these results suggest that THC interferes with trophoblast turnover, preventing trophoblast cell death and differentiation, and contribute to disclose the cellular mechanisms that lead to pregnancy complications in women that consume cannabis-derived drugs during gestation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Inhaled delivery of Δ(9)-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology.

    Science.gov (United States)

    Nguyen, Jacques D; Aarde, Shawn M; Vandewater, Sophia A; Grant, Yanabel; Stouffer, David G; Parsons, Loren H; Cole, Maury; Taffe, Michael A

    2016-10-01

    Most human Δ(9)-tetrahydrocannabinol (THC) use is via inhalation, and yet few animal studies of inhalation exposure are available. Popularization of non-combusted methods for the inhalation of psychoactive drugs (Volcano(®), e-cigarettes) further stimulates a need for rodent models of this route of administration. This study was designed to develop and validate a rodent chamber suitable for controlled exposure to vaporized THC in a propylene glycol vehicle, using an e-cigarette delivery system adapted to standard size, sealed rat housing chambers. The in vivo efficacy of inhaled THC was validated using radiotelemetry to assess body temperature and locomotor responses, a tail-flick assay for nociception and plasma analysis to verify exposure levels. Hypothermic responses to inhaled THC in male rats depended on the duration of exposure and the concentration of THC in the vehicle. The temperature nadir was reached after ∼40 min of exposure, was of comparable magnitude (∼3 °Celsius) to that produced by 20 mg/kg THC, i.p. and resolved within 3 h (compared with a 6 h time course following i.p. THC). Female rats were more sensitive to hypothermic effects of 30 min of lower-dose THC inhalation. Male rat tail-flick latency was increased by THC vapor inhalation; this effect was blocked by SR141716 pretreatment. The plasma THC concentration after 30 min of inhalation was similar to that produced by 10 mg/kg THC i.p. This approach is flexible, robust and effective for use in laboratory rats and will be of increasing utility as users continue to adopt "vaping" for the administration of cannabis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. The acute effects of synthetic intravenous Delta9-tetrahydrocannabinol on psychosis, mood and cognitive functioning.

    Science.gov (United States)

    Morrison, P D; Zois, V; McKeown, D A; Lee, T D; Holt, D W; Powell, J F; Kapur, S; Murray, R M

    2009-10-01

    Recent work suggests that heavy use of cannabis is associated with an increased risk of schizophrenia-like psychosis. However, there is a dearth of experimental studies of the effects of the constituents of cannabis, such as Delta9-tetrahydrocannabinol (THC). In a study of intravenous (i.v.) synthetic THC in healthy humans, we aimed to study the relationship of the psychotic symptoms induced by THC to the consequent anxiety and neuropsychological impairment. Twenty-two healthy adult males aged 28+/-6 years (mean+/-s.d.) participated in experimental sessions in which i.v. THC (2.5 mg) was administered under double-blind, placebo-controlled conditions. Self-rated and investigator-rated measurements of mood and psychosis [the University of Wales Institute of Science and Technology Mood Adjective Checklist (UMACL), the Positive and Negative Syndrome Scale (PANSS) and the Community Assessment of Psychic Experiences (CAPE)] were made at baseline and at 30, 80 and 120 min post-injection. Participants also completed a series of neuropsychological tests [the Rey Auditory Verbal Learning Task (RAVLT), Digit Span, Verbal Fluency and the Baddeley Reasoning Task] within 45 min of injection. THC-induced positive psychotic symptoms, and participant- and investigator-rated measurements of these were highly correlated. Participants showed an increase in anxiety ratings but there was no relationship between either self- or investigator-rated positive psychotic symptoms and anxiety. THC also impaired neuropsychological performance but once again there was no relationship between THC-induced positive psychotic symptoms and deficits in working memory/executive function. These findings confirm that THC can induce a transient, acute psychotic reaction in psychiatrically well individuals. The extent of the psychotic reaction was not related to the degree of anxiety or cognitive impairment.

  10. Involvement of opioid system in cognitive deficits induced by ∆⁹-tetrahydrocannabinol in rats.

    Science.gov (United States)

    Egashira, Nobuaki; Manome, Naomi; Mishima, Kenichi; Iwasaki, Katsunori; Oishi, Ryozo; Fujiwara, Michihiro

    2012-02-01

    Cannabis is a widely used illicit substance. ∆(9)-Tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to induce cognitive deficits that closely resemble the impairment observed in schizophrenic patients. We previously reported that THC (6 mg/kg) impairs spatial memory in the eight-arm radial maze, and that this memory disturbance was reversed by the cannabinoid CB(1) receptor antagonist rimonabant (0.1 mg/kg), suggesting that the effect of THC is mediated through cannabinoid CB(1) receptors. The present study was designed to examine the possible involvement of opioid receptors in the THC-induced impairment of spatial memory. The effects of treatment with the nonselective opioid receptor antagonist naloxone (0.3 and 1 mg/kg), the μ-opioid receptor antagonist β-funaltrexamine (0.3 and 1 mg/kg), the δ-opioid receptor antagonist naltrindole (1 and 3 mg/kg), and the κ-opioid receptor antagonist nor-binaltorphimine (0.03 and 0.1 mg/kg) on the impairment of spatial memory induced by THC were evaluated using the eight-arm radial maze. The nonselective opioid receptor antagonist naloxone, the μ-opioid receptor antagonist β-funaltrexamine, and the κ-opioid receptor antagonist nor-binaltorphimine, but not the δ-opioid receptor antagonist naltrindole, attenuated THC-induced cognitive deficits, suggesting an involvement of μ- and κ-opioid receptors in this behavioral response. These results demonstrate that the endogenous opioid system is involved in the regulation of the acute short-term and working memory deficits induced by cannabis.

  11. Delta-9 tetrahydrocannabinol (THC inhibits lytic replication of gamma oncogenic herpesviruses in vitro

    Directory of Open Access Journals (Sweden)

    Friedman Herman

    2004-09-01

    Full Text Available Abstract Background The major psychoactive cannabinoid compound of marijuana, delta-9 tetrahydrocannabinol (THC, has been shown to modulate immune responses and lymphocyte function. After primary infection the viral DNA genome of gamma herpesviruses persists in lymphoid cell nuclei in a latent episomal circular form. In response to extracellular signals, the latent virus can be activated, which leads to production of infectious virus progeny. Therefore, we evaluated the potential effects of THC on gamma herpesvirus replication. Methods Tissue cultures infected with various gamma herpesviruses were cultured in the presence of increasing concentrations of THC and the amount of viral DNA or infectious virus yield was compared to those of control cultures. The effect of THC on Kaposi's Sarcoma Associated Herpesvirus (KSHV and Epstein-Barr virus (EBV replication was measured by the Gardella method and replication of herpesvirus saimiri (HVS of monkeys, murine gamma herpesvirus 68 (MHV 68, and herpes simplex type 1 (HSV-1 was measured by yield reduction assays. Inhibition of the immediate early ORF 50 gene promoter activity was measured by the dual luciferase method. Results Micromolar concentrations of THC inhibit KSHV and EBV reactivation in virus infected/immortalized B cells. THC also strongly inhibits lytic replication of MHV 68 and HVS in vitro. Importantly, concentrations of THC that inhibit virus replication of gamma herpesviruses have no effect on cell growth or HSV-1 replication, indicating selectivity. THC was shown to selectively inhibit the immediate early ORF 50 gene promoter of KSHV and MHV 68. Conclusions THC specifically targets viral and/or cellular mechanisms required for replication and possibly shared by these gamma herpesviruses, and the endocannabinoid system is possibly involved in regulating gamma herpesvirus latency and lytic replication. The immediate early gene ORF 50 promoter activity was specifically inhibited by THC

  12. Effects of tetrahydrocannabinol on balance and gait in patients with dementia: A randomised controlled crossover trial.

    Science.gov (United States)

    van den Elsen, Geke Ah; Tobben, Lieke; Ahmed, Amir Ia; Verkes, Robbert Jan; Kramers, Cornelis; Marijnissen, Radboud M; Olde Rikkert, Marcel Gm; van der Marck, Marjolein A

    2017-02-01

    Oral tetrahydrocannabinol (THC) is currently studied for its possible efficacy on dementia-related neuropsychiatric symptoms (NPS), but might lead to increased risk of falling. This was a randomised, double-blind, crossover study to evaluate the effects of THC on mobility in dementia patients. Eighteen community-dwelling patients ( Mage=77 years) received 1.5 mg of oral THC twice daily and placebo, in random order, for three days, separated by a four-day washout. Balance and gait were assessed using SwayStarTM and GAITRiteTM within two hours after administration, in two consecutive intervention periods, under the following conditions: standing with eyes open (EO) and eyes closed (EC), preferred speed walking with and without a cognitive dual task. THC significantly increased sway during standing EC (roll angle 0.32[±0.6]°, p=0.05; pitch angle 1.04[±1.5]°, p=0.009; pitch velocity 1.96[±3.3]°/s, p=0.02), but not during standing EO. During preferred speed walking, THC increased stride length (4.3[±5.4] cm, p=0.005) and trunk sway (pitch angle 1.18[±1.6]°, p=0.005). No effects were observed during dual task walking. No differences in the number and type of adverse events were found, and no falls occurred after administration of THC. This study showed that 3 mg of THC per day has a benign adverse event profile regarding mobility and was well tolerated by community-dwelling dementia patients.

  13. Tetrahydrocannabinol in Behavioral Disturbances in Dementia: A Crossover Randomized Controlled Trial.

    Science.gov (United States)

    van den Elsen, Geke A H; Ahmed, Amir I A; Verkes, Robbert-Jan; Feuth, Ton; van der Marck, Marjolein A; Olde Rikkert, Marcel G M

    2015-12-01

    Neuropsychiatric symptoms (NPS) are highly prevalent in dementia, but effective pharmacotherapy without important side effects is lacking. This study aims to assess the efficacy and safety of oral tetrahydrocannabinol (THC) in the treatment of NPS in dementia. Randomized, double-blind, placebo-controlled, repeated crossover trial, consisting of six treatment blocks of 2 weeks each. Two hospital sites in The Netherlands, September 2011 to December 2013. Patients with dementia and clinically relevant NPS. Within each block THC (0.75 mg twice daily in blocks 1-3 and 1.5 mg twice daily in blocks 4-6) and placebo were administered in random order for 3 consecutive days, followed by a 4-day washout. Primary outcome was change in Neuropsychiatric Inventory (NPI) score. Analyses were performed intention-to-treat. Data from all subjects were used without imputation. Sample size required for a power of 80% was 20 patients, because of repeated crossover. 22 patients (15 men, mean age 76.4 [5.3] years) were included, of whom 20 (91%) completed the trial. THC did not reduce NPI compared to placebo (blocks 1-3: 1.8, 97.5% CI: -2.1 to 5.8; blocks 4-6: -2.8, 97.5% CI: -7.4 to 1.8). THC was well tolerated, as assessed by adverse event monitoring, vital signs, and mobility. The incidence of adverse events was similar between treatment groups. Four non-related serious adverse events occurred. This is the largest randomized controlled trial studying the efficacy of THC for NPS, to date. Oral THC did not reduce NPS in dementia, but was well tolerated by these vulnerable patients, supporting future higher dosing studies. Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  14. Involvement of central and peripheral cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain.

    Science.gov (United States)

    Bagüés, Ana; Martín, M Isabel; Sánchez-Robles, Eva M

    2014-12-15

    Cannabinoid (CB) receptors have emerged as an attractive therapeutic target for pain management in recent years and the interest in the use of cannabinoids is gradually increasing, particularly in patients where conventional treatments fail. Muscle pain is a major clinical problem and new pharmacological approaches are being studied. Recently, we have demonstrated that cannabinoid synthetic agonists are useful to reduce muscular pain in two animal models, where the local administration is effective. Now, we want to know if tetrahydrocannabinol (THC), a cannabinoid natural derivative with therapeutic use in humans, is also effective in reducing acute muscle pain. The antinociceptive effect of THC by systemic (i.p.) and local (i.m.) administration was tested in two animal models of acute muscle pain, rat masseter and gastrocnemius, induced by hypertonic saline (HS) injection. The drugs used were the non-selective agonist THC and two selective cannabinoid antagonists, AM251 (CB1) and AM630 (CB2). THC, i.p. and i.m. administered, reduced the nociceptive behaviours induced by HS in both muscular pain models. The antinociceptive effect induced by the systemic administration of THC was mediated by CB1 receptors in the masseter muscle whereas in gastrocnemius both CB1 and CB2 receptors participated. When THC was administered locally, only CB2 receptors were involved in the antinociceptive effect in both muscles. This study suggests that THC could be a future pharmacological option in the treatment of muscle pain. The local administration of THC could be an interesting option to treat this type of pain avoiding the central adverse effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Effects of low doses of alcohol on delta-9-tetrahydrocannabinol's effects in pregnant rats

    Energy Technology Data Exchange (ETDEWEB)

    Abel, E.L.; Subramanian, M.G. (Wayne State Univ., Detroit, MI (USA))

    1990-01-01

    Pregnant rats were intubated with 50 mg/kg of delta-9-tetrahydrocannabinol (THC) or with THC plus alcohol to determine if a low dose of alcohol would significantly increase blood levels of THC. On the basis of this study, a second study was conducted in which pregnant rats were intubated with THC plus alcohol from gestation day six to parturition. THC reduced birth weights but did not significantly affect litter size or passive avoidance learning. Alcohol did not have a significant effect on offspring birth weight nor did it interact with THC to affect offspring.

  16. An assessment of the immunofluorescence technique as a method for demonstrating the histological localization of tetrahydrocannabinol in mammalian tissues

    Energy Technology Data Exchange (ETDEWEB)

    Morley, M.; Gee, D.J.

    1982-10-01

    The use of the indirect immunofluorescence technique as a method for demonstrating the histological localization of tetrahydrocannabinol (delta-THC) has been examined. The experimental protocol was designed in order that optimal staining conditions with respect to temperature, the length of time of incubations and washes, and the dilution of the antisera should be defined. No marked differences were detected between frozen sections of liver from normal and delta-THC-injected mice. Results from radiotracer experiments using human liver suggest that the success of the method is dependent upon the solubility characteristics of the antigen-antibody complex.

  17. Development and validation of a LC/MS method for the determination of Δ(9)-tetrahydrocannabinol and 11-carboxy-Δ(9)-tetrahydrocannabinol in the larvae of the blowfly Lucilia sericata: Forensic applications.

    Science.gov (United States)

    Karampela, Sevasti; Pistos, Constantinos; Moraitis, Konstantinos; Stoukas, Vasilios; Papoutsis, Ioannis; Zorba, Eleni; Koupparis, Michalis; Spiliopoulou, Chara; Athanaselis, Sotiris

    2015-12-01

    In a number of forensic toxicological cases, Δ(9)-tetrahydrocannabinol (THC) and its metabolite 11-carboxy-delta-9-tetrahydrocannabinol (THCA) are frequently considered as contributor factors to the event. To that, a liquid chromatographic mass spectrometric method is described for the identification and quantitation of THC and its metabolite THCA in the forensically important larvae of L. sericata. Larvae of Lucilia sericata were fortified with varying concentrations of THC and THCA covering the calibration range between 10 and 500pg/mg. For the isolation of the analytes from larvae, several extraction techniques were evaluated and finally liquid-liquid extraction under acidic pH was selected using hexane-ethyl acetate (50:50, v/v) as extraction solvent. For the chromatographic separation, a Waters Symmetry® C18 analytical column was used while the mobile phase was acetonitrile-ammonium acetate (2mM) (30:70, v/v). The detection was performed using electrospray ionization source in negative mode (ESI-) and the selected ions monitored were m/z 313 for THC and m/z 343 for THCA. The proposed method which is simple and sufficiently sensitive for the detection of THC and THCA even in a single larva sampling, assisted the investigation of a forensic case. Copyright © 2015 The Chartered Society of Forensic Sciences. Published by Elsevier Ireland Ltd. All rights reserved.

  18. Differential effects of delta-9-tetrahydrocannabinol and its 11-hydroxy metabolite on sodium current in neuroblastoma cells.

    Science.gov (United States)

    Turkanis, S A; Karler, R; Partlow, L M

    1991-09-27

    Whole-cell voltage-clamp techniques were used to study the comparative effects of delta-9-tetrahydrocannabinol (THC) and its principal metabolite, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC), on the voltage-gated sodium current in neuroblastoma cells. The parent compound markedly depressed the inward sodium current with minimal reduction of the outward current, demonstrating that the effects of the drug were related to the membrane potential. In addition, THC reduced the reversal potential, indicating that the drug modified the ion selectivity of the channel. 11-OH-THC similarly depressed inward sodium current; however, in marked contrast to the effects of the parent compound, the drug equally depressed the outward voltage-gated sodium current, indicating that its effects were not related to the membrane potential. Furthermore, 11-OH-THC differed from THC in that it did not alter the reversal potential. The results demonstrate that THC and its 11-OH metabolite both reduce inward sodium current, but their effects on the outward current and ion selectivity are distinctly different. The sum of the actions of these two cannabinoids on the voltage-gated sodium channel provides a plausible cellular basis for THC's depression of action potentials in vivo and for some of its central depressant effects.

  19. Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.

    Science.gov (United States)

    Gerak, L R; France, C P

    2016-05-01

    Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not

  20. Impairment due to alcohol, tetrahydrocannabinol, and benzodiazepines in impaired drivers compared to experimental studies.

    Science.gov (United States)

    Høiseth, Gudrun; Berg-Hansen, Grim Otto; Øiestad, Åse Marit L; Bachs, Liliana; Mørland, Jørg

    2017-04-03

    In some countries, per se laws for other drugs than alcohol are used to judge drunk and drugged drivers. These blood concentration limits are often derived from experimental studies on traffic relevant behavior of healthy volunteers. Knowledge about how results from experimental studies could be transferred to a real-life setting is missing. The aim of this study was to compare impairment seen in experimental studies to the impairment seen at equivalent concentrations in apprehended drunk and drugged drivers. Results from previously performed meta-analyses of experimental studies regarding impairment from alcohol, tetrahydrocannabinol (THC), and benzodiazepines were compared to impairment in apprehended drunk and drugged drivers as judged by a clinical test of impairment. Both experimental studies and real-life cases were divided into 4 groups according to increasing blood drug concentration intervals. The percentage of impaired test results in experimental studies was compared to the percentage of impaired subjects among drivers within the same blood drug concentration window. For ethanol, the percentage of impaired drivers (n = 1,223) increased from 59% in the lowest drug concentration group to 95% in the highest drug concentration group, compared to 7 and 72% in the respective groups in experimental studies. For THC, the percentage of impaired drivers (n = 950) increased from 42 to 58%, the corresponding numbers being 11 and 42% for experimental studies. For benzodiazepines, the percentage of impaired drivers (n = 245) increased from 46 to 76%, the corresponding numbers being 16 and 60% for experimental studies. The increased odds ratio for impairment between 2 concentration groups was comparable for experimental studies and impaired drivers. Fewer test results indicated impairment in experimental studies compared to impaired drivers in real life when influenced by similar blood concentrations of either ethanol, THC, or benzodiazepines. In addition, a comparable

  1. Novel Δ9-tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

    Science.gov (United States)

    Klumpers, Linda E; Beumer, Tim L; van Hasselt, Johan G C; Lipplaa, Astrid; Karger, Lennard B; Kleinloog, H Daniël; Freijer, Jan I; de Kam, Marieke L; van Gerven, Joop M A

    2012-01-01

    AIMS Among the main disadvantages of currently available Δ9-tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®. METHODS This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed. RESULTS Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t1/2 was 72–80 min, tmax was 39–56 min and Cmax 2.92–4.69 ng ml−1. THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (−2.7 mm, 95% CI −4.5, −0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min–1, 95% CI 2.7, 6.5). Namisol® was well tolerated. CONCLUSIONS Oral Namisol® showed promising PK and PD characteristics. Variability and tmax of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations. PMID:22680341

  2. Effects of Δ(9)-tetrahydrocannabinol (THC) on human amniotic epithelial cell proliferation and migration.

    Science.gov (United States)

    Yao, J L; He, Q Z; Liu, M; Chang, X W; Wu, J T; Duan, T; Wang, K

    2018-02-01

    The deleterious effects of cannabis consumption for fertility and pregnancy outcome are recognized for years. The main psychoactive molecule of cannabis, Δ(9)-tetrahydrocannabinol (THC) is able to cross the placenta barrier and cause alterations in fetal growth, low birth weight and preterm labor. However, the effects of THC on the human placenta amnion are still unknown. The distributions of CB1R and CB2R in human amnion tissues were observed by immunohistochemistry (IHC). Human amniotic epithelial cell proliferation and migration in response to THC treatment were measured by MTS and transwell assays, respectively. The PCR array was performed to study the key regulators involved in the cell migration. The protein levels of CB1R, CB2R in amnion tissues and MMP2, MMP9 in cells were detected by western blotting. Small interfering RNAs (siRNAs) were used to knockdown MMP2 and MMP9 in WISH cells. Our results indicated that both CB1R and CB2R primarily identified in the epithelial layer of human placental amnion tissue. The CB1R expression in the amnion tissue was higher in the preterm group than normal control. High-dose of THC (30uM, but not 20 and 10uM) significantly inhibited (p<0.01) human amniotic epithelial cell lines (WISH) proliferation. Meanwhile, THC at both 10uM and 20uM (p<0.05) significantly suppressed cells migration in both WISH and primary human amniotic epithelial cells. The PCR array data and siRNA experiments demonstrated that MMP2/9 were tightly involved in the regulation of THC-inhibited cell migration in WISH cells. These results suggested that THC inhibited the migration of human amniotic epithelial cell through the regulation of MMP2 and MMP9, which in turn altered the development of the amnion during the gestation and partially resulted in preterm labor and other adverse pregnancy outcomes. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Preparation of 2-(/sup 125/I) iodohistamine-labelled. delta. /sup 8/-tetrahydrocannabinol-11-oic acid for use in cannabinoid radioimmunoassay

    Energy Technology Data Exchange (ETDEWEB)

    Law, B.; Mason, P.A.; Moffat, A.C. (Home Office Central Research Establishment, Aldermaston (UK)); King, L.J. (Surrey Univ., Guildford (UK))

    1982-08-01

    A simple method is described for the preparation of 2-(/sup 125/I)iodohistamine-labelled ..delta../sup 8/-tetrahydrocannabinol-11-oic acid with high specific activity for use in radioimmunoassay. This compound is produced in high yield and shows excellent radiochemical stability when stored at 4/sup 0/C.

  4. Acute effects of MDMA (3,4-methylenedioxymethamphetamine) on EEG oscillations: alone and in combination with ethanol or THC (delta-9-tetrahydrocannabinol)

    NARCIS (Netherlands)

    Lansbergen, M.M.; Dumont, G.J.H.; Gerven, J.M. van; Buitelaar, J.K.; Verkes, R.J.

    2011-01-01

    RATIONALE: Typical users of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") are polydrug users, combining MDMA with alcohol or cannabis [most active compound: delta-9-tetrahydrocannabinol (THC)]. OBJECTIVES: The aim of the present study was to investigate whether co-administration of alcohol

  5. Cognitive and psychomotor effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg delta-9-tetrahydrocannabinol (THC).

    NARCIS (Netherlands)

    Hunault, C.C.; Mensinga, T.T.; Böcker, K.B.E.; Schipper, C.M.; Kruidenier, M.; Leenders, M.E.C.; de Vries, I.; Meulenbelt, J.|info:eu-repo/dai/nl/079479227

    2009-01-01

    RATIONALE: Delta(9)-Tetrahydrocannabinol (THC) is the main active constituent of cannabis. In recent years, the average THC content of some cannabis cigarettes has increased up to approximately 60 mg per cigarette (20% THC cigarettes). Acute cognitive and psychomotor effects of THC among

  6. Acute subjective effects after smoking joints containing up to 69 mg Δ9-tetrahydrocannabinol in recreational users : a randomized, crossover clinical trial

    NARCIS (Netherlands)

    Hunault, Claudine C.; Böcker, Koen B E; Stellato, R. K.; Kenemans, J. Leon; de Vries, Irma; Meulenbelt, Jan

    2014-01-01

    Rationale An increase in the potency of the cannabis cigarettes has been observed over the past three decades. Objectives In this study, we aimed to establish the impact of Δ9-tetrahydrocannabinol (THC) on the rating of subjective effects (intensity and duration of the effects), up to 23 % THC

  7. Molecularly imprinted polymer for selective determination of Δ9-tetrahydrocannabinol and 11-nor-Δ9-tetrahydrocannabinol carboxylic acid using LC-MS/MS in urine and oral fluid.

    Science.gov (United States)

    Lendoiro, E; de Castro, A; Fernández-Vega, H; Cela-Pérez, M C; López-Vilariño, J M; González-Rodríguez, M V; Cruz, A; López-Rivadulla, M

    2014-06-01

    The use of molecularly imprinted polymers (MIPs) for solid phase extraction (MISPE) allows a rapid and selective extraction compared with traditional methods. Determination of Δ(9)-tetrahydrocannabinol (THC) and 11-nor-Δ(9)-tetrahydrocannabinol carboxylic acid (THC-COOH) in oral fluid (OF) and urine was performed using homemade MISPEs for sample clean-up and liquid chromatography tandem mass spectrometry (LC-MS/MS). Cylindrical MISPE shaped pills were synthesized using catechin as a mimic template. MISPEs were added to 0.5 mL OF or urine sample and sonicated 30 min for adsorption of analytes. For desorption, the MISPE was transfered to a clean tube, and sonicated for 15 min with 2 mL acetone:acetonitrile (3:1, v/v). The elution solvent was evaporated and reconstituted in mobile phase. Chromatographic separation was performed using a SunFire C18 (2.5 μm; 2.1 × 20 mm) column, and formic acid 0.1% and acetonitrile as mobile phase, with a total run time of 5 min. The method was fully validated including selectivity (no endogenous or exogenous interferences), linearity (1-500 ng/mL in OF, and 2.5-500 ng/mL in urine), limit of detection (0.75 and 1 ng/mL in OF and urine, respectively), imprecision (%CV <12.3%), accuracy (98.2-107.0% of target), extraction recovery (15.9-53.5%), process efficiency (10.1-46.2%), and matrix effect (<-55%). Analytes were stable for 72 h in the autosampler. Dilution 1:10 was assured in OF, and Quantisal™ matrix effect showed ion suppression (<-80.4%). The method was applied to the analysis of 20 OF and 11 urine specimens. This is the first method for determination of THC and THC-COOH in OF using MISPE technology.

  8. delta. /sup 9/-tetrahydrocannabinol and 17. beta. -estradiol bind to different macromolecules in estrogen target tissues. [Mice

    Energy Technology Data Exchange (ETDEWEB)

    Okey, A.B.; Bondy, G.P.

    1978-04-21

    DELTA/sup 9/-Tetrahydrocannabinol (DELTA/sup 9/-THC), added to the limit of its solubility, did not compete with tritiated 17 beta-estradiol for binding to estrogen receptor sites in mouse mammary or uterine cytosols. On sucrose density gradients of low-ionic strength, mammary cytosol labeled with (/sup 3/H)estradiol exhibited a binding peak near the ''8S'' region typical of estrogen receptor whereas in cytosol labeled with DELTA/sup 9/-(/sup 3/H)THC binding was limited to the nonspecific 4- to 5S region. Differences in sedimentation properties and reciprocal competition studies strongly refute previous claims that DELTA/sup 9/-THC binds to estrogen receptor and that by so doing it directly acts as an estrogen.

  9. Rapid isolation procedure for Δ9-tetrahydrocannabinolic acid A (THCA) from Cannabis sativa using two flash chromatography systems.

    Science.gov (United States)

    Wohlfarth, Ariane; Mahler, Hellmut; Auwärter, Volker

    2011-10-15

    Two isolation procedures for Δ9-tetrahydrocannabinolic acid A (THCA), the biogenetic precursor in the biosynthesis of the psychoactive Δ9-tetrahydrocannabinol (THC) in the cannabis plant, are presented. Two flash chromatography systems that can be used independently from each other were developed to separate THCA from other compounds of a crude cannabis extract. In both systems UV absorption at 209 and 270 nm was monitored. Purity was finally determined by HPLC-DAD, NMR and GC-MS analysis with a focus on the impurity THC. System 1 consisted of a normal phase silica column (120 g) as well as cyclohexane and acetone--both spiked with the modifier pyridine--as mobile phases. Gradient elution was performed over 15 min. After the chromatographic run the fractions containing THCA fractions were pooled, extracted with hydrochloric acid to eliminate pyridine and evaporated to dryness. Loading 1800 mg cannabis extract yielded 623 mg THCA with a purity of 99.8% and a THC concentration of 0.09%. System 2 was based on a reversed-phase C18 column (150 g) combined with 0.55% formic acid and methanol as mobile phases. A very flat gradient was set over 20 minutes. After pooling the THCA-containing fractions methanol was removed in a rotary evaporator. THCA was re-extracted from the remaining aqueous phase with methyl tert-butyl ether. The organic phase was finally evaporated under high vacuum conditions. Loading 300 mg cannabis extract yielded 51 mg THCA with a purity of 98.8% and a THC concentration of 0.67%. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Effects of 20 mg oral Δ(9) -tetrahydrocannabinol on the olfactory function of healthy volunteers.

    Science.gov (United States)

    Walter, Carmen; Oertel, Bruno G; Ludyga, Dagmar; Ultsch, Alfred; Hummel, Thomas; Lötsch, Jörn

    2014-11-01

    Olfactory loss impairs the patient's quality of life. In individualized therapies, olfactory drug effects gain clinical importance. Molecular evidence suggests that among drugs with potential olfactory effects is Δ(9) -tetrahydrocannabinol (THC), which is approved for several indications, including neuropathic pain or analgesia in cancer patients. The present study aimed at assessing the olfactory effects of THC to be expected during analgesic treatment. The effects of 20 mg oral THC on olfaction were assessed in a placebo-controlled, randomized cross-over study in healthy volunteers. Using an established olfactory test (Sniffin' Sticks), olfactory thresholds, odour discrimination and odour identification were assessed in 15 subjects at baseline and 2 h after THC administration. Δ(9) -Tetrahydrocannabinol impaired the performance of subjects (n = 15) in the olfactory test. Specifically, olfactory thresholds were increased and odour discrimination performance was reduced. This resulted in a significant drop in composite threshold, discrimination, identification (TDI) olfactory score by 5.5 points (from 37.7 ± 4.2 to 32.2 ± 5.6, 95% confidence interval for differences THC vs. placebo, -7.8 to -2.0, P = 0.003), which is known to be a subjectively perceptible impairment of olfactory function. Considering the resurgence of THC in medical use for several pathological conditions, the present results indicate that THC-based analgesics may be accompanied by subjectively noticeable reductions in olfactory acuity. In particular, for patients relying on their sense of smell, this might be relevant information for personalized therapy strategies. © 2014 The British Pharmacological Society.

  11. Δ(9)-Tetrahydrocannabinol concentrations in exhaled breath and physiological effects following cannabis intake - A pilot study using illicit cannabis.

    Science.gov (United States)

    Coucke, Line; Massarini, Enrico; Ostijn, Zachery; Beck, Olof; Verstraete, Alain G

    2016-09-01

    Δ(9)-Tetrahydrocannabinol (THC) can be measured in exhaled breath by using an aerosol particle collection device. The sampling procedure is simple, non-invasive and takes only 2-3min. In the present study we measured the amount of THC in exhaled breath of cannabis users at specific time intervals up to 3h after smoking one cannabis cigarette. The breath concentration-effect relationship was studied by measuring the pulse rate and the pupil diameter to assess physiological changes. THC and the main metabolite 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol were analyzed in exhaled breath by a liquid chromatography-tandem mass spectrometry method. Thirteen subjects (9 males and 4 females, aged 23-24years) participated. Five of those were using cannabis more frequently than monthly. THC was detected in most subjects already at baseline, concentrations increased following smoking and remained detectable for over 3h (mean THC concentration in breath at 3h: 1479pg/sample). Pulse rate (p=0.015) and pupil diameter (p=0.044) were significantly altered up to 30min after smoking. The detection window of cannabis in breath after smoking one cannabis cigarette in occasional and chronic smokers was at least 3h. Only THC was detected, and not the metabolite. The THC concentration in exhaled breath was related to the physiological changes that occur over time. Exhaled breath can be used to detect recent cannabis exposure. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  12. 11-Nor-9-carboxy-∆9-tetrahydrocannabinol quantification in human oral fluid by liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Scheidweiler, Karl B; Himes, Sarah K; Chen, Xiaohong; Liu, Hua-Fen; Huestis, Marilyn A

    2013-07-01

    Currently, ∆9-tetrahydrocannabinol (THC) is the analyte quantified for oral fluid cannabinoid monitoring. The potential for false-positive oral fluid cannabinoid results from passive exposure to THC-laden cannabis smoke raises concerns for this promising new monitoring technology. Oral fluid 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THCCOOH) is proposed as a marker of cannabis intake since it is not present in cannabis smoke and was not measureable in oral fluid collected from subjects passively exposed to cannabis. THCCOOH concentrations are in the picogram per milliliter range in oral fluid and pose considerable analytical challenges. A liquid chromatography-tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying THCCOOH in 1 mL Quantisal-collected oral fluid. After solid phase extraction, chromatography was performed on a Kinetex C18 column with a gradient of 0.01% acetic acid in water and 0.01% acetic acid in methanol with a 0.5-mL/min flow rate. THCCOOH was monitored in negative mode electrospray ionization and multiple reaction monitoring mass spectrometry. The THCCOOH linear range was 12-1,020 pg/mL (R(2) > 0.995). Mean extraction efficiencies and matrix effects evaluated at low and high quality control (QC) concentrations were 40.8-65.1 and -2.4-11.5%, respectively (n = 10). Analytical recoveries (bias) and total imprecision at low, mid, and high QCs were 85.0-113.3 and 6.6-8.4% coefficient of variation, respectively (n = 20). This is the first oral fluid THCCOOH LCMSMS triple quadrupole method not requiring derivatization to achieve a <15 pg/mL limit of quantification. The assay is applicable for the workplace, driving under the influence of drugs, drug treatment, and pain management testing.

  13. Chronic Adolescent Δ9-Tetrahydrocannabinol Treatment of Male Mice Leads to Long-Term Cognitive and Behavioral Dysfunction, Which Are Prevented by Concurrent Cannabidiol Treatment

    OpenAIRE

    Murphy, Michelle; Mills, Sierra; Winstone, Joanna; Leishman, Emma; Wager-Miller, Jim; Bradshaw, Heather; Mackie, Ken

    2017-01-01

    Abstract Introduction: The high prevalence of adolescent cannabis use, the association between this use and later psychiatric disease, and increased access to high-potency cannabis highlight the need for a better understanding of the long-term effects of adolescent cannabis use on cognitive and behavioral outcomes. Furthermore, increasing Δ9-tetrahydrocannabinol (THC) in high-potency cannabis is accompanied by a decrease in cannabidiol (CBD), thus an understanding of the interactions between ...

  14. Schedules of Controlled Substances: Placement of FDA-Approved Products of Oral Solutions Containing Dronabinol [(-)-delta-9-trans- tetrahydrocannabinol (delta-9-THC)] in Schedule II. Final rule.

    Science.gov (United States)

    2017-11-22

    This final rule adopts without changes an interim final rule with request for comments published in the Federal Register on March 23, 2017. On July 1, 2016, the U.S. Food and Drug Administration (FDA) approved a new drug application for Syndros, a drug product consisting of dronabinol [(-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC)] oral solution. The Drug Enforcement Administration (DEA) maintains FDA-approved products of oral solutions containing dronabinol in schedule II of the Controlled Substances Act.

  15. Using Functional Near-Infrared Spectroscopy to Measure Effects of Delta 9-Tetrahydrocannabinol on Prefrontal Activity and Working Memory in Cannabis Users

    OpenAIRE

    Keles, Hasan O.; Radoman, Milena; Pachas, Gladys N.; Evins, A. Eden; Gilman, Jodi M.

    2017-01-01

    Intoxication from cannabis impairs cognitive performance, in part due to the effects of Δ9-tetrahydrocannabinol (THC, the primary psychoactive compound in cannabis) on prefrontal cortex (PFC) function. However, a relationship between impairment in cognitive functioning with THC administration and THC-induced change in hemodynamic response has not been demonstrated. We explored the feasibility of using functional near-infrared spectroscopy (fNIRS) to examine the functional changes of the human...

  16. Immunochemical approach using monoclonal antibody against Δ(9)-tetrahydrocannabinolic acid (THCA) to discern cannabis plants and to investigate new drug candidates.

    Science.gov (United States)

    Tanaka, Hiroyuki

    2011-03-01

    A monoclonal antibody (MAb-4A4) against Δ9- tetrahydrocannabinolic acid (THCA) showing extensive cross-reactivity against various cannabinoids was prepared. Using this antibody, a competitive enzyme-linked immunoassay (ELISA) was developed to detect Δ9-THCA in the range of 1 to 100 mg/ml. Various cannabinoids including Δ9-THC (Δ9-tetrahydrocannabinolic acid), Δ8-THCA (Δ8-tetrahydrocannabinolic acid), Δ8-THC (Δ8-tetrahydrocannabinol), CBD (cannabidiol), and CBN (cannabinol) were recognized by MAb-4A4, and their cross-reactivities were 55-1600% compared with Δ9-THCA (100%). This novel characteristic of this MAb enabled detection of marijuana residues in biological samples by detection of residual cannabinoids. The ELISA using MAb-4A4 was found to be applicable even for withered samples which contained only trace amounts of Δ9-THCA and Δ9-THC. In addition, this method using MAb-4A4 could be useful in forensic analysis since the MAb-4A4 also shows cross-reactivities against cannabinoid metabolites in body fluids. As well as forensic applications using this MAb, an investigation of new drug candidates focusing on cannabinoid metabolites arising from biotransformation in plant tissue was performed using immunochemical screening. The resulting new drug candidates were cannabinoid glycosides biotransformed by Pinellia ternata whose bioactivity is as yet unidentified. Our results indicate the utility of the application of ELISA using MAb-4A4 for further experiments involving marijuana and cannabinoids not only in the forensic field but also in the context of drug discovery.

  17. Chronic Δ9-Tetrahydrocannabinol Administration Reduces IgE+B Cells but Unlikely Enhances Pathogenic SIVmac251 Infection in Male Rhesus Macaques of Chinese Origin

    OpenAIRE

    Qin, CHUN-CHUNG; Molina, P; Liu, L; Cong, Z; Wu, X; Wang, H; Chen, Z; Wei, Q

    2016-01-01

    Delta9-tetrahydrocannabinol (Δ9-THC) is the major psychoactive component of the cannabis plant. Δ9-THC has been used in the active ingredient of Marinol as an appetite stimulant for AIDS patients. Its impact on progression of HIV-1 infection, however, remains debatable. Previous studies indicated that Δ9-THC administration enhanced HIV-1 infection in huPBL-SCID mice but seemingly decreased early mortality in simian immunodeficiency virus (SIV) infected male Indian-derived rhesus macaques. Her...

  18. Analysis of 11-nor-Δ9 -tetrahydrocannabinol-9-carboxylic acid and its glucuronide in urine by capillary electrophoresis/mass spectrometry.

    Science.gov (United States)

    Iwamuro, Yoshiaki; Iio-Ishimaru, Reiko; Chinaka, Satoshi; Takayama, Nariaki; Hayakawa, Kazuichi

    2012-11-01

    Δ(9) -Tetrahydrocannabinol is the primary psychoactive component in cannabis, one of the most commonly used illicit drugs in the world. This paper describes a simple and rapid method for direct analysis of major metabolites of Δ(9) -tetrahydrocannabinol; 11-nor-Δ(9) -tetrahydrocannabinol-9-carboxylic acid and its glucuronide in urine by capillary electrophoresis/mass spectrometry. The only pretreatment needed for a urine sample was dilution with methanol containing an internal standard and centrifugation. Electrophoresis was carried out in an untreated fused-silica capillary (50 µm i.d. × 85 cm) filled with 40 m m ammonium formate (pH 6.4). An analysis could be completed within 10 min. For both compounds, the assay was linear over the range 0.1-10 µg/mL in urine with correlation coefficients (r(2) ) >0.99 and the limit of detection was 0.5 pg (10 nL injection). The detection yields and reproducibilities were determined at three different concentrations (0.1, 0.5 and 2 µg/mL in urine). The mean detection yields were 60-99%. The intra- and inter-day relative standard deviations of migration times were 0.063-0.19 and 0.18-0.36%, and those of peak areas were 4.2-18 and 5.9-25%, respectively. The proposed method successfully analyzed the urine samples of cannabis users. Copyright © 2012 John Wiley & Sons, Ltd.

  19. Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15.

    Science.gov (United States)

    Niesink, Raymond J M; Rigter, Sander; Koeter, Maarten W; Brunt, Tibor M

    2015-12-01

    Between 2000 and 2005 the average percentage of Δ(9) -tetrahydrocannabinol (THC) in marijuana as sold in Dutch coffeeshops has increased substantially; the potency of domestic products (Nederwiet and Nederhasj) has particularly increased. In contrast with imported marijuana, Nederwiet hardly contained any cannabidiol (CBD), a cannabinoid that is thought to offset some of the adverse effects of THC. In 2005, the THC content in Nederwiet was significantly lower than in 2004. This study investigates the further decrease or increase of cannabinoids in these cannabis products. From 2005 to 2015 five different cannabis products were bought anonymously in 50 coffeeshops that were selected randomly each year from all coffeeshops in the Netherlands. A total of 2126 cannabis samples were bought, consisting of 664 Nederwiet samples (most popular), 537 Nederwiet samples (supposed strongest varieties), 183 imported herbal cannabis samples, 140 samples of cannabis resin made of Nederwiet and 602 samples of imported cannabis resin. All samples were analysed chemically for their THC, CBD and cannabinol (CBN) content. Between 2005 and 2015, the mean potencies of the most popular and the strongest Nederwiet and of imported cannabis resin were 16.0±4.0%, 17.0±3,9% and 16.5±6.3%, respectively. Imported herbal cannabis (6.5±3.5%) and cannabis resin made from Nederwiet (30.2±16.4%) contained, respectively, less (β=-10.0, Pcannabidiol ratio. © 2015 Society for the Study of Addiction.

  20. Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production.

    Science.gov (United States)

    Shmist, Yelena A; Goncharov, Igor; Eichler, Maor; Shneyvays, Vladimir; Isaac, Ahuva; Vogel, Zvi; Shainberg, Asher

    2006-02-01

    Delta-9-tetrahydrocannabinol (THC), the major active component of marijuana, has a beneficial effect on the cardiovascular system during stress conditions, but the defence mechanism is still unclear. The present study was designed to investigate the central (CB1) and the peripheral (CB2) cannabinoid receptor expression in neonatal cardiomyoctes and possible function in the cardioprotection of THC from hypoxia. Pre-treatment of cardiomyocytes that were grown in vitro with 0.1 - 10 microM THC for 24 h prevented hypoxia-induced lactate dehydrogenase (LDH) leakage and preserved the morphological distribution of alpha-sarcomeric actin. The antagonist for the CB2 (10 microM), but not CB1 receptor antagonist (10 microM) abolished the protective effect of THC. In agreement with these results using RT-PCR, it was shown that neonatal cardiac cells express CB2, but not CB1 receptors. Involvement of NO in the signal transduction pathway activated by THC through CB2 was examined. It was found that THC induces nitric oxide (NO) production by induction of NO synthase (iNOS) via CB2 receptors. L-NAME (NOS inhibitor, 100 microM) prevented the cardioprotection provided by THC. Taken together, our findings suggest that THC protects cardiac cells against hypoxia via CB2 receptor activation by induction of NO production. An NO mechanism occurs also in the classical pre-conditioning process; therefore, THC probably pre-trains the cardiomyocytes to hypoxic conditions.

  1. Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors.

    Science.gov (United States)

    Bhattacharyya, Sagnik; Egerton, Alice; Kim, Euitae; Rosso, Lula; Riano Barros, Daniela; Hammers, Alexander; Brammer, Michael; Turkheimer, Federico E; Howes, Oliver D; McGuire, Philip

    2017-11-03

    Use of Cannabis, the most widely used illicit drug worldwide, is associated with acute anxiety, and anxiety disorders following regular use. The precise neural and receptor basis of these effects have not been tested in man. Employing a combination of functional MRI (fMRI) and positron emission tomography (PET), we investigated whether the effects of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on anxiety and on amygdala response while processing fearful stimuli were related to local availability of its main central molecular target, cannabinoid-1 (CB1) receptors in man. Fourteen healthy males were studied with fMRI twice, one month apart, following an oral dose of either delta-9-THC (10 mg) or placebo, while they performed a fear-processing task. Baseline availability of the CB1 receptor was studied using PET with [(11)C]MePPEP, a CB1 inverse agonist radioligand. Relative to the placebo condition, delta-9-THC induced anxiety and modulated right amygdala activation while processing fear. Both these effects were positively correlated with CB1 receptor availability in the right amygdala. These results suggest that the acute effects of cannabis on anxiety in males are mediated by the modulation of amygdalar function by delta-9-THC and the extent of these effects are related to local availability of CB1 receptors.

  2. The Cannabinoid Delta-9-tetrahydrocannabinol Mediates Inhibition of Macrophage Chemotaxis to RANTES/CCL5 through the CB2 Receptor

    Science.gov (United States)

    Raborn, Erinn S.; Marciano-Cabral, Francine; Buckley, Nancy E.; Martin, Billy R.; Cabral, Guy A.

    2009-01-01

    The chemotactic response of murine peritoneal macrophages to RANTES/CCL5 was inhibited significantly following pretreatment with delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana. Significant inhibition of this chemokine directed migratory response was obtained also when the full cannabinoid agonist CP55940 was used. The CB2 receptor-selective ligand O-2137 exerted a robust inhibition of chemotaxis while the CB1 receptor-selective ligand ACEA had a minimal effect. The THC-mediated inhibition was reversed by the CB2 receptor-specific antagonist SR144528 but not by the CB1 receptor-specific antagonist SR141716A. In addition, THC treatment had a minimal effect on the chemotactic response of peritoneal macrophages from CB2 knockout mice. Collectively, these results suggest that cannabinoids act through the CB2 receptor to trans-deactivate migratory responsiveness to RANTES/CCL5. Furthermore, the results suggest that the CB2 receptor may be a constituent element of a network of G protein-coupled receptor signal transductional systems, inclusive of chemokine receptors, that act coordinately to modulate macrophage migration. PMID:18247131

  3. Cannabinoid Receptor CB2 Is Involved in Tetrahydrocannabinol-Induced Anti-Inflammation against Lipopolysaccharide in MG-63 Cells

    Directory of Open Access Journals (Sweden)

    Lei Yang

    2015-01-01

    Full Text Available Cannabinoid Δ9-tetrahydrocannabinol (THC is effective in treating osteoarthritis (OA, and the mechanism, however, is still elusive. Activation of cannabinoid receptor CB2 reduces inflammation; whether the activation CB2 is involved in THC-induced therapeutic action for OA is still unknown. Cofilin-1 is a cytoskeleton protein, participating in the inflammation of OA. In this study, MG-63 cells, an osteosarcoma cell-line, were exposed to lipopolysaccharide (LPS to mimic the inflammation of OA. We hypothesized that the activation of CB2 is involved in THC-induced anti-inflammation in the MG-63 cells exposed to LPS, and the anti-inflammation is mediated by cofilin-1. We found that THC suppressed the release of proinflammatory factors, including tumor necrosis factor α (TNF-α, interleukin- (IL- 1β, IL-6, and IL-8, decreased nuclear factor-κB (NF-κB expression, and inhibited the upregulation of cofilin-1 protein in the LPS-stimulated MG-63 cells. However, administration of CB2 receptor antagonist or the CB2-siRNA, not CB1 antagonist AM251, partially abolished the THC-induced anti-inflammatory effects above. In addition, overexpression of cofilin-1 significantly reversed the THC-induced anti-inflammatory effects in MG-63 cells. These results suggested that CB2 is involved in the THC-induced anti-inflammation in LPS-stimulated MG-63 cells, and the anti-inflammation may be mediated by cofilin-1.

  4. Enhanced brain disposition and effects of Δ9-tetrahydrocannabinol in P-glycoprotein and breast cancer resistance protein knockout mice.

    Directory of Open Access Journals (Sweden)

    Adena S Spiro

    Full Text Available The ABC transporters P-glycoprotein (P-gp, Abcb1 and breast cancer resistance protein (Bcrp, Abcg2 regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Δ(9-tetrahydrocannabinol (THC has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT mice. Abcb1a/b (-/-, Abcg2 (-/- and wild-type (WT mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b (-/- and Abcg2 (-/- mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (-/- mice. ABC transporter knockout mice were more sensitive to THC-induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis.

  5. Tetrahydrocannabinol Induces Brain Mitochondrial Respiratory Chain Dysfunction and Increases Oxidative Stress: A Potential Mechanism Involved in Cannabis-Related Stroke

    Directory of Open Access Journals (Sweden)

    Valérie Wolff

    2015-01-01

    Full Text Available Cannabis has potential therapeutic use but tetrahydrocannabinol (THC, its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities Vmax (complexes I, III, and IV activities, Vsucc (complexes II, III, and IV activities, Vtmpd (complex IV activity, together with mitochondrial coupling (Vmax/V0, were determined in control conditions and after exposure to THC in isolated mitochondria extracted from rat brain, using differential centrifugations. Oxidative stress was also assessed through hydrogen peroxide (H2O2 production, measured with Amplex Red. THC significantly decreased Vmax (−71%; P<0.0001, Vsucc (−65%; P<0.0001, and Vtmpd (−3.5%; P<0.001. Mitochondrial coupling (Vmax/V0 was also significantly decreased after THC exposure (1.8±0.2 versus 6.3±0.7; P<0.001. Furthermore, THC significantly enhanced H2O2 production by cerebral mitochondria (+171%; P<0.05 and mitochondrial free radical leak was increased from 0.01±0.01 to 0.10±0.01% (P<0.001. Thus, THC increases oxidative stress and induces cerebral mitochondrial dysfunction. This mechanism may be involved in young cannabis users who develop ischemic stroke since THC might increase patient’s vulnerability to stroke.

  6. Urine Toxicology Screen in Multiple Sleep Latency Test: The Correlation of Positive Tetrahydrocannabinol, Drug Negative Patients, and Narcolepsy

    Science.gov (United States)

    Dzodzomenyo, Samuel; Stolfi, Adrienne; Splaingard, Deborah; Earley, Elizabeth; Onadeko, Oluwole; Splaingard, Mark

    2015-01-01

    Objective: Drugs can influence results of multiple sleep latency tests (MSLT). We sought to identify the effect of marijuana on MSLT results in pediatric patients evaluated for excessive daytime sleepiness (EDS). Methods: This is a retrospective study of urine drug screens performed the morning before MSLT in 383 patients narcolepsy, 0% consistent with idiopathic hypersomnia, 29% other, and 29% normal. This was statistically different from those with (−) screens (24% narcolepsy, 20% idiopathic hypersomnia, 6% other, 50% normal), and those (+) for drugs other than THC (17% narcolepsy, 33% idiopathic hypersomnia, 4% other, 46% normal (p = 0.01). Six percent (6/93) of patients with MSLT findings consistent with narcolepsy were drug screen (+) for THC; 71% of patients with drug screen (+) for THC had multiple sleep onset REM periods (SOREMS). There were no (+) urine drug screens in patients Many pediatric patients with (+) urine drug screens for THC met MSLT criteria for narcolepsy or had multiple SOREMs. Drug screening is important in interpreting MSLT findings for children ≥ 13 years. Citation: Dzodzomenyo S, Stolfi A, Splaingard D, Earley E, Onadeko O, Splaingard M. Urine toxicology screen in multiple sleep latency test: the correlation of positive tetrahydrocannabinol, drug negative patients, and narcolepsy. J Clin Sleep Med 2015;11(2):93–99. PMID:25348245

  7. Δ⁹Tetrahydrocannabinol impairs visuo-spatial associative learning and spatial working memory in rhesus macaques.

    Science.gov (United States)

    Taffe, Michael A

    2012-10-01

    Cannabis remains the most commonly abused illicit drug and is rapidly expanding in quasi-licit use in some jurisdictions under medical marijuana laws. Effects of the psychoactive constituent Δ⁹tetrahydrocannabinol (Δ⁹THC) on cognitive function remain of pressing concern. Prior studies in monkeys have not shown consistent evidence of memory-specific effects of Δ⁹THC on recognition tasks, and it remains unclear to what extent Δ⁹THC causes sedative versus specific cognitive effects. In this study, adult male rhesus monkeys were trained on tasks which assess spatial working memory, visuo-spatial associative memory and learning as well as motivation for food reward. Subjects were subsequently challenged with 0.1-0.3 mg/kg Δ⁹THC, i.m., in randomized order and evaluated on the behavioral measures. The performance of both vsPAL and SOSS tasks was impaired by Δ⁹THC in a dose and task-difficulty dependent manner. It is concluded that Δ⁹THC disrupts cognition in a way that is consistent with a direct effect on memory. There was evidence for interference with spatial working memory, visuo-spatial associative memory and incremental learning in the latter task. These results and the lack of specific effect of Δ⁹THC in prior visual recognition studies imply a sensitivity of spatial memory processing and/or working memory to endocannabinoid perturbation.

  8. Chronic adolescent exposure to Δ-9-tetrahydrocannabinol in COMT mutant mice: impact on psychosis-related and other phenotypes.

    Science.gov (United States)

    O'Tuathaigh, Colm M P; Hryniewiecka, Magdalena; Behan, Aine; Tighe, Orna; Coughlan, Catherine; Desbonnet, Lieve; Cannon, Mary; Karayiorgou, Maria; Gogos, Joseph A; Cotter, David R; Waddington, John L

    2010-10-01

    Cannabis use confers a two-fold increase in the risk for psychosis, with adolescent use conferring even greater risk. A high-low activity catechol-O-methyltransferase (COMT) polymorphism may modulate the effects of adolescent Δ-9-tetrahydrocannabinol (THC) exposure on the risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with THC (4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32-52) or adulthood (PDs 70-90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis: exploratory activity, spatial working memory (spontaneous and delayed alternation), object recognition memory, social interaction (sociability and social novelty preference), and anxiety (elevated plus maze). Adolescent THC administration induced a larger increase in exploratory activity, greater impairment in spatial working memory, and a stronger anti-anxiety effect in COMT knockouts than in wild types, primarily among males. No such effects of selective adolescent THC administration were evident for other behaviors. Both object recognition memory and social novelty preference were disrupted by either adolescent or adult THC administration, independent of genotype. The COMT genotype exerts specific modulation of responsivity to chronic THC administration during adolescence in terms of exploratory activity, spatial working memory, and anxiety. These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype.

  9. Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway

    Science.gov (United States)

    Tortoriello, Giuseppe; Morris, Claudia V; Alpar, Alan; Fuzik, Janos; Shirran, Sally L; Calvigioni, Daniela; Keimpema, Erik; Botting, Catherine H; Reinecke, Kirstin; Herdegen, Thomas; Courtney, Michael; Hurd, Yasmin L; Harkany, Tibor

    2014-01-01

    Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ9-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor-driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N-terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring. PMID:24469251

  10. An on-line stacking capillary electrophoresis method for the analysis of Δ(9)-tetrahydrocannabinol and its metabolites.

    Science.gov (United States)

    Cheng, Hui-Ling; Tsai, Yi-Hsuan; Hsu, Wan-Ling; Lin, Yi-Hui

    2015-12-24

    The objective of this study was to establish a practical and reliable analytical method for monitoring trace amounts of Δ(9)-tetrahydrocannabinol (THC) and its metabolites in biological samples. A novel on-line preconcentration capillary electrophoresis method combining large volume sample injection, anion selective exhaustive injection and sweeping was developed to enhance analytical sensitivity. A background buffer composed with 30mM phosphate buffer (pH 2.5) containing 40% methanol and 100mM SDS was used to suppress the electroosmotic flow of the uncoated fused silica capillary (40cm×50μm i.d.). High conductivity buffer (200mM phosphate, pH 2.5) was injected for analyte accumulation. The samples, prepared in phosphate buffer or Tris buffer, were introduced by hydrodynamic injection and electrokinetic injection. After sweeping, the separation was performed in micellar electrokinetic chromatography (MEKC) mode at -15kV. During the method validation, the coefficient of determination of the regression curve was measured at greater than 0.993, and the relative standard deviation and relative error were lower than 11.06% and 9.24%, respectively. Under optimized conditions, an improvement of up to 2000-fold higher sensitivity was achieved. This method was applied to the analysis of urine samples, indicating that it could be satisfactorily utilized in the toxicological and clinical monitoring of cannabis. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Δ9-Tetrahydrocannabinol Suppresses Secretion of IFNα by Plasmacytoid Dendritic Cells From Healthy and HIV-Infected Individuals.

    Science.gov (United States)

    Henriquez, Joseph E; Rizzo, Michael D; Schulz, Matthias A; Crawford, Robert B; Gulick, Peter; Kaminski, Norbert E

    2017-08-15

    Plasmacytoid dendritic cells (pDCs) play a crucial role in host antiviral immune response through secretion of type I interferon. Interferon alpha (IFNα), a type I IFN, is critical for mounting the initial response to viral pathogens. A consequence of Human Immunodeficiency Virus-1 (HIV) infection is a decrease in both pDC number and function, but prolonged pDC activity has been linked with progression from HIV infection to the development of AIDS. Patients with HIV in the United States routinely use cannabinoid-based therapies to combat the side effects of HIV infection and antiretroviral therapy. However, cannabinoids, including Δ-tetrahydrocannabinol (THC), are well-characterized immunosuppressants. Here, we report that THC suppressed secretion of IFNα by pDC from both healthy and HIV+ donors through a mechanism involving impaired phosphorylation of interferon regulatory factor 7. These results suggest that THC can suppress pDC function during the early host antiviral response by dampening pDC activation.

  12. Tolerance to Effects of High-Dose Oral Δ9-Tetrahydrocannabinol and Plasma Cannabinoid Concentrations in Male Daily Cannabis Smokers

    Science.gov (United States)

    Gorelick, David A.; Goodwin, Robert S.; Schwilke, Eugene; Schwope, David M.; Darwin, William D.; Kelly, Deanna L.; McMahon, Robert P.; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A.

    2013-01-01

    Oral cannabinoids are taken for medicinal or recreational purposes, yet little is known about tolerance to their effects after high-dose extended exposure. The development of tolerance to effects of around-the-clock oral synthetic Δ9-tetrahydrocannabinol (THC) (20 mg every 3.5–6 h) was evaluated in 13 healthy male daily cannabis smokers residing on a secure research unit: 40 mg on Day 1; 100 mg on Days 2–4; 120 mg on Days 5–6. Systolic and diastolic blood pressure (BP), heart rate, and symptoms of subjective intoxication (100 mm visual-analogue scales, VAS) were assessed the morning of Day 1 (before any oral THC), and on Days 2, 4 and 6, every 30 min for 3 h after the first morning THC dose. Morning subjective intoxication ratings increased from Days 1 to 2, and then declined on Days 4 and 6. The morning THC dose increased intoxication ratings on Day 2, but had less effect on Days 4 and 6, a pattern consistent with tolerance. THC lowered BP and increased heart rate over the six days. Plasma THC and 11-OH-THC concentrations increased significantly over the first five days of dosing. Six days of around-the-clock, oral THC produced tolerance to subjective intoxication, but not to cardiovascular effects. PMID:23074216

  13. Δ9-Tetrahydrocannabinol reverses TNFα-induced increase in airway epithelial cell permeability through CB2 receptors.

    Science.gov (United States)

    Shang, Valerie C M; Kendall, David A; Roberts, Richard E

    2016-11-15

    Despite pharmacological treatment, bronchial hyperresponsiveness continues to deteriorate as airway remodelling persists in airway inflammation. Previous studies have demonstrated that the phytocannabinoid Δ9-tetrahydrocannabinol (THC) reverses bronchoconstriction with an anti-inflammatory action. The aim of this study was to investigate the effects of THC on bronchial epithelial cell permeability after exposure to the pro-inflammatory cytokine, TNFα. Calu-3 bronchial epithelial cells were cultured at air-liquid interface. Changes in epithelial permeability were measured using Transepithelial Electrical Resistance (TEER), then confirmed with a paracellular permeability assay and expression of tight junction proteins by Western blotting. Treatment with THC prevented the TNFα-induced decrease in TEER and increase in paracellular permeability. Cannabinoid CB1 and CB2 receptor-like immunoreactivity was found in Calu-3 cells. Subsequent experiments revealed that pharmacological blockade of CB2, but not CB1 receptor inhibited the THC effect. Selective stimulation of CB2 receptors displayed a similar effect to that of THC. TNFα decreased expression of the tight junction proteins occludin and ZO-1, which was prevented by pre-incubation with THC. These data indicate that THC prevents cytokine-induced increase in airway epithelial permeability through CB2 receptor activation. This highlights that THC, or other cannabinoid receptor ligands, could be beneficial in the prevention of inflammation-induced changes in airway epithelial cell permeability, an important feature of airways diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Human urinary excretion profile after smoking and oral administration of ( sup 14 C)delta 1-tetrahydrocannabinol

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    Johansson, E.; Gillespie, H.K.; Halldin, M.M. (BMC, Uppsala (Sweden))

    1990-05-01

    The urinary excretion profiles of delta 1-tetrahydrocannabinol (delta 1-THC) metabolites have been evaluated in two chronic and two naive marijuana users after smoking and oral administration of ({sup 14}C)delta 1-THC. Urine was collected for five days after each administration route and analyzed for total delta 1-THC metabolites by radioactivity determination, for delta 1-THC-7-oic acid by high-performance liquid chromatography, and for cross-reacting cannabinoids by the EMIT d.a.u. cannabinoid assay. The average urinary excretion half-life of {sup 14}C-labeled delta 1-THC metabolites was calculated to be 18.2 +/- 4.9 h (+/- SD). The excretion profiles of delta 1-THC-7-oic acid and EMIT readings were similar to the excretion profile of {sup 14}C-labeled metabolites in the naive users. However, in the chronic users the excretion profiles of delta 1-THC-7-oic acid and EMIT readings did not resemble the radioactive excretion due to the heavy influence from previous Cannabis use. Between 8-14% of the radioactive dose was recovered in the urine in both user groups after oral administration. Lower urinary recovery was obtained both in the chronic and naive users after smoking--5 and 2%, respectively.

  15. Role of vasopressin V1a receptor in ∆9-tetrahydrocannabinol-induced cataleptic immobilization in mice.

    Science.gov (United States)

    Egashira, Nobuaki; Koushi, Emi; Myose, Takayuki; Tanoue, Akito; Mishima, Kenichi; Tsuchihashi, Ryota; Kinjo, Junei; Tanaka, Hiroyuki; Morimoto, Satoshi; Iwasaki, Katsunori

    2017-12-01

    Cannabis is a widely used illicit substance. ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to cause catalepsy in rodents. Recent studies have shown that vasopressin V1a and V1b receptors are widely distributed in the central nervous system and are capable of influencing a wide variety of brain functions such as social behavior, emotionality, and learning and memory. The present study was designed to examine the possible involvement of V1a and V1b receptors in THC-induced catalepsy-like immobilization. The induction of catalepsy following treatment with THC (10 mg/kg, i.p.) or haloperidol (1 mg/kg, i.p.) was evaluated in wild-type (WT), V1a receptor knockout (V1aRKO), and V1b receptor knockout (V1bRKO) mice. The effect of treatment with the selective 5-hydroxytryptamine1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.) on THC-induced catalepsy was also evaluated in V1aRKO mice. Moreover, the effects of the V1a receptor antagonist VMAX-357 and the V1b receptor antagonist ORG-52186 on THC-induced catalepsy were evaluated in ddY mice. THC and haloperidol markedly caused catalepsy in V1bRKO mice as well as in WT mice. However, V1aRKO mice exhibited a reduction in catalepsy induced by THC but not by haloperidol. WAY100635 dramatically enhanced THC-induced catalepsy in V1aRKO mice. Although VMAX-357 (10 mg/kg, p.o.) but not ORG-52186 significantly attenuated THC-induced catalepsy, it had no significant effect on the enhancement of THC-induced catalepsy by WAY100635 in ddY mice. These findings suggest that V1a receptor regulates THC-induced catalepsy-like immobilization.

  16. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

    Science.gov (United States)

    Elmes, Matthew W; Kaczocha, Martin; Berger, William T; Leung, KwanNok; Ralph, Brian P; Wang, Liqun; Sweeney, Joseph M; Miyauchi, Jeremy T; Tsirka, Stella E; Ojima, Iwao; Deutsch, Dale G

    2015-04-03

    Δ(9)-Tetrahydrocannabinol (THC) and cannabidiol (CBD) occur naturally in marijuana (Cannabis) and may be formulated, individually or in combination in pharmaceuticals such as Marinol or Sativex. Although it is known that these hydrophobic compounds can be transported in blood by albumin or lipoproteins, the intracellular carrier has not been identified. Recent reports suggest that CBD and THC elevate the levels of the endocannabinoid anandamide (AEA) when administered to humans, suggesting that phytocannabinoids target cellular proteins involved in endocannabinoid clearance. Fatty acid-binding proteins (FABPs) are intracellular proteins that mediate AEA transport to its catabolic enzyme fatty acid amide hydrolase (FAAH). By computational analysis and ligand displacement assays, we show that at least three human FABPs bind THC and CBD and demonstrate that THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Furthermore, we show that in contrast to rodent FAAH, CBD does not inhibit the enzymatic actions of human FAAH, and thus FAAH inhibition cannot account for the observed increase in circulating AEA in humans following CBD consumption. Using computational molecular docking and site-directed mutagenesis we identify key residues within the active site of FAAH that confer the species-specific sensitivity to inhibition by CBD. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. These data shed light on the mechanism of action of CBD in modulating the endocannabinoid tone in vivo and may explain, in part, its reported efficacy toward epilepsy and other neurological disorders. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Neural correlates of interactions between cannabidiol and Δ9‐tetrahydrocannabinol in mice: implications for medical cannabis

    Science.gov (United States)

    Todd, S M

    2015-01-01

    Background and Purpose It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ9‐tetrahydrocannabinol (THC) to cannabidiol (CBD), as CBD reduces the adverse psychotropic effects of THC. However, our understanding of CBD and THC interactions is limited and the brain circuitry mediating interactions between CBD and THC are unknown. The aim of this study was to investigate whether CBD modulated the functional effects and c‐Fos expression induced by THC, using a 1:1 dose ratio that approximates therapeutic strains of cannabis and nabiximols. Experimental Approach Male C57BL/6 mice were treated with vehicle, CBD, THC or a combination of CBD and THC (10 mg·kg−1 i.p. for both cannabinoids) to examine effects on locomotor activity, anxiety‐related behaviour, body temperature and brain c‐Fos expression (a marker of neuronal activation). Key Results CBD potentiated THC‐induced locomotor suppression but reduced the hypothermic and anxiogenic effects of THC. CBD alone had no effect on these measures. THC increased brain activation as measured by c‐Fos expression in 11 of the 35 brain regions studied. CBD co‐administration suppressed THC‐induced c‐Fos expression in six of these brain regions. This effect was most pronounced in the medial preoptic nucleus and lateral periaqueductal gray. Treatment with CBD alone diminished c‐Fos expression only in the central nucleus of the amygdala compared with vehicle. Conclusions and Implications These data confirm that CBD modulated the pharmacological actions of THC and provide new information regarding brain regions involved in the interaction between CBD and THC. PMID:26377899

  18. Psychomotor performance in relation to acute oral administration of Delta9-tetrahydrocannabinol and standardized cannabis extract in healthy human subjects.

    Science.gov (United States)

    Roser, Patrik; Gallinat, Jürgen; Weinberg, Gordon; Juckel, Georg; Gorynia, Inge; Stadelmann, Andreas M

    2009-08-01

    Abnormalities in psychomotor performance are a consistent finding in schizophrenic patients as well as in chronic cannabis users. The high levels of central cannabinoid (CB(1)) receptors in the basal ganglia, the cerebral cortex and the cerebellum indicate their implication in the regulation of motor activity. Based on the close relationship between cannabis use, the endogenous cannabinoid system and motor disturbances found in schizophrenia, we expected that administration of cannabinoids may change pattern of psychomotor activity like in schizophrenic patients. This prospective, double-blind, placebo-controlled cross-over study investigated the acute effects of cannabinoids on psychomotor performance in 24 healthy right-handed volunteers (age 27.9 +/- 2.9 years, 12 male) by comparing Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and standardized cannabis extract containing Delta(9)-THC and cannabidiol. Psychomotor performance was assessed by using a finger tapping test series. Cannabis extract, but not Delta(9)-THC, revealed a significant reduction of right-hand tapping frequencies that was also found in schizophrenia. As to the pure Delta(9)-THC condition, left-hand tapping frequencies were correlated with the plasma concentrations of the Delta(9)-THC metabolite 11-OH-THC. These effects are thought to be related to cannabinoid actions on CB(1) receptors in the basal ganglia, the cerebral cortex and the cerebellum. Our data further demonstrate that acute CB(1) receptor activation under the cannabis extract condition may also affect intermanual coordination (IMC) as an index of interhemispheric transfer. AIR-Scale scores as a measure of subjective perception of intoxication were dose-dependently related to IMC which was shown by an inverted U-curve. This result may be due to functional changes involving GABAergic and glutamatergic neurotransmission within the corpus callosum.

  19. A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice.

    Science.gov (United States)

    Long, Leonora E; Chesworth, Rose; Huang, Xu-Feng; McGregor, Iain S; Arnold, Jonathon C; Karl, Tim

    2010-08-01

    Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Delta9-tetrahydrocannabinol (Delta9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Delta9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Delta9-THC produced the classic cannabinoid CB1 receptor-mediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, Delta9-THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open-field and light-dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light-dark test at a low dose (1 mg/kg). Acute and chronic Delta9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with Delta9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic Delta9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic-like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats.

  20. The combination of cannabidiol and Δ9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model.

    Science.gov (United States)

    Scott, Katherine A; Dalgleish, Angus G; Liu, Wai M

    2014-12-01

    High-grade glioma is one of the most aggressive cancers in adult humans and long-term survival rates are very low as standard treatments for glioma remain largely unsuccessful. Cannabinoids have been shown to specifically inhibit glioma growth as well as neutralize oncogenic processes such as angiogenesis. In an attempt to improve treatment outcome, we have investigated the effect of Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) both alone and in combination with radiotherapy in a number of glioma cell lines (T98G, U87MG, and GL261). Cannabinoids were used in two forms, pure (P) and as a botanical drug substance (BDS). Results demonstrated a duration- and dose-dependent reduction in cell viability with each cannabinoid and suggested that THC-BDS was more efficacious than THC-P, whereas, conversely, CBD-P was more efficacious than CBD-BDS. Median effect analysis revealed all combinations to be hyperadditive [T98G 48-hour combination index (CI) at FU50, 0.77-1.09]. Similarly, pretreating cells with THC-P and CBD-P together for 4 hours before irradiation increased their radiosensitivity when compared with pretreating with either of the cannabinoids individually. The increase in radiosensitivity was associated with an increase in markers of autophagy and apoptosis. These in vitro results were recapitulated in an orthotopic murine model for glioma, which showed dramatic reductions in tumor volumes when both cannabinoids were used with irradiation (day 21: 5.5 ± 2.2 mm(3) vs. 48.7 ± 24.9 mm(3) in the control group; P < 0.01). Taken together, our data highlight the possibility that these cannabinoids can prime glioma cells to respond better to ionizing radiation, and suggest a potential clinical benefit for glioma patients by using these two treatment modalities. ©2014 American Association for Cancer Research.

  1. Δ9-tetrahydrocannabinol suppresses cytotoxic T lymphocyte function independent of CB1 and CB 2, disrupting early activation events.

    Science.gov (United States)

    Karmaus, Peer W F; Chen, Weimin; Kaplan, Barbara L F; Kaminski, Norbert E

    2012-12-01

    Previously, CD8(+) T cells were found to be a sensitive target for suppression by Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in a murine model of influenza infection. To study the effect of Δ(9)-THC on CD8(+) cytotoxic T lymphocytes (CTL), an allogeneic model of MHC I mismatch was used to elicit CTL. In addition, to determine the requirement for the cannabinoid receptors 1 (CB(1)) and 2 (CB(2)) in Δ(9)-THC-mediated CTL response modulation, mice null for both receptors were used (CB(1) (-/-)CB(2) (-/-)). Δ(9)-THC suppressed CTL function independent of CB(1) and CB(2) as evidenced by reduction of (51)Cr release by CTL generated from CB(1) (-/-)CB(2) (-/-) mice. Furthermore, viability in CD4(+) and CD8(+) cells was reduced in a concentration-dependent manner with Δ(9)-THC, independent of CB(1) and CB(2), but no effect of Δ(9)-THC on proliferation was observed, suggesting that Δ(9)-THC decreases the number of T cells initially activated. Δ(9)-THC increased expression of the activation markers, CD69 in CD8(+) cells and CD25 in CD4(+) cells in a concentration-dependent manner in cells derived from WT and CB(1) (-/-)CB(2) (-/-) mice. Furthermore, Δ(9)-THC synergized with the calcium ionophore, ionomycin, to increase CD69 expression on both CD4(+) and CD8(+) cells. In addition, without stimulation, Δ(9)-THC increased CD69 expression in CD8(+) cells from CB(1) (-/-)CB(2) (-/-) and WT mice. Overall, these results suggest that CB(1) and CB(2) are dispensable for Δ(9)-THC-mediated suppression and that perturbation of Ca(2+) signals during T cell activation plays an important role in the mechanism by which Δ(9)-THC suppresses CTL function.

  2. Single-dose pharmacokinetics and tolerability of oral delta-9- tetrahydrocannabinol in patients with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Joerger, Markus; Wilkins, Justin; Fagagnini, Stefania; Baldinger, Reto; Brenneisen, Rudolf; Schneider, Ursula; Goldman, Bea; Weber, Markus

    2012-06-01

    Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS). We assessed the pharmacokinetics (PK) and tolerability of delta-9-tetrahydrocannabinol (THC) in ALS patients. Nine patients received THC single oral doses of 5mg and 10mg, separated by a wash-out period of two weeks. Blood samples for the determination of THC, 11-nor-9-carboxy-THC (THC-COOH) and hydroxy-THC (THC-OH) were taken up to 8 hours after intake. Adverse events were assessed by visual analogue scales (VAS). Plasma concentrations of the active metabolite THC-OH were submitted to sequential pharmacokinetic-pharmacodynamic population modeling on individual heart rate as a proxy for THC's cardiovasculatory effects. Drowsiness, euphoria, orthostasis, sleepiness, vertigo and weakness were significantly more frequent in patients receiving 10mg compared to 5 mg THC. A marked interindividual variability was found for the absorption of oral THC (84%) and elimination of THC-COOH (45%). PK data did not support any clinically relevant deviation from linear PK in the investigated range of concentrations. Plasma concentrations of THC-OH were positively correlated with the individual heart rate. An E(max-model) was successfully fitted to individual heart rate, with a THC-OH plasma concentration of 3.2 x 10(-4) μmol/L for EC(50) and an E(max) of 93 bpm for heart rate. The higher 10mg dose of THC was dose-limiting in patients with ALS. High interindividual PK variability requires individuell titration of THC for potential therapeutic use in patients with ALS.

  3. A protocol for the delivery of cannabidiol (CBD) and combined CBD and ∆9-tetrahydrocannabinol (THC) by vaporisation.

    Science.gov (United States)

    Solowij, Nadia; Broyd, Samantha J; van Hell, Hendrika H; Hazekamp, Arno

    2014-10-16

    Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids. Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally. We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in combination with ∆9-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials and emulate smoked cannabis. Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad in a Volcano vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg CBD to be the highest dose effectively vaporised at 230 ° C, yielding an availability of approximately 40% in the vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg CBD was loaded together with 8 mg of THC. THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the availability of high dose CBD impacted upon the availability of THC when co-administered, with each compound affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised protocols that enable delivery of 160 mg CBD through vaporisation. While THC administration by vaporisation is increasingly adopted in experimental studies, often with oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance that may inform methodology for clinical trials in humans, especially for examining interactions between THC and CBD and for therapeutic applications of CBD. Current Controlled Trials ISRCTN24109245.

  4. Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

    Science.gov (United States)

    Bossong, Matthijs G; Mehta, Mitul A; van Berckel, Bart N M; Howes, Oliver D; Kahn, René S; Stokes, Paul R A

    2015-08-01

    Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results. The objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants. We combined human neurochemical imaging data from two previous studies that used [(11)C]raclopride positron emission tomography (PET) (n = 7 and n = 13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis. THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 ± 0.26 to 2.30 ± 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions. In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

  5. Multifractal analysis of information processing in hippocampal neural ensembles during working memory under Δ⁹-tetrahydrocannabinol administration.

    Science.gov (United States)

    Fetterhoff, Dustin; Opris, Ioan; Simpson, Sean L; Deadwyler, Sam A; Hampson, Robert E; Kraft, Robert A

    2015-04-15

    Multifractal analysis quantifies the time-scale-invariant properties in data by describing the structure of variability over time. By applying this analysis to hippocampal interspike interval sequences recorded during performance of a working memory task, a measure of long-range temporal correlations and multifractal dynamics can reveal single neuron correlates of information processing. Wavelet leaders-based multifractal analysis (WLMA) was applied to hippocampal interspike intervals recorded during a working memory task. WLMA can be used to identify neurons likely to exhibit information processing relevant to operation of brain-computer interfaces and nonlinear neuronal models. Neurons involved in memory processing ("Functional Cell Types" or FCTs) showed a greater degree of multifractal firing properties than neurons without task-relevant firing characteristics. In addition, previously unidentified FCTs were revealed because multifractal analysis suggested further functional classification. The cannabinoid type-1 receptor (CB1R) partial agonist, tetrahydrocannabinol (THC), selectively reduced multifractal dynamics in FCT neurons compared to non-FCT neurons. WLMA is an objective tool for quantifying the memory-correlated complexity represented by FCTs that reveals additional information compared to classification of FCTs using traditional z-scores to identify neuronal correlates of behavioral events. z-Score-based FCT classification provides limited information about the dynamical range of neuronal activity characterized by WLMA. Increased complexity, as measured with multifractal analysis, may be a marker of functional involvement in memory processing. The level of multifractal attributes can be used to differentially emphasize neural signals to improve computational models and algorithms underlying brain-computer interfaces. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Effects of chronic Δ9-tetrahydrocannabinol treatment on Rho/Rho-kinase signalization pathway in mouse brain

    Directory of Open Access Journals (Sweden)

    Halil Mahir Kaplan

    2017-11-01

    Full Text Available Δ9-Tetrahydrocannabinol (Δ9-THC shows its effects by activating cannabinoid receptors which are on some tissues and neurons. Cannabinoid systems have role on cell proliferation and development of neurons. Furthermore, it is interesting that cannabinoid system and rho/rho-kinase signalization pathway, which have important role on cell development and proliferation, may have role on neuron proliferation and development together. Thus, a study is planned to investigate rhoA and rho-kinase enzyme expressions and their activities in the brain of chronic Δ9-THC treated mice. One group of mice are treated with Δ9-THC once to see effects of acute treatment. Another group of mice are treated with Δ9-THC three times per day for one month. After this period, rhoA and rho-kinase enzyme expressions and their activities in mice brains are analyzed by ELISA method. Chronic administration of Δ9-THC decreased the expression of rhoA while acute treatment has no meaningful effect on it. Administration of Δ9-THC did not affect expression of rho-kinase on both chronic and acute treatment. Administration of Δ9-THC increased rho-kinase activity on both chronic and acute treatment, however, chronic treatment decreased its activity with respect to acute treatment. This study showed that chronic Δ9-THC treatment down-regulated rhoA expression and did not change the expression level of rho-kinase which is downstream effector of rhoA. However, it elevated the rho-kinase activity. Δ9-THC induced down-regulation of rhoA may cause elevation of cypin expression and may have benefit on cypin related diseases. Furthermore, use of rho-kinase inhibitors and Δ9-THC together can be useful on rho-kinase related diseases.

  7. Chronic Δ9-Tetrahydrocannabinol Administration May Not Attenuate Simian Immunodeficiency Virus Disease Progression in Female Rhesus Macaques

    Science.gov (United States)

    Amedee, Angela M.; Nichols, Whitney A.; LeCapitaine, Nicole J.; Stouwe, Curtis Vande; Birke, Leslie L.; Lacour, Nedra; Winsauer, Peter J.

    2014-01-01

    Abstract Persons living with HIV/AIDS (PLWHA) frequently use cannabinoids, either recreationally by smoking marijuana or therapeutically (delta-9-tetrahydrocannabinol; Δ9-THC dronabinol). Previously, we demonstrated that chronic Δ9-THC administration decreases early mortality in male simian immunodeficiency virus (SIV)-infected macaques. In this study, we sought to examine whether similar protective effects resulted from chronic cannabinoid administration in SIV-infected female rhesus macaques. Clinical and viral parameters were evaluated in eight female rhesus macaques that received either Δ9-THC (0.18–0.32 mg/kg, intramuscularly, twice daily) or vehicle (VEH) starting 28 days prior to intravenous inoculation with SIVmac251. SIV disease progression was assessed by changes in body weight, mortality, viral levels in plasma and mucosal sites, and lymphocyte subsets. In contrast to our results in male animals, chronic Δ9-THC did not protect SIV-infected female rhesus macaques from early mortality. Markers of SIV disease, including viral load and CD4+/CD8+ ratio, were not altered by Δ9-THC compared to control females; however, females that received chronic Δ9-THC did not gain as much weight as control animals. In addition, Δ9-THC administration increased total CXCR4 expression in both peripheral and duodenal CD4+ and CD8+ T lymphocytes prior to SIV inoculation. Although protection from early mortality was not evident, chronic Δ9-THC did not affect clinical markers of SIV disease progression. The contrasting effects of chronic Δ9-THC in males versus females remain to be explained, but highlight the need for further studies to explore the sex-dependent effects of Δ9-THC and other cannabinoids on the HIV disease course and their implications for virus transmission. PMID:25113915

  8. The psychosis-like effects of Δ(9)-tetrahydrocannabinol are associated with increased cortical noise in healthy humans.

    Science.gov (United States)

    Cortes-Briones, Jose A; Cahill, John D; Skosnik, Patrick D; Mathalon, Daniel H; Williams, Ashley; Sewell, R Andrew; Roach, Brian J; Ford, Judith M; Ranganathan, Mohini; D'Souza, Deepak Cyril

    2015-12-01

    Drugs that induce psychosis may do so by increasing the level of task-irrelevant random neural activity or neural noise. Increased levels of neural noise have been demonstrated in psychotic disorders. We tested the hypothesis that neural noise could also be involved in the psychotomimetic effects of delta-9-tetrahydrocannabinol (Δ(9)-THC), the principal active constituent of cannabis. Neural noise was indexed by measuring the level of randomness in the electroencephalogram during the prestimulus baseline period of an oddball task using Lempel-Ziv complexity, a nonlinear measure of signal randomness. The acute, dose-related effects of Δ(9)-THC on Lempel-Ziv complexity and signal power were studied in humans (n = 24) who completed 3 test days during which they received intravenous Δ(9)-THC (placebo, .015 and .03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Δ(9)-THC increased neural noise in a dose-related manner. Furthermore, there was a strong positive relationship between neural noise and the psychosis-like positive and disorganization symptoms induced by Δ(9)-THC, which was independent of total signal power. Instead, there was no relationship between noise and negative-like symptoms. In addition, Δ(9)-THC reduced total signal power during both active drug conditions compared with placebo, but no relationship was detected between signal power and psychosis-like symptoms. At doses that produced psychosis-like effects, Δ(9)-THC increased neural noise in humans in a dose-dependent manner. Furthermore, increases in neural noise were related with increases in Δ(9)-THC-induced psychosis-like symptoms but not negative-like symptoms. These findings suggest that increases in neural noise may contribute to the psychotomimetic effects of Δ(9)-THC. Published by Elsevier Inc.

  9. Oral fluid cannabinoids in chronic cannabis smokers during oral Δ9-tetrahydrocannabinol therapy and smoked cannabis challenge

    Science.gov (United States)

    Lee, Dayong; Vandrey, Ryan; Mendu, Damodara R.; Anizan, Sebastien; Milman, Garry; Murray, Jeannie A.; Barnes, Allan J.; Huestis, Marilyn A.

    2014-01-01

    BACKGROUND Oral Δ9-tetrahydrocannabinol (THC) is effective for attenuating cannabis withdrawal and may benefit treatment of cannabis use disorders. Oral fluid (OF) cannabinoid testing, increasing in forensic and workplace settings, could be valuable for monitoring during cannabis treatment. METHODS Eleven cannabis smokers resided on a closed research unit for 51 days, and received daily 0, 30, 60, and 120 mg oral THC in divided doses for 5 days. There was a 5-puff smoked cannabis challenge on the 5th day. Each medication session was separated by 9 days of ad libitum cannabis smoking. OF was collected the evening prior to and throughout oral THC sessions and analyzed by 2-dimensional GC-MS for THC, cannabidiol (CBD), cannabinol (CBN), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). RESULTS During all oral THC administrations, THC OF concentrations decreased to ≤78.2, 33.2, and 1.4 μg/L by 24, 48, and 72h, respectively. CBN also decreased over time with concentrations 10-fold lower than THC, with none detected beyond 69h. CBD and 11-OH-THC were rarely detected, only within 19 and 1.6h post smoking, respectively. THCCOOH OF concentrations were dose-dependent and increased over time during 120 mg THC dosing. After cannabis smoking, THC, CBN, and THCCOOH concentrations showed a significant dose-effect and decreased significantly over time. CONCLUSIONS Oral THC dosing significantly affected OF THCCOOH but minimally contributed to THC OF concentrations; prior ad libitum smoking was the primary source of THC, CBD and CBN. Higher cannabinoid concentrations following active oral THC administrations versus placebo suggest a compensatory effect of THC tolerance on smoking topography. PMID:23938457

  10. Sex differences in Δ(9)-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats.

    Science.gov (United States)

    Wiley, Jenny L; Burston, James J

    2014-07-25

    Mechanisms that may underlie age and sex differences in the pharmacological effects of cannabinoids are relatively unexplored. The purpose of the present study was to determine whether sex differences in metabolism of Δ(9)-tetrahydrocannabinol (THC), similar to those observed previously in adult rats, also occurred in adolescent rats and might contribute to age and sex differences in its in vivo pharmacology. Male and female adolescent rats were exposed to THC acutely or repeatedly for 10 days. Subsequently, some of the rats were sacrificed and blood and brain levels of THC and one of its metabolites, 11-hydroxy-Δ(9)-THC (11-OH-THC), were measured. Other rats were evaluated in a battery of in vivo tests that are sensitive to cannabinoids. Concentrations of 11-OH-THC in the brains of female adult and adolescent rats exceeded those observed in male conspecifics, particularly after repeated THC administration. In contrast, brain levels of THC did not differ between the sexes. In vivo, acute THC produced dose-related hypothermia, catalepsy and suppression of locomotion in adolescent rats of both sexes, with tolerance developing after repeated administration. With a minor exception, sex differences in THC's effects in the in vivo assays were not apparent. Together with previous findings, the present results suggest that sex differences in pharmacokinetics cannot fully explain the patterns of sex differences (and lack of sex differences) in cannabinoid effects across behaviors. Hormonal and/or pharmacodynamic factors are also likely to play a role. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Oral fluid and plasma cannabinoid ratios after around-the-clock controlled oral Δ(9)-tetrahydrocannabinol administration.

    Science.gov (United States)

    Milman, Garry; Schwope, David M; Schwilke, Eugene W; Darwin, William D; Kelly, Deanna L; Goodwin, Robert S; Gorelick, David A; Huestis, Marilyn A

    2011-11-01

    Oral fluid (OF) testing is increasingly important for drug treatment, workplace, and drugged-driving programs. There is interest in predicting plasma or whole-blood concentrations from OF concentrations; however, the relationship between these matrices is incompletely characterized because of few controlled drug-administration studies. Ten male daily cannabis smokers received around-the-clock escalating 20-mg oral Δ(9)-tetrahydrocannabinol (THC, dronabinol) doses (40-120 mg/day) for 8 days. Plasma and OF samples were simultaneously collected before, during, and after dosing. OF THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCCOOH) were quantified by GC-MS at 0.5-μg/L, 0.5-μg/L, and 7.5-ng/L limits of quantification (LOQs), respectively. In plasma, the LOQs were 0.25 μg/L for THC and THCCOOH, and 0.5 μg/L for 11-hydroxy-THC. Despite multiple oral THC administrations each day and increasing plasma THC concentrations, OF THC concentrations generally decreased over time, reflecting primarily previously self-administered smoked cannabis. The logarithms of the THC concentrations in oral fluid and plasma were not significantly correlated (r = -0.10; P = 0.065). The OF and plasma THCCOOH concentrations, albeit with 1000-fold higher concentrations in plasma, increased throughout dosing. The logarithms of OF and plasma THCCOOH concentrations were significantly correlated (r = 0.63; P < 0.001), although there was high interindividual variation. A high OF/plasma THC ratio and a high OF THC/THCCOOH ratio indicated recent cannabis smoking. OF monitoring does not reliably detect oral dronabinol intake. The time courses of THC and THCCOOH concentrations in plasma and OF were different after repeated oral THC doses, and high interindividual variation was observed. For these reasons, OF cannabinoid concentrations cannot predict concurrent plasma concentrations.

  12. Oral Fluid and Plasma Cannabinoid Ratios after Around-the-Clock Controlled Oral Δ9-Tetrahydrocannabinol Administration

    Science.gov (United States)

    Milman, Garry; Schwope, David M.; Schwilke, Eugene W.; Darwin, William D.; Kelly, Deanna L.; Goodwin, Robert S.; Gorelick, David A.; Huestis, Marilyn A.

    2013-01-01

    BACKGROUND Oral fluid (OF) testing is increasingly important for drug treatment, workplace, and drugged-driving programs. There is interest in predicting plasma or whole-blood concentrations from OF concentrations; however, the relationship between these matrices is incompletely characterized because of few controlled drug-administration studies. METHODS Ten male daily cannabis smokers received around-the-clock escalating 20-mg oral Δ9-tetrahydrocannabinol (THC, dronabinol) doses (40–120 mg/day) for 8 days. Plasma and OF samples were simultaneously collected before, during, and after dosing. OF THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCCOOH) were quantified by GC-MS at 0.5-μg/L, 0.5-μg/L, and 7.5-ng/L limits of quantification (LOQs), respectively. In plasma, the LOQs were 0.25 μg/L for THC and THCCOOH, and 0.5 μg/L for 11-hydroxy-THC. RESULTS Despite multiple oral THC administrations each day and increasing plasma THC concentrations, OF THC concentrations generally decreased over time, reflecting primarily previously self-administered smoked cannabis. The logarithms of the THC concentrations in oral fluid and plasma were not significantly correlated (r = −0.10; P = 0.065). The OF and plasma THCCOOH concentrations, albeit with 1000-fold higher concentrations in plasma, increased throughout dosing. The logarithms of OF and plasma THCCOOH concentrations were significantly correlated (r = 0.63; P < 0.001), although there was high interindividual variation. A high OF/plasma THC ratio and a high OF THC/THCCOOH ratio indicated recent cannabis smoking. CONCLUSIONS OF monitoring does not reliably detect oral dronabinol intake. The time courses of THC and THCCOOH concentrations in plasma and OF were different after repeated oral THC doses, and high inter-individual variation was observed. For these reasons, OF cannabinoid concentrations cannot predict concurrent plasma concentrations. PMID:21875944

  13. Acute administration of Δ⁹ tetrahydrocannabinol does not prevent enhancement of sensory gating by clozapine in DBA/2 mice.

    Science.gov (United States)

    Smucny, Jason; Stevens, Karen E; Tregellas, Jason R

    2014-03-01

    Despite high rates of marijuana abuse in schizophrenia, the physiological interactions between tetrahydrocannabinol (THC) and antipsychotic medications are poorly understood. A well-characterized feature of schizophrenia is poor gating of the P50 auditory-evoked potential. This feature has been translationally modeled by the DBA/2 mouse, which exhibits poor suppression of the P20-N40 AEP, the rodent analog of the human P50. Previous work has demonstrated that this deficit is reversed by the antipsychotic clozapine. It is unknown, however, if this effect is altered by THC administration. Using a conditioning-testing paradigm with paired auditory stimuli, the effects of clozapine and dronabinol (a pharmaceutical THC formulation) on inhibitory P20-N40 AEP processing were assessed from in vivo hippocampal CA3 recordings in anesthetized DBA/2 mice. The effects of clozapine (0.33 mg/kg) and dronabinol (10 mg/kg) were assessed alone and in combination (0.33, 1 or 1.83 mg/kg clozapine with 10mg/kg dronabinol). Improved P20-N40 AEP gating was observed after acute administration of 0.33 mg/kg clozapine. Co-injection of 0.33 mg/kg clozapine and 10 mg/kg THC, however, did not improve gating relative to baseline. This effect was overcome by higher doses of clozapine (1 and 1.83 mg/kg), as these doses improved gating relative to baseline in the presence of 10 mg/kg THC. 10 mg/kg THC alone did not affect gating. In conclusion, THC does not prevent improvement of P20-N40 gating by clozapine. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Sex-specific alterations in hippocampal cannabinoid 1 receptor expression following adolescent delta-9-tetrahydrocannabinol treatment in the rat.

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    Silva, Lindsay; Harte-Hargrove, Lauren; Izenwasser, Sari; Frank, Ashley; Wade, Dean; Dow-Edwards, Diana

    2015-08-18

    Marijuana use by adolescents has been on the rise since the early 1990s. With recent legalization and decriminalization acts passed, cannabinoid exposure in adolescents will undoubtedly increase. Human studies are limited in their ability to examine underlying changes in brain biochemistry making rodent models valuable. Studies in adult and adolescent animals show region and sex specific downregulation of the cannabinoid 1 (CB1) receptor following chronic cannabinoid treatment. However, although sex-dependent changes in behavior have been observed during the drug abstinence period following adolescent cannabinoid exposure, little is known about CB1 receptor expression during this critical time. In order to characterize CB1 receptor expression following chronic adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we used [(3)H] CP55,940 binding to assess CB1 receptor expression in the dentate gyrus and areas CA1, CA2, and CA3 of the hippocampus in both male and female adolescent rats at both 24h and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24h post treatment. While this downregulation persisted in both sexes following two weeks of abstinence in the CA2 region, in females, this downregulation also persisted in areas CA1 and CA3. Expression in the dentate gyrus returned to the normal range by two weeks. These data suggest that selective regions of the hippocampus show persistent reductions in CB1 receptor expression and that these reductions are more widespread in female compared to male adolescents. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. Quantitative determination of 11-nor-9-carboxy-tetrahydrocannabinol in hair by column switching LC-ESI-MS(3).

    Science.gov (United States)

    Park, Meejung; Kim, Jihyun; Park, Yuran; In, Sanghwan; Kim, Eunmi; Park, Yonghoon

    2014-02-01

    Hair analysis has been regarded as an alternative method to urine analysis in forensic and criminal cases. Cannabis (marijuana) is one of the most widely used drugs in the world and it has been controlled in South Korea since 1976. Identification of 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH) in hair can be an important proof of cannabis use because it can exclude the possibility of passive cannabis smoke exposure. In this study, we described a quantitative method of THCCOOH in hair using simple liquid-liquid extraction (LLE), selective column switching liquid chromatography with electrospray ionization (ESI)-MS(3). For the column switching system three columns (precolumn, trap column and analytical column) were used. Valve switch from the precolumn to the trap column was set from 3.0 to 4.0 min because THCCOOH appeared around 3.5 min with this precolumn. After 4.0 min the valve was switched to the original position and the analytes in the trap column were eluted onto the analytical column. Resolution occurred in this column and eluted into the ESI-MS(3) system. The internal standard was THCCOOH-d3. We used ESI-negative-MS(3) transition of ions at m/z 343 to 299 to 245 (343/299/245) and m/z 346 to 302 to 248 (346/302/248) for quantification of THCCOOH and THCCOOH-d3, respectively. The validation results of selectivity, matrix effect, recovery, linearity, precision and accuracy, and processed sample stability were satisfactory. The limit of detection (LOD) was 0.05 pg/mg and the limit of quantification (LOQ) was 0.10 pg/mg. The range of concentration of THCCOOH from 98 authentic human hair was 0.13-15.75 pg/mg. This method was successfully applied in the analysis of authentic human hair samples. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Effects of Δ9-tetrahydrocannabinol administration on human encoding and recall memory function: a pharmacological FMRI study.

    Science.gov (United States)

    Bossong, Matthijs G; Jager, Gerry; van Hell, Hendrika H; Zuurman, Lineke; Jansma, J Martijn; Mehta, Mitul A; van Gerven, Joop M A; Kahn, René S; Ramsey, Nick F

    2012-03-01

    Deficits in memory function are an incapacitating aspect of various psychiatric and neurological disorders. Animal studies have recently provided strong evidence for involvement of the endocannabinoid (eCB) system in memory function. Neuropsychological studies in humans have shown less convincing evidence but suggest that administration of cannabinoid substances affects encoding rather than recall of information. In this study, we examined the effects of perturbation of the eCB system on memory function during both encoding and recall. We performed a pharmacological MRI study with a placebo-controlled, crossover design, investigating the effects of Δ9-tetrahydrocannabinol (THC) inhalation on associative memory-related brain function in 13 healthy volunteers. Performance and brain activation during associative memory were assessed using a pictorial memory task, consisting of separate encoding and recall conditions. Administration of THC caused reductions in activity during encoding in the right insula, the right inferior frontal gyrus, and the left middle occipital gyrus and a network-wide increase in activity during recall, which was most prominent in bilateral cuneus and precuneus. THC administration did not affect task performance, but while during placebo recall activity significantly explained variance in performance, this effect disappeared after THC. These findings suggest eCB involvement in encoding of pictorial information. Increased precuneus activity could reflect impaired recall function, but the absence of THC effects on task performance suggests a compensatory mechanism. These results further emphasize the eCB system as a potential novel target for treatment of memory disorders and a promising target for development of new therapies to reduce memory deficits in humans.

  17. Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification: cannabis withdrawal syndrome and its correlation with delta-9-tetrahydrocannabinol and -metabolites in serum.

    Science.gov (United States)

    Bonnet, U; Specka, M; Stratmann, U; Ochwadt, R; Scherbaum, N

    2014-10-01

    To investigate the course of cannabis withdrawal syndrome (CWS) within a controlled inpatient detoxification setting and to correlate severity of CWS with the serum-levels of delta-9-tetrahydrocannabinol (THC) and its main metabolites 11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). Thirty-nine treatment-seeking chronic cannabis dependents (ICD-10) were studied on admission and on abstinent days 2, 4, 8 and 16, using a CWS-checklist (MWC) and the Clinical Global Impression-Severity scale (CGI-S). Simultaneously obtained serum was analysed to its concentration of THC, THC-OH and THC-COOH. MWC peaked on day 4 (10.4 ± 4.6 from 39 points) and declined to 2.9 ± 2.4 points on day 16. Women had a significantly stronger CWS than men. The CWS was dominated by craving>restlessness>nervousness>sleeplessness. CGI-S peaked with 5 out of 7 points. On admission, THC and its metabolites did negatively correlate with the severity of CWS. There was no significant correlation afterwards, no matter if CWS was medicated or not. THC-OH in serum declined most rapidly below detection limit, on median at day 4. At abstinence day 16, the THC-levels of 28.2% of the patients were still above 1g/ml (range: 1.3 to 6.4 ng/ml). CWS increased and then decreased without any correlation between its severity and the serum-levels of THC or its main metabolites after admission. According to the CGI-S, most patients achieved the condition of 'markedly ill'. Serum THC-OH was most clearly associated with recent cannabis use. Residual THC was found in the serum of almost one-third of the patients at abstinence day 16. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Medicinal Δ(9) -tetrahydrocannabinol (dronabinol) impairs on-the-road driving performance of occasional and heavy cannabis users but is not detected in Standard Field Sobriety Tests.

    Science.gov (United States)

    Bosker, Wendy M; Kuypers, Kim P C; Theunissen, Eef L; Surinx, Anke; Blankespoor, Roos J; Skopp, Gisela; Jeffery, Wayne K; Walls, H Chip; van Leeuwen, Cees J; Ramaekers, Johannes G

    2012-10-01

    The acute and chronic effects of dronabinol [medicinal Δ(9) -tetrahydrocannabinol (THC)] on actual driving performance and the Standard Field Sobriety Test (SFST) were assessed. It was hypothesized that occasional users would be impaired on these tests and that heavy users would show less impairment due to tolerance. Double-blind, placebo-controlled, randomized, three-way cross-over study. Twelve occasional and 12 heavy cannabis users (14 males/10 females) received single doses of placebo, 10 and 20 mg dronabinol. Standard deviation of lateral position (SDLP; i.e. weaving) is the primary measure of road-tracking control. Time to speed adaptation (TSA) is the primary reaction-time measure in the car-following test. Percentage of impaired individuals on the SFST and subjective high on a visual analogue scale were secondary measures. Superiority tests showed that SDLP (P = 0.008) and TSA (P = 0.011) increased after dronabinol in occasional users. Equivalence tests demonstrated that dronabinol-induced increments in SDLP were bigger than impairment associated with BAC of 0.5 mg/ml in occasional and heavy users, although the magnitude of driving impairment was generally less in heavy users. The SFST did not discriminate between conditions. Levels of subjective high were comparable in occasional and heavy users. Dronabinol (medicinal tetrahydrocannabinol) impairs driving performance in occasional and heavy users in a dose-dependent way, but to a lesser degree in heavy users due possibly to tolerance. The Standard Field Sobriety Test is not sensitive to clinically relevant driving impairment caused by oral tetrahydrocannabinol. © 2012 The Authors. Addiction © 2012 Society for the Study of Addiction.

  19. Trace detection of tetrahydrocannabinol (THC) with a SERS-based capillary platform prepared by the in situ microwave synthesis of AgNPs.

    Science.gov (United States)

    Yüksel, Sezin; Schwenke, Almut M; Soliveri, Guido; Ardizzone, Silvia; Weber, Karina; Cialla-May, Dana; Hoeppener, Stephanie; Schubert, Ulrich S; Popp, Jürgen

    2016-10-05

    In the present study, an ultra-sensitive and highly reproducible novel SERS-based capillary platform was developed and utilized for the trace detection of tetrahydrocannabinol (THC). The approach combines the advantages of microwave-assisted nanoparticle synthesis, plasmonics and capillary forces. By employing a microwave-assisted preparation method, glass capillaries were reproducibly coated with silver nanoparticles in a batch fabrication process that required a processing time of 3 min without needing to use any pre-surface modifications or add surfactants. The coated capillaries exhibited an excellent SERS activity with a high reproducibility and enabled the detection of low concentrations of target molecules. At the same time, only a small amount of analyte and a short and simple incubation process was required. The developed platform was applied to the spectroscopic characterization of tetrahydrocannabinol (THC) and its identification at concentration levels down to 1 nM. Thus, a highly efficient detection system for practical applications, e.g., in drug monitoring/detection, is introduced, which can be fabricated at low cost by using microwave-assisted batch synthesis techniques. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. One-pot heterogeneous synthesis of Δ(3)-tetrahydrocannabinol analogues and xanthenes showing differential binding to CB(1) and CB(2) receptors.

    Science.gov (United States)

    Rosati, Ornelio; Messina, Federica; Pelosi, Azzurra; Curini, Massimo; Petrucci, Vanessa; Gertsch, Jürg; Chicca, Andrea

    2014-10-06

    Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive cannabinoid in hemp (Cannabis sativa L.) and responsible for many of the pharmacological effects mediated via cannabinoid receptors. Despite being the major cannabinoid scaffold in nature, Δ(9)-THC double bond isomers remain poorly studied. The chemical scaffold of tetrahydrocannabinol can be assembled from the condensation of distinctly substituted phenols and monoterpenes. Here we explored a microwave-assisted one pot heterogeneous synthesis of Δ(3)-THC from orcinol (1a) and pulegone (2). Four Δ(3)-THC analogues and corresponding Δ(4a)-tetrahydroxanthenes (Δ(4a)-THXs) were synthesized regioselectively and showed differential binding affinities for CB1 and CB2 cannabinoid receptors. Here we report for the first time the CB1 receptor binding of Δ(3)-THC, revealing a more potent receptor binding affinity for the (S)-(-) isomer (hCB1Ki = 5 nM) compared to the (R)-(+) isomer (hCB1Ki = 29 nM). Like Δ(9)-THC, also Δ(3)-THC analogues are partial agonists at CB receptors as indicated by [(35)S]GTPγS binding assays. Interestingly, the THC structural isomers Δ(4a)-THXs showed selective binding and partial agonism at CB2 receptors, revealing a simple non-natural natural product-derived scaffold for novel CB2 ligands. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  1. The effects of Δ9-Tetrahydrocannabinole treatment on gonadal micro-vascularization and affected fertility examined by SEM and 3D-morphometry

    Science.gov (United States)

    Erlbacher, K. M. T.; Minnich, B.

    2015-10-01

    The present study focuses on the effects of Δ9-tetrahydrocannabinol (THC) on the reproductive system in nude rats with special emphasis on how Δ9-THC impacts the vascularization of testes which in turn indirectly influences fertility. Basically, Δ9-tetrahydrocannabinol (THC) causes not only negative (psychoactive) effects in the human body as cannabinole administration in medical use (dose-dependent) offers multiple new treatment opportunities such as pain relief or containment of various cancers. Concerning the reproductive system it strongly influences CB-receptors along the hypothalamic-pituitary-gonadal axis resulting in reduced plasma testosterone levels. There is also altered sperm quality parameters reported such as sperm motility or sperm count. On the other hand Δ9-THC effects endothelial growth factors (VEGF, Ang-1 etc.) respectively acts on their specific receptors which in turn modify angiogenesis and vascularization of tissues and organs (e.g. tumorous tissues). This leads to new therapeutical strategies in the suppression of various cancers by inhibiting (neo-)vascularization and in turn famishment of tumorous tissues (lack of nutrition supply). Here we studied the micro-vascularization of gonads in a long-term THC-treated nude rat model by vascular corrosion casting, SEM and 3D-morphometry.

  2. Rimonabant-induced Delta9-tetrahydrocannabinol withdrawal in rhesus monkeys: discriminative stimulus effects and other withdrawal signs.

    Science.gov (United States)

    Stewart, Jennifer L; McMahon, Lance R

    2010-07-01

    Marijuana-dependent individuals report using marijuana to alleviate withdrawal, suggesting that pharmacotherapy of marijuana withdrawal could promote abstinence. To identify potential pharmacotherapies for marijuana withdrawal, this study first characterized rimonabant-induced Delta(9)-tetrahydrocannabinol (Delta(9)-THC) withdrawal in rhesus monkeys by using drug discrimination and directly observable signs. Second, drugs were examined for their capacity to modify cannabinoid withdrawal. Monkeys receiving chronic Delta(9)-THC (1 mg/kg/12 h s.c.) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) under a fixed ratio schedule of stimulus-shock termination. The discriminative stimulus effects of rimonabant were dose-dependent (ED(50) = 0.25 mg/kg) and accompanied by head shaking. In the absence of chronic Delta(9)-THC treatment (i.e., in nondependent monkeys), a larger dose (3.2 mg/kg) of rimonabant produced head shaking and tachycardia. Temporary discontinuation of Delta(9)-THC treatment resulted in increased responding on the rimonabant lever, head shaking, and activity during the dark cycle. The rimonabant discriminative stimulus was attenuated fully by Delta(9)-THC (at doses larger than mg/kg/12 h) and the cannabinoid agonist CP 55940 [5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and partially by the cannabinoid agonist WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and the alpha(2)-adrenergic agonist clonidine. In contrast, a benzodiazepine (diazepam) and monoamine agonist (cocaine) did not attenuate the rimonabant discriminative stimulus. Head shaking was attenuated by all test compounds. These results show that the discriminative stimulus effects of rimonabant in Delta(9)-THC-treated monkeys are a more pharmacologically selective measure of cannabinoid withdrawal than rimonabant-induced head shaking. These results suggest

  3. Rimonabant-Induced Δ9-Tetrahydrocannabinol Withdrawal in Rhesus Monkeys: Discriminative Stimulus Effects and Other Withdrawal Signs

    Science.gov (United States)

    Stewart, Jennifer L.

    2010-01-01

    Marijuana-dependent individuals report using marijuana to alleviate withdrawal, suggesting that pharmacotherapy of marijuana withdrawal could promote abstinence. To identify potential pharmacotherapies for marijuana withdrawal, this study first characterized rimonabant-induced Δ9-tetrahydrocannabinol (Δ9-THC) withdrawal in rhesus monkeys by using drug discrimination and directly observable signs. Second, drugs were examined for their capacity to modify cannabinoid withdrawal. Monkeys receiving chronic Δ9-THC (1 mg/kg/12 h s.c.) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) under a fixed ratio schedule of stimulus-shock termination. The discriminative stimulus effects of rimonabant were dose-dependent (ED50 = 0.25 mg/kg) and accompanied by head shaking. In the absence of chronic Δ9-THC treatment (i.e., in nondependent monkeys), a larger dose (3.2 mg/kg) of rimonabant produced head shaking and tachycardia. Temporary discontinuation of Δ9-THC treatment resulted in increased responding on the rimonabant lever, head shaking, and activity during the dark cycle. The rimonabant discriminative stimulus was attenuated fully by Δ9-THC (at doses larger than mg/kg/12 h) and the cannabinoid agonist CP 55940 [5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol], and partially by the cannabinoid agonist WIN 55212-2 [(R)-(+)-[2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and the α2-adrenergic agonist clonidine. In contrast, a benzodiazepine (diazepam) and monoamine agonist (cocaine) did not attenuate the rimonabant discriminative stimulus. Head shaking was attenuated by all test compounds. These results show that the discriminative stimulus effects of rimonabant in Δ9-THC-treated monkeys are a more pharmacologically selective measure of cannabinoid withdrawal than rimonabant-induced head shaking. These results suggest that cannabinoid and noncannabinoid (α2

  4. Delta-9-tetrahydrocannabinol (THC) affects forelimb motor map expression but has little effect on skilled and unskilled behavior.

    Science.gov (United States)

    Scullion, K; Guy, A R; Singleton, A; Spanswick, S C; Hill, M N; Teskey, G C

    2016-04-05

    It has previously been shown in rats that acute administration of delta-9-tetrahydrocannabinol (THC) exerts a dose-dependent effect on simple locomotor activity, with low doses of THC causing hyper-locomotion and high doses causing hypo-locomotion. However the effect of acute THC administration on cortical movement representations (motor maps) and skilled learned movements is completely unknown. It is important to determine the effects of THC on motor maps and skilled learned behaviors because behaviors like driving place people at a heightened risk. Three doses of THC were used in the current study: 0.2mg/kg, 1.0mg/kg and 2.5mg/kg representing the approximate range of the low to high levels of available THC one would consume from recreational use of cannabis. Acute peripheral administration of THC to drug naïve rats resulted in dose-dependent alterations in motor map expression using high resolution short duration intracortical microstimulation (SD-ICMS). THC at 0.2mg/kg decreased movement thresholds and increased motor map size, while 1.0mg/kg had the opposite effect, and 2.5mg/kg had an even more dramatic effect. Deriving complex movement maps using long duration (LD)-ICMS at 1.0mg/kg resulted in fewer complex movements. Dosages of 1.0mg/kg and 2.5mg/kg THC reduced the number of reach attempts but did not affect percentage of success or the kinetics of reaching on the single pellet skilled reaching task. Rats that received 2.5mg/kg THC did show an increase in latency of forelimb removal on the bar task, while dose-dependent effects of THC on unskilled locomotor activity using the rotorod and horizontal ladder tasks were not observed. Rats may be employing compensatory strategies after receiving THC, which may account for the robust changes in motor map expression but moderate effects on behavior. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Gonadal hormone modulation of ∆9-tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats.

    Science.gov (United States)

    Craft, R M; Haas, A E; Wiley, J L; Yu, Z; Clowers, B H

    2017-01-01

    The gonadal hormones testosterone (T) in adult males and estradiol (E2) in adult females have been reported to modulate behavioral effects of ∆9-tetrahydrocannabinol (THC). This study determined whether activational effects of T and E2 are sex-specific, and whether hormones modulate production of the active metabolite 11-hydroxy-THC (11-OH-THC) and the inactive metabolite 11-nor-9-carboxy-THC (THC-COOH). Adult male and female rats were gonadectomized (GDX) and treated with nothing (0), T (10-mm Silastic capsule/100g body weight), or E2 (1-mm Silastic capsule/rat). Three weeks later, saline or the cytochrome P450 inhibitor proadifen (25mg/kg; to block THC metabolism and boost THC's effects) was injected i.p.; 1h later, vehicle or THC (3mg/kg females, 5mg/kg males) was injected i.p., and rats were tested for antinociceptive and motoric effects 15-240min post-injection. T did not consistently alter THC-induced antinociception in males, but decreased it in females (tail withdrawal test). Conversely, T decreased THC-induced catalepsy in males, but had no effect in females. E2 did not alter THC-induced antinociception in females, but enhanced it in males. The discrepant effects of T and E2 on males' and females' behavioral responses to THC suggests that sexual differentiation of THC sensitivity is not simply due to activational effects of hormones, but also occurs via organizational hormone or sex chromosome effects. Analysis of serum showed that proadifen increased THC levels, E2 increased 11-OH-THC in GDX males, and T decreased 11-OH-THC (and to a lesser extent, THC) in GDX females. Thus, hormone modulation of THC's behavioral effects is caused in part by hormone modulation of THC oxidation to its active metabolite. However, the fact that hormone modulation of metabolism did not alter THC sensitivity similarly on all behavioral measures within each sex suggests that other mechanisms also play a role in gonadal hormone modulation of THC sensitivity in adult rats

  6. Safety, pharmacodynamics, and pharmacokinetics of multiple oral doses of delta-9-tetrahydrocannabinol in older persons with dementia.

    Science.gov (United States)

    Ahmed, Amir I A; van den Elsen, Geke A H; Colbers, Angela; Kramers, Cornelis; Burger, David M; van der Marck, Marjolein A; Olde Rikkert, Marcel G M

    2015-07-01

    Data on safety, pharmacodynamics, and pharmacokinetics of tetrahydrocannabinol (THC) are lacking in dementia patients. In this randomized, double-blind, placebo-controlled, crossover trial, we evaluated the safety, pharmacodynamics, and pharmacokinetics of THC in ten patients with dementia (mean age 77.3 ± 5.6). For 12 weeks, participants randomly received oral THC (weeks 1-6, 0.75 mg; weeks 7-12, 1.5 mg) or placebo twice daily for 3 days, separated by a 4-day washout period. Only 6 of the 98 reported adverse events were related to THC. Visual analog scale (VAS) feeling high, VAS external perception, body sway-eyes-open, and diastolic blood pressure were not significantly different with THC. After the 0.75-mg dose, VAS internal perception (0.025 units; 95% CI 0.010-0.040) and heart rate (2 beats/min; 95% CI 0.4-3.8) increased significantly. Body sway-eyes-closed increased only after 1.5 mg (0.59°/s; 95% CI 0.13-1.06). Systolic blood pressure changed significantly after both doses of THC (0.75 mg, -7 mmHg, 95% CI -11.4, -3.0; 1.5 mg, 5 mmHg, 95% CI 1.0-9.2). The median T max was 1-2 h, with THC pharmacokinetics increasing linearly with increasing dose, with wide interindividual variability (CV% up to 140%). The mean C max (ng/mL) after the first dose (0-6 h) was 0.41 (0.18-0.90) for the 0.75-mg dose and 1.01 (0.53-1.92) for the 1.5-mg dose. After the second dose (6-24 h), the C max was 0.50 (0.27-0.92) and 0.98 (0.46-2.06), respectively. THC was rapidly absorbed and had dose-linear pharmacokinetics with considerable interindividual variation. Pharmacodynamic effects, including adverse events, were minor. Further studies are warranted to evaluate the pharmacodynamics and efficacy of higher THC doses in older persons with dementia.

  7. In planta imaging of Δ9-tetrahydrocannabinolic acid in Cannabis sativa L. with hyperspectral coherent anti-Stokes Raman scattering microscopy

    Science.gov (United States)

    Garbacik, Erik T.; Korai, Roza P.; Frater, Eric H.; Korterik, Jeroen P.; Otto, Cees; Offerhaus, Herman L.

    2013-04-01

    Nature has developed many pathways to produce medicinal products of extraordinary potency and specificity with significantly higher efficiencies than current synthetic methods can achieve. Identification of these mechanisms and their precise locations within plants could substantially increase the yield of a number of natural pharmaceutics. We report label-free imaging of Δ9-tetrahydrocannabinolic acid (THCa) in Cannabis sativa L. using coherent anti-Stokes Raman scattering microscopy. In line with previous observations we find high concentrations of THCa in pistillate flowering bodies and relatively low amounts within flowering bracts. Surprisingly, we find differences in the local morphologies of the THCa-containing bodies: organelles within bracts are large, diffuse, and spheroidal, whereas in pistillate flowers they are generally compact, dense, and have heterogeneous structures. We have also identified two distinct vibrational signatures associated with THCa, both in pure crystalline form and within Cannabis plants; at present the exact natures of these spectra remain an open question.

  8. Correlations and agreement between delta-9-tetrahydrocannabinol (THC) in blood plasma and timeline follow-back (TLFB)-assisted self-reported use of cannabis of patients with cannabis use disorder and psychotic illness attending the CapOpus randomized clinical trial

    DEFF Research Database (Denmark)

    Hjorthøj, Carsten Rygaard; Fohlmann, Allan; Larsen, Anne-Mette

    2012-01-01

    disorder and psychosis, providing 239 self-reports of cannabis use and 88 valid blood samples. Measurements Delta-9-tetrahydrocannabinol (THC), 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) detected in plasma using high......Aims To assess correlations and agreement between timeline follow-back (TLFB)-assisted self-report and blood samples for cannabis use. Design Secondary analysis of a randomized trial. Setting Copenhagen, Denmark. Participants One hundred and three patients from the CapOpus trial with cannabis use.......96. Conclusions Timeline follow-back (TLFB)-assisted self-report of cannabis use correlates highly with plasma-delta-9-tetrahydrocannabinol in patients with comorbid cannabis use disorder and psychosis. Sensitivity and specificity of timeline follow-back appear to be optimized with 19 days as the cut-off point...

  9. Identification and quantification of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-COOH-glu) in hair by ultra-performance liquid chromatography tandem mass spectrometry as a potential hair biomarker of cannabis use.

    Science.gov (United States)

    Pichini, Simona; Marchei, Emilia; Martello, Simona; Gottardi, Massimo; Pellegrini, Manuela; Svaizer, Fiorenza; Lotti, Andrea; Chiarotti, Marcello; Pacifici, Roberta

    2015-04-01

    We developed and validated an ultra-high-pressure liquid chromatography-tandem mass spectrometry method to identify and quantify 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in hair of cannabis consumers. After hair washing with methyl alcohol and diethyl ether and subsequent addition of amiodarone as internal standard hair samples were treated with 500 μl VMA-T M3 buffer reagent for 1 h at 100 °C. After cooling, 10 μl VMA-T M3 extract were injected into chromatographic system. Chromatographic separation was carried out on a reversed phase column using a linear gradient elution with two solvents: 5 mM ammonium formate pH 3.0 (solvent A) and 0.1% formic acid in acetonitrile (solvent B). The flow rate was kept constant at 0.4 ml/min during the analysis. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode via positive electrospray ionization. Linear calibration curves were obtained for 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide with correlation coefficients (r(2)) of 0.99 and a limit of quantification of 0.25 pg/mg hair. Analytical recovery was between 79.6% and 100.7% and intra- and inter-assay imprecision and inaccuracy were always lower than 15%. Ultra-high-pressure liquid chromatography-tandem mass spectrometry analysis of 20 different hair samples of cannabis consumers disclosed the presence of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in the range of 0.5-8.6 pg/mg hair. These data provided a good start to consider 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide as alternative hair biomarker of cannabis consumption. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. The effects of cannabidiol (CBD) on Δ⁹-tetrahydrocannabinol (THC) self-administration in male and female Long-Evans rats.

    Science.gov (United States)

    Wakeford, Alison G P; Wetzell, Bradley B; Pomfrey, Rebecca L; Clasen, Matthew M; Taylor, William W; Hempel, Briana J; Riley, Anthony L

    2017-08-01

    Despite widespread cannabis use in humans, few rodent models exist demonstrating significant Δ⁹-tetrahydrocannabinol (THC) self-administration, possibly due to THC's co-occurring aversive effects, which impact drug reinforcement. Cannabis contains a number of phytocannabinoids in addition to THC, one of which, cannabidiol (CBD), has been reported to antagonize some of the aversive effects of THC. Given such effects of CBD, it is possible that it might influence THC intravenous self-administration in rodents. Accordingly, male and female Long-Evans rats were trained to self-administer THC over a 3-week period and then were assessed for the effects of CBD on responding for THC at 1:1 and 1:10 dose ratios or for the establishment of cocaine self-administration (as a positive control for drug self-administration). Consistent with previous research, THC self-administration was modest and only evident in a subset of animals (and unaffected by sex). Cocaine self-administration was high and evident in the majority of animals tested, indicating that the design was sensitive to drug reinforcement. There was no effect of CBD pretreatment on THC intravenous self-administration at any CBD:THC dose ratio. Future developments of animal models of THC self-administration and the examination of factors that affect its display remain important to establish procedures designed to assess the basis for and treatment of cannabis use and abuse. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  11. Using Functional Near-Infrared Spectroscopy to Measure Effects of Delta 9-Tetrahydrocannabinol on Prefrontal Activity and Working Memory in Cannabis Users

    Directory of Open Access Journals (Sweden)

    Hasan O. Keles

    2017-10-01

    Full Text Available Intoxication from cannabis impairs cognitive performance, in part due to the effects of Δ9-tetrahydrocannabinol (THC, the primary psychoactive compound in cannabis on prefrontal cortex (PFC function. However, a relationship between impairment in cognitive functioning with THC administration and THC-induced change in hemodynamic response has not been demonstrated. We explored the feasibility of using functional near-infrared spectroscopy (fNIRS to examine the functional changes of the human PFC associated with cannabis intoxication and cognitive impairment. Eighteen adult regular cannabis users (final sample, n = 13 performed a working memory task (n-back during fNIRS recordings, before and after receiving a single dose of oral synthetic THC (dronabinol; 20–50 mg. Functional data were collected using a continuous-wave NIRS device, in which 8 Sources and 7 detectors were placed on the forehead, resulting in 20 channels covering PFC regions. Physiological changes and subjective intoxication measures were collected. We found a significant increase in the oxygenated hemoglobin (HbO concentration after THC administration in several channels on the PFC during both the high working memory load (2-back and the low working memory load (0-back condition. The increased HbO response was accompanied by a trend toward an increased number of omission errors after THC administration. The current study suggests that cannabis intoxication is associated with increases in hemodynamic blood flow to the PFC, and that this increase can be detected with fNIRS.

  12. Effects of acute oral Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers.

    Science.gov (United States)

    Roser, Patrik; Juckel, Georg; Rentzsch, Johannes; Nadulski, Thomas; Gallinat, Jürgen; Stadelmann, Andreas M

    2008-08-01

    Reduced amplitudes of auditory evoked P300 are a robust finding in schizophrenic patients, indicating deficient attentional resource allocation and active working memory. Delta9-Tetrahydrocannabinol (Delta9-THC), the main active constituent of Cannabis sativa, has been known to acutely impair cognitive abilities in several domains, particularly in memory and attention. Given the psychotic-like effects of Delta9-THC, a cannabinoid hypothesis of schizophrenia has been proposed. This prospective, double-blind, placebo-controlled cross-over study investigated the acute effects of cannabinoids on P300 amplitude in 20 healthy volunteers (age 28.2+/-3.1 years, 10 male) by comparing Delta9-THC and standardized cannabis extract containing Delta9-THC and cannabidiol (CBD). P300 waves were recorded during a choice reaction task. As expected, Delta9-THC revealed a significant reduction of P300 amplitude at midline frontal, central, and parietal electrodes. CBD has been known to abolish many of the psychotropic effects of Delta9-THC, but, unexpectedly, failed to demonstrate a reversal of Delta9-THC-induced P300 reduction. Moreover, there were no correlations between cannabinoid plasma concentrations and P300 parameters. These data suggest that Delta(9)-THC may lead to acute impairment of attentional functioning and working memory. It can be speculated whether the lack of effect of CBD may be due to an insufficient dose used or to an involvement of neurotransmitter systems in P300 generation which are not influenced by CBD.

  13. [Simultaneous determination of delta-9-tetrahydrocannabinol cannabidiol and cannabinol in edible oil using ultra performance liquid chromatography-tandem mass spectrometry].

    Science.gov (United States)

    Zhang, Aizhi; Wang, Quanlin; Mo, Shijie

    2010-11-01

    A method for the simultaneous determination of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) in edible oil was developed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The target compounds were extracted with methanol, purified by an LC-Alumina-N solid phase extraction cartridge, separated and detected by the UPLC-MS/MS. Quantitative analysis was corrected by an isotope internal standard method using delta-9-THC-D3 as internal standard. Average recoveries for the target compounds varied from 68.0% to 101.6% with the relative standard deviations ranging from 7.0% to 20.1% at three spiked levels. The limits of detection (LOD) of the method were from 0.06-0.17 microg/kg and the limits of quantification (LOQ) were in the range of 0.20-0.52 microg/kg. The results showed that the method is able to meet the requirements for the simultaneous determination of THC, CBD and CBN in edible oil.

  14. Novel method of determination of D9-tetrahydrocannabinol(THC) in human serum by high-performance liquid chromatography with electrochemical detection.

    Science.gov (United States)

    Kokubun, Hideya; Uezono, Yasuhito; Matoba, Motohiro

    2014-04-01

    In Europe and the United States, D9-tetrahydrocannabinol(THC, dronabinol), one of the psychoactive constituents of cannabis, has been used for both its anti-emetic and orexigenic effects in cancer patient receiving chemotherapy.However, dronabinol has not yet been launched in the market in Japan.In the future, it is necessary to ascertain the pharmacokinetics of dronabinol in cancer paitient.Therefore, we developed an HPLC procedure using electrochemical detection(ECD)for quan- titation of the concentrations of dronabinol in blood.An eluent of 50mM KH2PO4/CH3CN(9:16)was used as the mobile phase.The column was used the XTerra®RP18, and the voltage of the electrochemical detector in dronabinol was set at 400 mV.As a result, the calibration curve was linear in the range of 10 ng/mL to 100 ng/mL(y=964.85x -3,419, r=0.997).The lower limit of quantification was 0.5 ng/mL(S/N=3).The relative within-runs and between-runs standard deviations for the assay dronabinol were less than 4.7%. The method reported here is superior to previously reported methods in cancer patient.

  15. Δ9-Tetrahydrocannabinol (Δ9-THC) Promotes Neuroimmune-Modulatory MicroRNA Profile in Striatum of Simian Immunodeficiency Virus (SIV)-Infected Macaques.

    Science.gov (United States)

    Simon, Liz; Song, Keijing; Vande Stouwe, Curtis; Hollenbach, Andrew; Amedee, Angela; Mohan, Mahesh; Winsauer, Peter; Molina, Patricia

    2016-03-01

    Cannabinoid administration before and after simian immunodeficiency virus (SIV)-inoculation ameliorated disease progression and decreased inflammation in male rhesus macaques. Δ9-tetrahydrocannabinol (Δ9-THC) did not increase viral load in brain tissue or produce additive neuropsychological impairment in SIV-infected macaques. To determine if the neuroimmunomodulation of Δ9-THC involved differential microRNA (miR) expression, miR expression in the striatum of uninfected macaques receiving vehicle (VEH) or Δ9-THC (THC) and SIV-infected macaques administered either vehicle (VEH/SIV) or Δ9-THC (THC/SIV) was profiled using next generation deep sequencing. Among the 24 miRs that were differentially expressed among the four groups, 16 miRs were modulated by THC in the presence of SIV. These 16 miRs were classified into four categories and the biological processes enriched by the target genes determined. Our results indicate that Δ9-THC modulates miRs that regulate mRNAs of proteins involved in 1) neurotrophin signaling, 2) MAPK signaling, and 3) cell cycle and immune response thus promoting an overall neuroprotective environment in the striatum of SIV-infected macaques. This is also reflected by increased Brain Derived Neurotrophic Factor (BDNF) and decreased proinflammatory cytokine expression compared to the VEH/SIV group. Whether Δ9-THC-mediated modulation of epigenetic mechanisms provides neuroprotection in other regions of the brain and during chronic SIV-infection remains to be determined.

  16. Quantification of 11-Carboxy-Delta-9-Tetrahydrocannabinol (THC-COOH) in Meconium Using Gas Chromatography/Mass Spectrometry (GC/MS).

    Science.gov (United States)

    Peat, Judy; Davis, Brehon; Frazee, Clint; Garg, Uttam

    2016-01-01

    Maternal substance abuse is an ongoing concern and detecting drug use during pregnancy is an important component of neonatal care when drug abuse is suspected. Meconium is the preferred specimen for drug testing because it is easier to collect than neonatal urine and it provides a much broader time frame of drug exposure. We describe a method for quantifying 11-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) in meconium. After adding a labeled internal standard (THC-COOH D9) and acetonitrile, samples are sonicated to release both free and conjugated THC-COOH. The acetonitrile/aqueous layer is removed and mixed with a strong base to hydrolyze the conjugated THC-COOH. The samples are then extracted with an organic solvent mixture as part of a sample "cleanup." The organic solvent layer is discarded and the remaining aqueous sample is acidified. Following extraction with a second organic mixture, the organic layer is removed and concentrated to dryness. The resulting residue is converted to a trimethylsilyl (TMS) derivative and analyzed using gas chromatography/mass spectrometry (GC/MS) in selective ion monitoring (SIM) mode.

  17. Simultaneous accelerated solvent extraction and hydrolysis of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide in meconium samples for gas chromatography-mass spectrometry analysis.

    Science.gov (United States)

    Mantovani, Cinthia de Carvalho; Silva, Jefferson Pereira E; Forster, Guilherme; Almeida, Rafael Menck de; Diniz, Edna Maria de Albuquerque; Yonamine, Mauricio

    2018-02-01

    Cannabis misuse during pregnancy is associated with severe impacts on the mother and baby health, such as newborn low birth weight, growth restriction, pre-term birth, neurobehavioral and developmental deficits. In most of the cases, drug abuse is omitted or denied by the mothers. Thus, toxicological analyzes using maternal-fetal matrices takes place as a suitable tool to assess drug use. Herein, meconium was the chosen matrix to evaluate cannabis exposure through identification and quantification of 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic (THCCOOH). Accelerated solvent extraction (ASE) was applied for sample preparation technique to simultaneously extract and hydrolyze conjugated THCCOOH from meconium, followed by a solid-phase extraction (SPE) procedure. The method was developed and validated for gas chromatography-mass spectrometry (GC-MS), reaching hydrolysis efficiency of 98%. Limits of detection (LOD) and quantification (LOQ) were, respectively, 5 and 10 ng/g. The range of linearity was LOQ to 500 ng/g. Inter and intra-batch coefficients of variation were <8.4% for all concentration levels. Accuracy was in 101.7-108.9% range. Recovery was on average 60.3%. Carryover effect was not observed. The procedure was applied in six meconium samples from babies whose mothers were drug users and showed satisfactory performance to confirm fetal cannabis exposure. Copyright © 2018 Elsevier B.V. All rights reserved.

  18. Delay- and dose-dependent effects of Δ⁹-tetrahydrocannabinol administration on spatial and object working memory tasks in adolescent rhesus monkeys.

    Science.gov (United States)

    Verrico, Christopher D; Liu, Shijing; Bitler, Elizabeth J; Gu, Hong; Sampson, Allan R; Bradberry, Charles W; Lewis, David A

    2012-05-01

    Among adolescents, the perception that cannabis can cause harm has decreased and use has increased. However, in rodents, cannabinoid administration during adolescence induces working memory (WM) deficits that are more severe than if the same exposure occurs during adulthood. As both object and spatial WM mature in a protracted manner, although apparently along different trajectories, adolescent cannabis users may be more susceptible to impairments in one type of WM. Here, we evaluate the acute effects of a range of doses (30-240 μg/kg) of intravenous Δ⁹-tetrahydrocannabinol (THC) administration on the performance of spatial and object WM tasks in adolescent rhesus monkeys. Accuracy on the object WM task was not significantly affected by any dose of THC. In contrast, THC administration impaired accuracy on the spatial WM task in a delay- and dose-dependent manner. Importantly, the THC-induced spatial WM deficits were not because of motor or motivational impairments. These data support the idea that immature cognitive functions are more sensitive to the acute effects of THC.

  19. Using Functional Near-Infrared Spectroscopy to Measure Effects of Delta 9-Tetrahydrocannabinol on Prefrontal Activity and Working Memory in Cannabis Users.

    Science.gov (United States)

    Keles, Hasan O; Radoman, Milena; Pachas, Gladys N; Evins, A Eden; Gilman, Jodi M

    2017-01-01

    Intoxication from cannabis impairs cognitive performance, in part due to the effects of Δ9-tetrahydrocannabinol (THC, the primary psychoactive compound in cannabis) on prefrontal cortex (PFC) function. However, a relationship between impairment in cognitive functioning with THC administration and THC-induced change in hemodynamic response has not been demonstrated. We explored the feasibility of using functional near-infrared spectroscopy (fNIRS) to examine the functional changes of the human PFC associated with cannabis intoxication and cognitive impairment. Eighteen adult regular cannabis users (final sample, n = 13) performed a working memory task (n-back) during fNIRS recordings, before and after receiving a single dose of oral synthetic THC (dronabinol; 20-50 mg). Functional data were collected using a continuous-wave NIRS device, in which 8 Sources and 7 detectors were placed on the forehead, resulting in 20 channels covering PFC regions. Physiological changes and subjective intoxication measures were collected. We found a significant increase in the oxygenated hemoglobin (HbO) concentration after THC administration in several channels on the PFC during both the high working memory load (2-back) and the low working memory load (0-back) condition. The increased HbO response was accompanied by a trend toward an increased number of omission errors after THC administration. The current study suggests that cannabis intoxication is associated with increases in hemodynamic blood flow to the PFC, and that this increase can be detected with fNIRS.

  20. Psychomotor performance, subjective and physiological effects and whole blood Δ⁹-tetrahydrocannabinol concentrations in heavy, chronic cannabis smokers following acute smoked cannabis.

    Science.gov (United States)

    Schwope, David M; Bosker, Wendy M; Ramaekers, Johannes G; Gorelick, David A; Huestis, Marilyn A

    2012-07-01

    Δ⁹-Tetrahydrocannabinol (THC) is the illicit drug most frequently observed in accident and driving under the influence of drugs investigations. Whole blood is often the only available specimen collected during such investigations, yet few studies have examined relationships between cannabis effects and whole blood concentrations following cannabis smoking. Nine male and one female heavy, chronic cannabis smokers resided on a closed research unit and smoked ad libitum one 6.8% THC cannabis cigarette. THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC were quantified in whole blood and plasma. Assessments were performed before and up to 6 h after smoking, including subjective [visual analog scales (VAS) and Likert scales], physiological (heart rate, blood pressure and respirations) and psychomotor (critical-tracking and divided-attention tasks) measures. THC significantly increased VAS responses and heart rate, with concentration-effect curves demonstrating counter-clockwise hysteresis. No significant differences were observed for critical-tracking or divided-attention task performance in this cohort of heavy, chronic cannabis smokers. The cannabis influence factor was not suitable for quantifying psychomotor impairment following cannabis consumption and was not precise enough to determine recent cannabis use with accuracy. These data inform our understanding of impairment and subjective effects following acute smoked cannabis and interpretation of whole blood cannabinoid concentrations in forensic investigations.

  1. Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

    Directory of Open Access Journals (Sweden)

    Rebecca Kuepper

    Full Text Available Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and (18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ(9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis. In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ(9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder, 8 patients with psychotic disorder (high risk psychotic disorder and 7 un-related first-degree relatives (intermediate risk psychotic disorder. PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM, which accounts for time-dependent changes in (18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ(9-THC administration, reflecting dopamine release. While Δ(9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ(9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ(9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.

  2. Enzymatic Digestion and Selective Quantification of Underivatised Delta-9-Tetrahydrocannabinol and Cocaine in Human Hair Using Gas Chromatography-Mass Spectrometry

    Directory of Open Access Journals (Sweden)

    Salah Eddine Breidi

    2012-01-01

    Full Text Available Gas chromatography-mass spectrometric (GC-MS methods for drug analysis routinely employ derivatising reagents. The aim of this paper was to develop a method for the analysis of two recreational drugs, delta-9-tetrahydrocannabinol (Δ9-THC and cocaine in hair samples using GC-MS, without prior derivatisation, thus allowing the sample to be reanalysed in its original form. An enzymatic digestion technique was also developed. Ten hair samples, that were known positive for either Δ9-THC and/or cocaine, were enzymatically digested, extracted, and then analysed by GC-MS. All samples measured contained Δ9-THC and one sample contained cocaine. The limits of detection (LOD and quantification (LOQ were 0.02 ng/mg and 0.05 ng/mg, respectively, for cocaine and 0.015 ng/mg and 0.02 ng/mg, respectively, for Δ9-THC. The wide detection window, ease of direct analysis by GC-MS, lower detection limits of underivatised samples, and the stability of drugs using this technique may offer an improved method of analysis.

  3. Investigation of the transformation of 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol during water chlorination by liquid chromatography-quadrupole-time-of-flight-mass spectrometry.

    Science.gov (United States)

    González-Mariño, Iria; Rodríguez, Isaac; Quintana, José Benito; Cela, Rafael

    2013-10-15

    The stability of the main metabolite of cannabis, (±)-11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol (THCCOOH), during water chlorination has been investigated. THCCOOH was degraded in few seconds following a pseudo-first order kinetics. Sample pH turned out to be a significant factor, decreasing THCCOOH half-life with an increase in its values. Seven by-products could be positively identified from accurate mass measurements: three compounds resulted from electrophilic substitutions of hydrogen per chlorine (or bromine) in the aromatic ring, whereas the formation of the remaining four involved additional reactions in the C-C double bond (hydration and halogenation). The software predicted toxicity of these products towards Daphnia magna indicates that they are expected to have toxicity values similar or higher than its precursor compound. Experiments conducted with diluted urine showed that THCCOOH was stable in this matrix, probably due to a rapid and complete reaction between chlorine and other organic constituents already present in the samples. In real surface waters, the extent of the reaction was also affected by the organic matter content, and so THCCOOH was rapidly degraded in samples scarcely affected by human activities, being more stable in waters with a higher level of pollution. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Simple quantitation of formoterol and 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid in human urine by liquid chromatography-tandem mass spectrometry in doping control.

    Science.gov (United States)

    Lee, Kang Mi; Kim, Ho Jun; Son, Junghyun; Park, Ju-Hyung; Kwon, Oh-Seung; Lee, Jaeick

    2014-09-15

    11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) and formoterol are newly revised prohibited threshold substances (150 ng/mL for THC-COOH and 40 ng/mL for formoterol) by the World Anti-Doping Agency (WADA). In continuation of our direct quantitation work of the prohibited threshold substances, direct LC-MS/MS methods combined with a simple sample preparation procedure have been developed and validated for the measurement of these two threshold substances in urine samples. After the enzymatic hydrolysis of urine samples, the resulting samples were diluted with acetonitrile and centrifuged. The supernatant was directly analyzed by LC-MS/MS using the selected reaction monitoring mode. The calibration curve range of the assay was ranged over 50-200% of the threshold value according to WADA guidelines. The limit of detection and limit of quantification were 6.1 and 18.4 ng/mL for THC-COOH and 2.0 and 6.2 ng/mL for formoterol, respectively. Intra- and inter-day precisions were between 2.08% and 7.28% and the accuracies ranged from 95.16% to 104.49%. The present methods were successfully applied to the analysis of the proficiency test samples. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Up-regulation of immunomodulatory effects of mouse bone-marrow derived mesenchymal stem cells by tetrahydrocannabinol pre-treatment involving cannabinoid receptor CB2.

    Science.gov (United States)

    Xie, Junran; Xiao, Dongju; Xu, Yun; Zhao, Jinning; Jiang, Li; Hu, Xuming; Zhang, Yaping; Yu, Lina

    2016-02-09

    Chronic pain is commonly and closely correlated with inflammation. Both cannabinoid signaling and mesenchymal stem cells (MSCs) have been demonstrated to reduce inflammatory pain. Although cannabinoid signaling is essential for mesenchymal stem cell survival and differentiation, little is known about its role in modulatory effect of MSCs on inflammation and pain sensitivity. Here we showed that mouse bone-marrow derived MSCs (BM-MSCs) expressed both cannabinoid receptor type 1 and 2 (CB1 and CB2). CB2 expression level in BM-MSCs increased with their maturation. In addition, we found that tetrahydrocannabinol (THC) activated CB2 receptor and ERK signaling, consequently enhancing the modulation of MSCs on inflammation-associated cytokine release from lipopolysaccharides-stimulated microglia. Consistent with in vitro data, THC pretreatment enhanced the immunomodulatory effects of BM-MSC on thermal hyperalgesia and mechanical allodynia in chronic constriction injury model, by decreasing the release of pro-inflammation cytokines. Our study revealed the crucial role of THC in promoting the immunomodulatory effects of MSCs and proposed a new strategy to alleviate pain based on stem cells therapy.

  6. Acute and chronic effects of cannabidiol on Δ9-tetrahydrocannabinol (Δ9-THC)-induced disruption in stop signal task performance

    Science.gov (United States)

    Jacobs, David S.; Kohut, Stephen J.; Jiang, Shan; Nikas, Spyros P.; Makriyannis, Alexandros; Bergman, Jack

    2016-01-01

    Recent clinical and preclinical research suggests that cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have interactive effects on measures of cognition; however, the nature of these interactions is not yet fully characterized. To address this, the effects of Δ9-THC and CBD were investigated independently and in combination with proposed therapeutic dose ratios of 1:1 and 1:3 Δ9-THC:CBD in adult rhesus monkeys (n=6) performing a stop signal task (SST). Additionally, the development of tolerance to the effects of THC on SST performance was evaluated by determining the effects of acutely administered Δ9-THC (0.1-3.2 mg/kg), during a 24-day chronic Δ9-THC treatment period with Δ9-THC alone or with CBD. Results indicate that Δ9-THC (0.032 - 0.32 mg/kg) dose-dependently decreased ‘go’ success but did not alter ‘go’ reaction time or stop signal reaction time (SSRT); CBD (0.1-1.0 mg/kg) was without effect on all measures and, when co-administered in a 1:1 dose-ratio, did not exacerbate or attenuate the effects of Δ9-THC. When co-administered in a 1:3 dose-ratio, CBD (1.0 mg/kg) attenuated the disruptive effects of 0.32 mg/kg Δ9-THC but did not alter the effects of other Δ9-THC doses. Increases in ED50 values for the effects of Δ9-THC on SST performance were apparent during chronic Δ9-THC treatment, with little evidence for modification of changes in sensitivity by CBD. These results indicate that CBD, when combined with THC in clinically available dose-ratios does not exacerbate and, under restricted conditions, may even attenuate Δ9-THC’s behavioral effects. PMID:27690502

  7. Development of a simple and sensitive HPLC-UV method for the simultaneous determination of cannabidiol and Δ(9)-tetrahydrocannabinol in rat plasma.

    Science.gov (United States)

    Zgair, Atheer; Wong, Jonathan C M; Sabri, Akmal; Fischer, Peter M; Barrett, David A; Constantinescu, Cris S; Gershkovich, Pavel

    2015-10-10

    There has been increased interest in the medical use of cannabinoids in recent years, particularly in the predominant natural cannabinoids, cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC). The aim of the current study was to develop a sensitive and reliable method for the quantification of CBD and THC in rat plasma. A combination of protein precipitation using cold acetonitrile and liquid-liquid extraction using n-hexane was utilised to extract CBD and THC from rat plasma. Samples were then evaporated and reconstituted in acetonitrile and 30 μL was injected into an HPLC system. Separation was achieved using an ACE C18-PFP 150 mm × 4.6 mm, 3 μm column at 55 °C with isocratic elution using a mobile phase consisting of acetonitrile-water (62:38, v/v) at 1 mL/min for 20 min. Both cannabinoids, as well as the internal standard (4,4-dichlorodiphenyltrichloroethane, DDT) were detected at 220 nm. Our new method showed linearity in the range of 10-10,000 ng/mL and a lower limit of quantification (LLOQ) of 10 ng/mL for both cannabinoids, which is comparable to previously reported LC-MS/MS methods. Inter- and intra-day precision and accuracy were below 15% RSD and RE, respectively. To demonstrate the suitability of the method for in vivo studies in rats, the assay was applied to a preliminary pharmacokinetic study following IV bolus administration of 5 mg/kg CBD or THC. In conclusion, a simple, sensitive, and cost-efficient HPLC-UV method for the simultaneous determination of CBD and THC has been successfully developed, validated and applied to a pharmacokinetic study in rats. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Behaviour in rats maintained by low differential reinforcement rate: effects of delta 1-tetrahydrocannabinol, cannabinol and cannabidiol, alone and in combination.

    Science.gov (United States)

    Hiltunen, A J; Järbe, T U; Kamkar, M R; Archer, T

    1989-02-01

    Rats were trained to respond according to a low rate differential reinforcement (DRL) 72 sec schedule of operant behaviour. The animals were then tested with delta 1-tetrahydrocannabinol (delta 1-THC), cannabinol, and cannabidiol alone and in combination. Tests with single doses of delta 1-THC (dose-range: 0.3-5.6 mg/kg) and cannabinol (dose-range: 1-56 mg/kg) but not cannabidiol (dose-range 3-100 mg/kg), yielded a dose-related biphasic effect on the response rate. Small doses of delta 1-THC and cannabinol increased the rate of responding, large doses of these agents decreased it. Cannabidiol alone only decreased the rate of responding (occurring at large doses). The rate of reinforcement generally was decreased when response rates increased and vice versa. Cannabidiol (10 and 30 kg/kg), together with delta 1-THC (1 and 3 mg/kg), decreased the response output and increased the rate of reinforcement. Similar results were observed with combinations of cannabinol (10 and 30 mg/kg) and cannabidiol (10 and 30 mg/kg). Combinations of delta 1-THC (0.3 and 1 mg/kg) and cannabinol (1 and 3 mg/kg) also reduced the response rate and there were no significant changes in the rate of reinforcement. Hence the actions of delta 1-THC and cannabinol on behaviour in rats maintained by low rate differential reinforcement were similar (approximate difference in potency 1:10), whereas no stimulation of response rate was demonstrated with cannabidiol. Vehicle and day of testing (Tuesday or Friday) variables were found not to affect the results.

  9. Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors.

    Directory of Open Access Journals (Sweden)

    Xavier Viñals

    2015-07-01

    Full Text Available Activation of cannabinoid CB1 receptors (CB1R by delta9-tetrahydrocannabinol (THC produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.

  10. Role of the endocannabinoid system in brain functions relevant for schizophrenia: an overview of human challenge studies with cannabis or ∆9-tetrahydrocannabinol (THC).

    Science.gov (United States)

    Bossong, Matthijs G; Jansma, J Martijn; Bhattacharyya, Sagnik; Ramsey, Nick F

    2014-07-03

    Accumulating evidence suggests involvement of the endocannabinoid system in the pathophysiology of schizophrenia, which signifies a potential application for this system in the treatment of this disorder. However, before new research can focus on potential treatments that work by manipulating the endocannabinoid system, it needs to be elucidated how this system is involved in symptoms of schizophrenia. Here we review human studies that investigated acute effects of cannabis or ∆9-tetrahydrocannabinol (THC) on brain functions that are implicated in schizophrenia. Results suggest that the impact of THC administration depends on the difficulty of the task performed. Impaired performance of cognitive paradigms is reported on more challenging tasks, which is associated with both activity deficits in temporal and prefrontal areas and a failure to deactivate regions of the default mode network. Comparable reductions in prefrontal activity and impairments in deactivation of the default mode network are seen in patients during performance of cognitive paradigms. Normal performance levels after THC administration demonstrated for less demanding tasks are shown to be related to either increased neural effort in task-specific regions ('neurophysiological inefficiency'), or recruitment of alternative brain areas, which suggests a change in strategy to meet cognitive demands. Particularly a pattern of performance and brain activity corresponding with an inefficient working memory system is consistently demonstrated in patients. These similarities in brain function between intoxicated healthy volunteers and schizophrenia patients provide an argument for a role of the endocannabinoid system in symptoms of schizophrenia, and further emphasize this system as a potential novel target for treatment of these symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. The effects of Δ9-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis

    Science.gov (United States)

    Jamontt, JM; Molleman, A; Pertwee, RG; Parsons, ME

    2010-01-01

    Background and purpose: Cannabis is taken as self-medication by patients with inflammatory bowel disease for symptomatic relief. Cannabinoid receptor agonists decrease inflammation in animal models of colitis, but their effects on the disturbed motility is not known. (-)-Cannabidiol (CBD) has been shown to interact with Δ9-tetrahydrocannabinol (THC) in behavioural studies, but it remains to be established if these cannabinoids interact in vivo in inflammatory disorders. Therefore the effects of CBD and THC alone and in combination were investigated in a model of colitis. Experimental approach: The 2,4,6-trinitrobenzene sulphonic acid (TNBS) model of acute colitis in rats was used to assess damage, inflammation (myeloperoxidase activity) and in vitro colonic motility. Sulphasalazine was used as an active control drug. Key results: Sulphasalazine, THC and CBD proved beneficial in this model of colitis with the dose–response relationship for the phytocannabinoids showing a bell-shaped pattern on the majority of parameters (optimal THC and CBD dose, 10 mg·kg−1). THC was the most effective drug. The effects of these phytocannabinoids were additive, and CBD increased some effects of an ineffective THC dose to the level of an effective one. THC alone and in combination with CBD protected cholinergic nerves whereas sulphasalazine did not. Conclusions and implications: In this model of colitis, THC and CBD not only reduced inflammation but also lowered the occurrence of functional disturbances. Moreover the combination of CBD and THC could be beneficial therapeutically, via additive or potentiating effects. This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x PMID:20590574

  12. Postmortem redistribution of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH).

    Science.gov (United States)

    Holland, Michael G; Schwope, David M; Stoppacher, Robert; Gillen, Shane B; Huestis, Marilyn A

    2011-10-10

    Postmortem redistribution (PMR), a well-described phenomenon in forensic toxicology for certain drugs, can result in increased central blood concentrations relative to peripheral blood concentrations. Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis or marijuana, is the illicit substance most commonly implicated in driving under the influence of drugs (DUID) cases and fatally-injured drivers. No investigation of PMR of THC in human blood has been reported to date. Matched heart and iliac postmortem blood specimens were collected from 19 medical examiner cases (16 Males, 3 Females) with positive cannabinoid urine immunoassay screens. THC, its equipotent metabolite 11-hydroxy-THC (11-OH-THC) and non-psychoactive metabolite 11-nor-9-carboxy-THC (THCCOOH) were quantified by two-dimensional gas chromatography-mass spectrometry with cryofocusing, with 0.5 ng/mL limits of quantification (LOQ) for all analytes. 10 cases had quantifiable THC and 11-OH-THC; THCCOOH was present in all 19. Median (range) heart:iliac blood ratios were 1.5 for THC (range: 0.3-3.1); 1.6 for 11-OH-THC (range: 0.3-2.7); and 1.8 for THCCOOH (range: 0.5-3.0). Cannabinoids, in general, exhibited a mean and median central:peripheral (C:P) concentration ratio of less than 2 following death. A trend was observed for greater PMR with increasing postmortem interval between death and sampling. To our knowledge, these are the first data on THC PMR in humans, providing important scientific data to aid in the interpretation of postmortem cannabinoid concentrations in medico-legal investigations. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  13. Delta9-tetrahydrocannabinol increases sequence-specific AP-1 DNA-binding activity and Fos-related antigens in the rat brain.

    Science.gov (United States)

    Porcella, A; Gessa, G L; Pani, L

    1998-05-01

    Delta-9-tetrahydrocannabinol (delta9-THC), the psychoactive principle of marijuana, has been shown to upregulate the mRNA levels of immediate-early genes in the rat brain. Using electrophoretic mobility-shift assay and one-dimensional Western blot, we here report that delta9-THC increases Activator protein-1 (AP-1) DNA-binding and Fos-related antigen activity in discrete areas of the rat brain. One hour after the intraperitoneal administration of delta9-THC at a dose of 10 or 15 mg/kg, AP-1 DNA-binding activity in the nucleus accumbens increased by 33 and 49%, respectively, while Western blot showed an increase in both c-Fos, FosB, Fra-1 (Fos-related antigen) and Fra-2. In the cingulate cortex and caudate-putamen, delta9-THC significantly increased AP-1 DNA-binding activity only at the highest dose used (57 and 71%, respectively). While in the caudate-putamen the increase in AP-1 DNA binding was mainly due to an elevation of the c-Fos and FosB proteins, the same phenomenon depended on the FosB, Fra-1 and Fra-2 peptides in the cingulate cortex. The effect of delta9-THC on the AP-1 DNA binding and the Fos-related antigens in the nucleus accumbens was blocked by the specific cannabinoid antagonist SR141716 A (3 mg/kg i.p.). delta9-THC failed to modify Specificity protein 1 (Sp1) DNA-binding activity. The results indicate that delta9-THC activates gene coding for AP-1 DNA-binding proteins by acting on cannabinoid receptors, and induces a different transcriptional program on the early-immediate gene of the Fos family, in different areas in the rat brain, suggesting that this mechanism might be involved in the central actions of cannabinoids.

  14. Determination of ∆-9-Tetrahydrocannabinol (THC), 11-hydroxy-THC, 11-nor-9-carboxy-THC and Cannabidiol in Human Plasma using Gas Chromatography-Tandem Mass Spectrometry.

    Science.gov (United States)

    Andrenyak, David M; Moody, David E; Slawson, Matthew H; O'Leary, Daniel S; Haney, Margaret

    2017-05-01

    Two marijuana compounds of particular medical interest are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). A gas chromatography-tandem mass spectrometry (GC-MS-MS) method was developed to test for CBD, THC, hydroxy-THC (OH-THC) and carboxy-THC (COOH-THC) in human plasma. Calibrators (THC and OH-THC, 0.1 to 100; CBD, 0.25 to 100; COOH-THC, 0.5-500 ng/mL) and controls (0.3, 5 and 80 ng/mL, except COOH-THC at 1.5, 25 and 400 ng/mL) were prepared in blank matrix. Deuterated (d3) internal standards were added to 1-mL samples. Preparation involved acetonitrile precipitation, liquid-liquid extraction (hexane:ethyl acetate, 9:1), and MSTFA derivatization. An Agilent 7890 A GC was interfaced with an Agilent 7000 MS Triple Quadrupole. Selected reaction monitoring was employed. Blood samples were provided from a marijuana smoking study (two participants) and a CBD ingestion study (eight participants). Three analytes with the same transitions (THC, OH-THC and COOH-THC) were chromatographically separated. Matrix selectivity studies showed endogenous chromatographic peak area ratios (PAR) at the analyte retention times were THC, OH-THC and COOH-THC were seen; low concentrations of CBD were detected at early time points. In moderate users who had not smoked for at least 9 hours before ingesting an 800 mg oral dose of CBD, the method was sensitive enough to follow residual concentrations of THC and OH-THC; sustained COOH-THC concentrations over 50 ng/mL validated its higher analytical range. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Hormonal status and age differentially affect tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC on learning in female rats

    Directory of Open Access Journals (Sweden)

    Peter J Winsauer

    2015-07-01

    Full Text Available The effects of hormone status and age on the development of tolerance to D9-THC were assessed in sham-operated (intact or ovariectomized (OVX female rats that received either intraperitoneal saline or 5.6 mg/kg of D9-THC daily from postnatal day (PD 75 to 180 (early adulthood onward or PD 35 to 140 (adolescence onward. During this time, the 4 groups for each age (i.e., intact/saline, intact/THC, OVX/saline, and OVX/THC were trained in a learning and performance procedure and dose-effect curves were established for D9-THC (0.56-56 mg/kg and the cannabinoid type-1 receptor (CB1R antagonist rimonabant (0.32-10 mg/kg. Despite the persistence of small rate-decreasing and error-increasing effects in intact and OVX females from both ages during chronic D9-THC, all of the D9-THC groups developed tolerance. However, the magnitude of tolerance, as well as the effect of hormone status, varied with the age at which chronic D9-THC was initiated. There was no evidence of dependence in any of the groups. Hippocampal protein expression of CB1R, AHA1 (a co-chaperone of CB1R and HSP90β (a molecular chaperone modulated by AHA-1 was affected more by OVX than chronic D9-THC; striatal protein expression was not consistently affected by either manipulation. Hippocampal BDNF expression varied with age, hormone status, and chronic treatment. Thus, hormonal status differentially affects the development of tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (D9-THC on learning and performance behavior in adolescent, but not adult, female rats. These factors and their interactions also differentially affect cannabinoid signaling proteins in the hippocampus and striatum, and ultimately, neural plasticity.

  16. Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats.

    Science.gov (United States)

    Klein, Charlotte; Karanges, Emily; Spiro, Adena; Wong, Alexander; Spencer, Jarrah; Huynh, Thanh; Gunasekaran, Nathan; Karl, Tim; Long, Leonora E; Huang, Xu-Feng; Liu, Kelly; Arnold, Jonathon C; McGregor, Iain S

    2011-11-01

    The interactions between Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models. The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses. Adolescent rats were treated with ascending daily THC doses over 21 days (1 then 3 then 10 mg/kg). Some rats were given equivalent CBD doses 20 min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB(1) and 5-HT(1A) receptor binding were assessed. CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB(1) receptor binding and no drug effects on 5-HT(1A) receptor binding were observed. CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs.

  17. Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC*

    Science.gov (United States)

    Karschner, Erin L.; Schwope, David M.; Schwilke, Eugene W.; Goodwin, Robert S.; Kelly, Deanna L.; Gorelick, David A.; Huestis, Marilyn A.

    2012-01-01

    Background Determining time since last cannabis/Δ9-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing. Methods Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography-mass spectrometry. Results Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5 h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11-hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1-5 h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5 h after the last THC dose, respectively. Conclusions Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily. PMID:22464363

  18. Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Δ9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys.

    Science.gov (United States)

    Justinová, Zuzana; Redhi, Godfrey H; Goldberg, Steven R; Ferré, Sergi

    2014-05-07

    Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.

  19. A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part I: development and validation of a pulmonary cannabinoid route of exposure for experimental pharmacology studies in rodents.

    Science.gov (United States)

    Manwell, Laurie A; Charchoglyan, Armen; Brewer, Dyanne; Matthews, Brittany A; Heipel, Heather; Mallet, Paul E

    2014-01-01

    Most studies evaluating the effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in animal models administer it via a parenteral route (e.g., intraperitoneal (IP) or intravenous injection (IV)), however, the common route of administration for human users is pulmonary (e.g., smoking or vapourizing marijuana). A vapourized Δ(9)-THC delivery system for rodents was developed and used to compare the effects of pulmonary and parenteral Δ(9)-THC administration on blood cannabinoid levels and behaviour. Sprague-Dawley rats were exposed to pulmonary Δ(9)-THC (1, 5, and 10mg of inhaled vapour) delivered via a Volcano® vapourizing device (Storz and Bickel, Germany) or to parenteral Δ(9)-THC (0.25, 0.5, 1.0, and 1.5mg/kg injected IP). Quantification of Δ(9)-THC and its psychoactive metabolite, 11-hydroxy-Δ(9)-THC (11-OH-Δ(9)-THC), in blood was determined by liquid chromatography/mass spectrometry (LC/MS). In order to verify the potential for the vapourization procedure to produce a robust conditioned place preference (CPP) or conditioned place avoidance CPA, classical conditioning procedures were systematically varied by altering the exposure time (10 or 20min) and number of exposed rats (1 or 2) while maintaining the same vapourization dose (10mg). Blood collected at 20min intervals showed similar dose-dependent and time-dependent changes in Δ(9)-THC and 11-OH-Δ(9)-THC for both pulmonary and parenteral administration of Δ(9)-THC. However, vapourized Δ(9)-THC induced CPP under certain conditions whereas IP-administered Δ(9)-THC induced CPA. These results support and extend the limited evidence (e.g., in humans, Naef et al., 2004; in rodents, Niyuhire et al., 2007) that Δ(9)-THC produces qualitatively different effects on behaviour depending upon the route of administration. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Effect of combined doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea using rat (Sprague- Dawley) models of conditioned gaping.

    Science.gov (United States)

    Rock, Erin M; Limebeer, Cheryl L; Parker, Linda A

    2015-12-01

    Δ(9)-Tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) found in cannabis both reduce the distressing symptom of nausea, but their combined effects are not understood. The potential of combined doses of THC and CBDA to reduce acute nausea and anticipatory nausea in rodent models was assessed. For acute nausea, the potential of cannabinoid pretreatment(s) to reduce LiCl-induced nausea paired with saccharin was evaluated in a subsequent drug free taste reactivity test, followed by a taste avoidance test. For anticipatory nausea, the potential of the cannabinoid pretreatment(s) to reduce the expression of LiCl-induced contextually elicited conditioned gaping was evaluated. Combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) reduced acute nausea. Higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses also reduced acute nausea. THC (10 mg/kg) interfered with conditioned taste avoidance, an effect attenuated by CBDA (10 μg/kg). On the other hand, combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) did not suppress contextually elicited conditioned gaping in a test for anticipatory nausea. However, higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses, also reduced anticipatory nausea. Only at the highest dose (10 mg/kg) did THC impair locomotor activity, but CBDA did not at any dose. Combined subthreshold doses of THC:CBDA are particularly effective as a treatment for acute nausea. At higher doses, CBDA may attenuate THC-induced interference with learning.

  1. Acute and chronic effects of cannabidiol on Δ⁹-tetrahydrocannabinol (Δ⁹-THC)-induced disruption in stop signal task performance.

    Science.gov (United States)

    Jacobs, David S; Kohut, Stephen J; Jiang, Shan; Nikas, Spyros P; Makriyannis, Alexandros; Bergman, Jack

    2016-10-01

    Recent clinical and preclinical research has suggested that cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have interactive effects on measures of cognition; however, the nature of these interactions is not yet fully characterized. To address this, we investigated the effects of Δ9-THC and CBD independently and in combination with proposed therapeutic dose ratios of 1:1 and 1:3 Δ9-THC:CBD in adult rhesus monkeys (n = 6) performing a stop signal task (SST). Additionally, the development of tolerance to the effects of Δ9-THC on SST performance was evaluated by determining the effects of acutely administered Δ9-THC (0.1-3.2 mg/kg), during a 24-day chronic Δ9-THC treatment period with Δ9-THC alone or in combination with CBD. Results indicate that Δ9-THC (0.032-0.32 mg/kg) dose-dependently decreased go success but did not alter go reaction time (RT) or stop signal RT (SSRT); CBD (0.1-1.0 mg/kg) was without effect on all measures and, when coadministered in a 1:1 dose ratio, did not exacerbate or attenuate the effects of Δ9-THC. When coadministered in a 1:3 dose ratio, CBD (1.0 mg/kg) attenuated the disruptive effects of 0.32 mg/kg Δ9-THC but did not alter the effects of other Δ9-THC doses. Increases in ED50 values for the effects of Δ9-THC on SST performance were apparent during chronic Δ9-THC treatment, with little evidence for modification of changes in sensitivity by CBD. These results indicate that CBD, when combined with Δ9-THC in clinically available dose ratios, does not exacerbate and, under restricted conditions may even attenuate, Δ9-THC's behavioral effects. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  2. Short-term exposure and long-term consequences of neonatal exposure to Δ(9)-tetrahydrocannabinol (THC) and ibuprofen in mice.

    Science.gov (United States)

    Philippot, Gaëtan; Nyberg, Fred; Gordh, Torsten; Fredriksson, Anders; Viberg, Henrik

    2016-07-01

    Both Δ(9)-tetrahydrocannabinol (THC) and ibuprofen have analgesic properties by interacting with the cannabinoid receptor type 1 (CB1R) and the cyclooxygenase (COX) systems, respectively. Evaluation of these analgesics is important not only clinically, since they are commonly used during pregnancy and lactation, but also to compare them with acetaminophen, with a known interaction with both CB1R and the COX systems. Short-term exposure of neonatal rodents to acetaminophen during the first weeks of postnatal life, which is comparable with a period from the third trimester of pregnancy to the first years of postnatal life in humans, induces long-term behavioral disturbances. This period, called the brain growth spurt (BGS) and is characterized by series of rapid and fundamental changes and increased vulnerability, peaks around postnatal day (PND) 10 in mice. We therefore exposed male NMRI mice to either THC or ibuprofen on PND 10. At 2 months of age, the mice were subjected to a spontaneous behavior test, consisting of a 60min recording of the variables locomotion, rearing and total activity. Mice exposed to THC, but not ibuprofen, exhibited altered adult spontaneous behavior and habituation capability in a dose-dependent manner. This highlights the potency of THC as a developmental neurotoxicant, since a single neonatal dose of THC was enough to affect adult cognitive function. The lack of effect from ibuprofen also indicates that the previously seen developmental neurotoxicity of acetaminophen is non-COX-mediated. These results might be of importance in future research as well as in the ongoing risk/benefit assessment of THC. Copyright © 2016. Published by Elsevier B.V.

  3. Effect of norbinaltorphimine on ∆⁹-tetrahydrocannabinol (THC)-induced taste avoidance in adolescent and adult Sprague-Dawley rats.

    Science.gov (United States)

    Flax, Shaun M; Wakeford, Alison G P; Cheng, Kejun; Rice, Kenner C; Riley, Anthony L

    2015-09-01

    The aversive effects of ∆(9)-tetrahydrocannabinol (THC) are mediated by activity at the kappa opioid receptor (KOR) as assessed in adult animals; however, no studies have assessed KOR involvement in the aversive effects of THC in adolescents. Given that adolescents have been reported to be insensitive to the aversive effects induced by KOR agonists, a different mechanism might mediate the aversive effects of THC in this age group. The present study was designed to assess the impact of KOR antagonism on the aversive effects of THC in adolescent and adult rats using the conditioned taste avoidance (CTA) procedure. Following a single pretreatment injection of norbinaltorphimine (norBNI; 15 mg/kg), CTAs induced by THC (0, 0.56, 1.0, 1.8, and 3.2 mg/kg) were assessed in adolescent (n = 84) and adult (n = 83) Sprague-Dawley rats. The KOR antagonist, norBNI, had weak and inconsistent effects on THC-induced taste avoidance in adolescent rats in that norBNI both attenuated and strengthened taste avoidance dependent on dose and trial. norBNI had limited impact on the final one-bottle avoidance and no effects on the two-bottle preference test. Interestingly, norBNI had no effect on THC-induced taste avoidance in adult rats as well. That norBNI had no significant effect on THC-induced avoidance in adults, and a minor and inconsistent effect in adolescents demonstrates that the aversive effects of THC are not mediated by KOR activity as assessed by the CTA design in Sprague-Dawley rats.

  4. Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC.

    Science.gov (United States)

    Karschner, Erin L; Schwope, David M; Schwilke, Eugene W; Goodwin, Robert S; Kelly, Deanna L; Gorelick, David A; Huestis, Marilyn A

    2012-10-01

    Determining time since last cannabis/Δ9-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing. Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography-mass spectrometry. Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11-hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1-5h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5h after the last THC dose, respectively. Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily. Published by Elsevier Ireland Ltd.

  5. Blunting of the HPA-axis underlies the lack of preventive efficacy of early post-stressor single-dose Delta-9-tetrahydrocannabinol (THC).

    Science.gov (United States)

    Mayer, Tzur Alexander; Matar, Michael Alex; Kaplan, Zeev; Zohar, Joseph; Cohen, Hagit

    2014-07-01

    The therapeutic value of Delta-9-tetrahydrocannabinol (Δ9-THC) in the aftermath of trauma has recently raised interest. A prospective animal model for posttraumatic stress disorder was employed to assess the behavioral effects of a single dose of Δ9-THC administered intraperitoneally following exposure to psychogenic stress. Animals were exposed to predator scent stress and treated 1h later with Δ9-THC (1, 5 and 10mg/kg) or vehicle. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 1, 6 and 24 h or 7 days after exposure and freezing behavior upon exposure to a trauma cue on day 8. Pre-set cut-off behavioral criteria classified exposed animals as those with "extreme," "minimal" or "intermediate" (partial) response. Circulating corticosterone levels were assessed over 2h after exposure with and without Δ9-THC. The behavioral effects of a CB1 antagonist (AM251) administered systemically 1h post exposure were evaluated. In the short term (1-6 h), 5 mg/kg of Δ9-THC effectively attenuated anxiety-like behaviors. In the longer-term (7 days), it showed no effect in attenuating PTSD-like behavioral stress responses, or freezing response to trauma cue. Δ9-THC significantly decreased corticosterone levels. In contrast, administration of AM251 (a CB1 antagonist/inverse agonist) 1 h post exposure attenuated long-term behavioral stress responses through activation of the HPA-axis. The demonstrated lack of preventive efficacy of early Δ9-THC treatment and reports of its anxiogenic effects in many individuals raises doubts not only regarding its potential clinical value, but also the advisability of clinical trials. The endocannabinoids exert complex effects on behavioral responses mediating glucocorticoid effects on memory of traumatic experiences. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.

    Science.gov (United States)

    Freeman, Daniel; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Antley, Angus; Slater, Mel; Godlewska, Beata; Cornish, Robert; Williams, Jonathan; Di Simplicio, Martina; Igoumenou, Artemis; Brenneisen, Rudolf; Tunbridge, Elizabeth M; Harrison, Paul J; Harmer, Catherine J; Cowen, Philip; Morrison, Paul D

    2015-03-01

    Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis-∆(9)-tetrahydrocannabinol (THC)-causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

  7. A Preliminary Investigation of Individual Differences in Subjective Responses to D-Amphetamine, Alcohol, and Delta-9-Tetrahydrocannabinol Using a Within-Subjects Randomized Trial.

    Directory of Open Access Journals (Sweden)

    Margaret C Wardle

    Full Text Available Polydrug use is common, and might occur because certain individuals experience positive effects from several different drugs during early stages of use. This study examined individual differences in subjective responses to single oral doses of d-amphetamine, alcohol, and delta-9-tetrahydrocannabinol (THC in healthy social drinkers. Each of these drugs produces feelings of well-being in at least some individuals, and we hypothesized that subjective responses to these drugs would be positively correlated. We also examined participants' drug responses in relation to personality traits associated with drug use. In this initial, exploratory study, 24 healthy, light drug users (12 male, 12 female, aged 21-31 years, participated in a fully within-subject, randomized, counterbalanced design with six 5.5-hour sessions in which they received d-amphetamine (20mg, alcohol (0.8 g/kg, or THC (7.5 mg, each paired with a placebo session. Participants rated the drugs' effects on both global measures (e.g. feeling a drug effect at all and drug-specific measures. In general, participants' responses to the three drugs were unrelated. Unexpectedly, "wanting more" alcohol was inversely correlated with "wanting more" THC. Additionally, in women, but not in men, "disliking" alcohol was negatively correlated with "disliking" THC. Positive alcohol and amphetamine responses were related, but only in individuals who experienced a stimulant effect of alcohol. Finally, high trait constraint (or lack of impulsivity was associated with lower reports of liking alcohol. No personality traits predicted responses across multiple drug types. Generally, these findings do not support the idea that certain individuals experience greater positive effects across multiple drug classes, but instead provide some evidence for a "drug of choice" model, in which individuals respond positively to certain classes of drugs that share similar subjective effects, and dislike other types

  8. Lack of hippocampal CB1 receptor desensitization by Δ(9)-tetrahydrocannabinol in aged mice and by low doses of JZL 184.

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    Feliszek, Monika; Bindila, Laura; Lutz, Beat; Zimmer, Andreas; Bilkei-Gorzo, Andras; Schlicker, Eberhard

    2016-06-01

    Activation of cannabinoid CB1 receptors may offer new therapeutic strategies, but the efficiency of CB1 receptor agonists may be impaired by tolerance development upon prolonged administration. We compared the influence of repeated administration of Δ(9)-tetrahydrocannabinol (THC) 10 mg/kg on the motility and on basal and CB1 receptor-stimulated (35)S-GTPγS binding of adolescent and aged mice. Moreover, we determined the influence of JZL 184 (which inhibits the 2-arachidonoylglycerol, 2-AG, degrading enzyme monoacylglycerol lipase, MAGL) on (35)S-GTPγS binding and 2-AG levels of young adult mice. Mouse motility was tested in the open field. (35)S-GTPγS binding was studied in hippocampal membranes. THC and CP 55,940 were used as cannabinoid agonists in the behavioural and biochemical studies, respectively. 2-AG levels were quantified by liquid chromatography-multiple reaction monitoring. The THC (10 mg/kg)-induced hypomotility was stronger in untreated than in THC-pretreated adolescent mice but similar in both treatment groups of aged mice. Basal and stimulated (35)S-GTPγS binding was decreased in membranes from THC-pretreated adolescent but not affected in membranes from aged mice. Treatment of young adult mice with JZL 184 (4, 10 and 40 mg/kg) for 14 days did not affect basal binding. Stimulated binding tended to be decreased by 25 % only in mice treated with JZL 184 (40 mg/kg). Hippocampal 2-AG level was increased by JZL 184 at 40 and 10 but not affected at 4 mg/kg. In conclusion, CB1 receptor tolerance does not occur in aged mice pretreated with THC and in young adult mice treated with a low dose of the MAGL inhibitor JZL 184.

  9. Blood levels do not predict behavioral or physiological effects of Δ⁹-tetrahydrocannabinol in rhesus monkeys with different patterns of exposure.

    Science.gov (United States)

    Ginsburg, Brett C; Hruba, Lenka; Zaki, Armia; Javors, Martin A; McMahon, Lance R

    2014-06-01

    Recent changes in the legality of cannabis have prompted evaluation of whether blood levels of Δ(9)-tetrahydrocannabinol (THC) or its metabolites could be used to substantiate impairment, particularly related to behavioral tasks such as driving. However, because marked tolerance develops to behavioral effects of THC, the applicability of a particular threshold of blood THC as an index of impairment in people with different patterns of use remains unclear. Studies relevant to this issue are difficult to accomplish in humans, as prior drug exposure is difficult to control. Here, effects of THC to decrease rectal temperature and operant response rate compared to levels of THC and its metabolites were studied in blood in two groups of monkeys: one received intermittent treatment with THC (0.1 mg/kg i.v. every 3-4 days) and another received chronic THC (1 mg/kg/12 h s.c.) for several years. In monkeys with intermittent THC exposure, a single dose of THC (3.2 mg/kg s.c.) decreased rectal temperature and response rate. The same dose did not affect response rate or rectal temperature in chronically exposed monkeys, indicative of greater tolerance. In both groups, blood levels of THC peaked 20-60 min post-injection and had a similar half-life of elimination, indicating no tolerance to the pharmacokinetics of THC. Notably, in both groups, the behavioral effects of THC were not apparent when blood levels were maximal (20-min post-administration). These data indicate that thresholds for blood levels of THC do not provide a consistent index of behavioral impairment across individuals with different patterns of THC exposure. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Electrospun biocompatible Chitosan/MIL-101 (Fe) composite nanofibers for solid-phase extraction of Δ9-tetrahydrocannabinol in whole blood samples using Box-Behnken experimental design.

    Science.gov (United States)

    Asiabi, Mina; Mehdinia, Ali; Jabbari, Ali

    2017-01-06

    The nanofibers of biocompatible Chitosan/MIL-101 (Fe) composite were synthesized by a simple, cheap and accessible electrospining method and applied for mat-based extraction of trace amount of Δ9-tetrahydrocannabinol (THC) from human whole blood sample following its combination by high performance liquid chromatography-ultraviolet detection. The composite nanofibres were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction and N2 adsorption-desorption experiments. The volume of eluting solvent, sorbent amount, pH and% NaCl (w/v) influencing on the responses were investigated using factorial experimental design. The optimum point was achieved by analysis of the results according to design expert (DX) software. The volume of eluting solvent, sorbent amount and pH were significant variables, and 150μL, 7mg and 7.0 were respectively chosen for obtaining the best extraction response. Under the optimum conditions, the method was exhibited a linear range of 0.1-100μgL-1 (R2=0.9943) for THC with a detection limit of 0.04μgL-1. Acceptable values for intra-day (3.2%) and inter-day (4.8%) relative standard deviations were obtained. The high preconcentration factor (970) and satisfactory recoveries (88.2%-92.4%) in whole blood samples were achieved which proved the capability of the method for trace determination of THC in the human whole blood samples. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ(9)-tetrahydrocannabinol challenge tests.

    Science.gov (United States)

    Guan, Zheng; Klumpers, Linda E; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M A; Stevens, Jasper

    2016-04-01

    The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed. The pharmacokinetic models of THC and four CB1 antagonists were built separately. THC-induced effects on heart rate and the visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in PD models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario. The final PK model of THC and antagonists was a two compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t1/2ke0 ranged from 0.00462 to 63.7 h for heart rate and from 0.964 to 150 h for VAS. IC50 ranged from 6.42 to 202 ng ml(-1) for heart rate and from 12.1 to 376 ng ml(-1) for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist. PK/PD modelling and simulation approach was suitable for describing and predicting heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might be of benefit to guide future studies. © 2015 The British Pharmacological Society.

  12. Comparison of the discriminative stimulus and response rate effects of Δ9-tetrahydrocannabinol and synthetic cannabinoids in female and male rats.

    Science.gov (United States)

    Wiley, Jenny L; Lefever, Timothy W; Marusich, Julie A; Craft, Rebecca M

    2017-03-01

    Women report greater sensitivity to the subjective effects of Δ9-tetrahydrocannabinol (THC). Similarly, female rodents tend to be more sensitive to some pharmacological effects of THC and synthetic cannabinoids. This study examined sex differences in discriminative stimulus and response rate effects of THC and synthetic cannabinoids in rats. A cumulative dosing THC discrimination procedure was utilized to evaluate sex differences in the discriminative stimulus effects of THC and three synthetic cannabinoids: CP47,497, WIN55,212-2, and JWH-018. Sex differences in the effects of these four compounds and a degradant of A-834735 on response rates also were assessed in a food-reinforced discrete dosing procedure. Females required a lower training dose than males for acquisition of the discrimination. Further, THC was more potent at producing rimonabant-reversible discriminative stimulus and response rate effects in females. While synthetic cannabinoids were more potent in producing THC-like effects than was THC in female rats, greater discrepancies were observed in male rats. Similar sensitivity to the response rate-decreasing effects induced by most, but not all (A-834735 degradant), synthetic cannabinoids was seen in both sexes. This study represents one of the first direct comparisons of sex differences in THC discrimination. Females were more sensitive to THC's effects, which may be related, in part, to sex differences in THC metabolism. Synthetic cannabinoids were more potent than THC in both sexes, but were considerably more so in male than in female rats. Future research should emphasize further characterization of sex differences in cannabinoid pharmacology. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC

    Science.gov (United States)

    Schwilke, Eugene W.; Schwope, David M.; Karschner, Erin L.; Lowe, Ross H.; Darwin, William D.; Kelly, Deanna L.; Goodwin, Robert S.; Gorelick, David A.; Huestis, Marilyn A.

    2011-01-01

    BACKGROUND Δ9-Tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis and an active cannabinoid pharmacotherapy component. No plasma pharmacokinetic data after repeated oral THC administration are available. METHODS Six adult male daily cannabis smokers resided on a closed clinical research unit. Oral THC capsules (20 mg) were administered every 4–8 h in escalating total daily doses (40–120 mg) for 7 days. Free and glucuronidated plasma THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THC COOH) were quantified by 2-dimensional GC-MS during and after dosing. RESULTS Free plasma THC, 11-OH-THC, and THCCOOH concentrations 19.5 h after admission (before controlled oral THC dosing) were mean 4.3 (SE 1.1), 1.3 (0.5), and 34.0 (8.4) μg/L, respectively. During oral dosing, free 11-OH-THC and THCCOOH increased steadily, whereas THC did not. Mean peak plasma free THC, 11-OH-THC, and THCCOOH concentrations were 3.8 (0.5), 3.0 (0.7), and 196.9 (39.9) μg/L, respectively, 22.5 h after the last dose. Escherichia coli β-glucuronidase hydrolysis of 264 cannabinoid specimens yielded statistically significant increases in THC, 11-OH-THC, and THCCOOH concentrations (P 1 μg/L for at least 1 day after daily cannabis smoking and also after cessation of multiple oral THC doses. We report for the first time free plasma THC concentrations after multiple high-dose oral THC throughout the day and night, and after Escherichia coli β-glucuronidase hydrolysis. These data will aid in the interpretation of plasma THC concentrations after multiple oral doses. PMID:19833841

  14. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.

    Science.gov (United States)

    Pertwee, R G

    2008-01-01

    Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Delta9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Delta9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

  15. Regulation of hippocampal cannabinoid CB1 receptor actions by adenosine A1 receptors and chronic caffeine administration: implications for the effects of Δ9-tetrahydrocannabinol on spatial memory.

    Science.gov (United States)

    Sousa, Vasco C; Assaife-Lopes, Natália; Ribeiro, Joaquim A; Pratt, Judith A; Brett, Ros R; Sebastião, Ana M

    2011-01-01

    The cannabinoid CB(1) receptor-mediated modulation of γ-aminobutyric acid (GABA) release from inhibitory interneurons is important for the integrity of hippocampal-dependent spatial memory. Although adenosine A(1) receptors have a central role in fine-tuning excitatory transmission in the hippocampus, A(1) receptors localized in GABAergic cells do not directly influence GABA release. CB(1) and A(1) receptors are the main targets for the effects of two of the most heavily consumed psychoactive substances worldwide: Δ(9)-tetrahydrocannabinol (THC, a CB(1) receptor agonist) and caffeine (an adenosine receptor antagonist). We first tested the hypothesis that an A(1)-CB(1) interaction influences GABA and glutamate release in the hippocampus. We found that A(1) receptor activation attenuated the CB(1)-mediated inhibition of GABA and glutamate release and this interaction was manifested at the level of G-protein activation. Using in vivo and in vitro approaches, we then investigated the functional implications of the adenosine-cannabinoid interplay that may arise following chronic caffeine consumption. Chronic administration of caffeine in mice (intraperitoneally, 3 mg/kg/day, for 15 days, >12 h before trials) led to an A(1)-mediated enhancement of the CB(1)-dependent acute disruptive effects of THC on a short-term spatial memory task, despite inducing a reduction in cortical and hippocampal CB(1) receptor number and an attenuation of CB(1) coupling with G protein. A(1) receptor levels were increased following chronic caffeine administration. This study shows that A(1) receptors exert a negative modulatory effect on CB(1)-mediated inhibition of GABA and glutamate release, and provides the first evidence of chronic caffeine-induced alterations on the cannabinoid system in the cortex and hippocampus, with functional implications in spatial memory.

  16. Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification (Part II): Psychiatric complaints and their relation to delta-9-tetrahydrocannabinol and its metabolites in serum.

    Science.gov (United States)

    Bonnet, Udo; Borda, Thorsten; Scherbaum, Norbert; Specka, Michael

    2015-10-01

    To investigate the impact of inpatient detoxification treatment on psychiatric symptoms of chronic cannabis addicts and to analyze the influence of serum cannabinoid levels on the severity of these symptoms. Thirty five treatment-seeking, not active co-morbid chronic cannabis dependents (ICD-10) were studied on admission and on abstinence days 8 and 16, using several observational and self-report scales, such as Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Young Mania Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS), and the Symptom Checklist-90-Revised (SCL-90-R). Simultaneously obtained serum was analyzed with regard to levels of delta-9-tetrahydrocannabinol (THC) and its main metabolites 11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). At admission, nearly 90% of the patients were not, or only mildly, affected by depression, anxiety or manic symptoms. In contrast, patients' self-description indicated a strong psychiatric burden in approximately 60% of the cases. All patients improved significantly within 16 days of the treatment. Effect sizes ranged from 0.7 to 1.4. (Cohen's d) for the respective scales. Serum THC-levels were positively associated with impairment of cognition in HAMA and motor retardation in BPRS. All other test results were not significantly related to the serum levels of the measured cannabinoids. Effects of the cannabis withdrawal syndrome and executive dysfunctions might explain the discrepancy between the observer ratings and self-reported psychiatric burden. Inpatient cannabis detoxification treatment significantly improved psychiatric symptoms. Serum THC-levels were not associated with affective symptoms and anxiety but predicted cognitive impairment and motor retardation. Copyright © 2015. Published by Elsevier Ireland Ltd.

  17. Chronic Adolescent Δ9-Tetrahydrocannabinol Treatment of Male Mice Leads to Long-Term Cognitive and Behavioral Dysfunction, Which Are Prevented by Concurrent Cannabidiol Treatment.

    Science.gov (United States)

    Murphy, Michelle; Mills, Sierra; Winstone, Joanna; Leishman, Emma; Wager-Miller, Jim; Bradshaw, Heather; Mackie, Ken

    2017-01-01

    Introduction: The high prevalence of adolescent cannabis use, the association between this use and later psychiatric disease, and increased access to high-potency cannabis highlight the need for a better understanding of the long-term effects of adolescent cannabis use on cognitive and behavioral outcomes. Furthermore, increasing Δ 9 -tetrahydrocannabinol (THC) in high-potency cannabis is accompanied by a decrease in cannabidiol (CBD), thus an understanding of the interactions between CBD and THC in the neurodevelopmental effects of THC is also important. The current study examined the immediate and long-term behavioral consequences of THC, CBD, and their combination in a mouse model of adolescent cannabis use. Materials and Methods: Male CD1 mice received daily injections of THC (3 mg/kg), CBD (3 mg/kg), CBD+THC (3 mg/kg each), vehicle, or remained undisturbed in their home cage (no handling/injections), either during adolescence (postnatal day [PND] 28-48) or during early adulthood (PND 69-89). Animals were then evaluated with a battery of behavioral tests 1 day after drug treatment, and again after 42 drug-free days. The tests included the following: open field (day 1), novel object recognition (NOR; day 2), marble burying (day 3), elevated plus maze (EPM; day 4), and Nestlet shredding (day 5). Results: Chronic administration of THC during adolescence led to immediate and long-term impairments in object recognition/working memory, as measured by the NOR task. In contrast, adult administration of THC caused immediate, but not long term, impairment of object/working memory. Adolescent chronic exposure to THC increased repetitive and compulsive-like behaviors, as measured by the Nestlet shredding task. Chronic administration of THC, either during adolescence or during adulthood, led to a delayed increase in anxiety as measured by the EPM. All THC-induced behavioral abnormalities were prevented by the coadministration of CBD+THC, whereas CBD alone did not

  18. Adolescent Female Cannabinoid Exposure Diminishes the Reward-Facilitating Effects of Δ9-Tetrahydrocannabinol and d-Amphetamine in the Adult Male Offspring

    Directory of Open Access Journals (Sweden)

    George Panagis

    2017-04-01

    Full Text Available Marijuana is currently the most commonly abused illicit drug. According to recent studies, cannabinoid use occurring prior to pregnancy can impact brain plasticity and behavior in future generations. The purpose of the present study was to determine whether adolescent exposure of female rats to Δ9-tetrahydrocannabinol (Δ9-THC induces transgenerational effects on the reward-facilitating effects of Δ9-THC and d-amphetamine in their adult male offspring. Female Sprague-Dawley rats received Δ9-THC (0.1 or 1 mg/kg, i.p. or vehicle during postnatal days 28–50. As adults, females were mated with drug-naïve males. We then assessed potential alterations of the Δ9-THC’s (0, 0.1, 0.5, and 1 mg/kg, i.p. and d-amphetamine’s (0, 0.1, 0.5, and 1 mg/kg, i.p. reward-modifying effects using the curve-shift variant of the intracranial self-stimulation (ICSS procedure in their adult male F1 offspring. The reward-facilitating effect of the 0.1 mg dose of Δ9-THC was abolished in the F1 offspring of females that were exposed to Δ9-THC (0.1 or 1 mg/kg, whereas the reward-attenuating effect of the 1 mg dose of Δ9-THC remained unaltered. The reward-facilitating effects of 0.5 and 1 mg of d-amphetamine were significantly decreased in the F1 offspring of females that were exposed to Δ9-THC (1 mg/kg and 0.1 or 1 mg, respectively. The present results reveal that female Δ9-THC exposure during adolescence can diminish the reward-facilitating effects of Δ9-THC and d-amphetamine in the adult male offspring. These transgenerational effects occur in the absence of in utero exposure. It is speculated that Δ9-THC exposure during female adolescence may affect neural mechanisms that are shaping reward-related behavioral responses in a subsequent generation, as indicated by the shifts in the reward-facilitating effects of commonly used and abused drugs.

  19. Effect of combined oral doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models.

    Science.gov (United States)

    Rock, Erin M; Connolly, Cassidy; Limebeer, Cheryl L; Parker, Linda A

    2016-09-01

    The purpose of this study was to evaluate the potential of oral combined cannabis constituents to reduce nausea. The objective of this study was to determine the effect of combining subthreshold oral doses of Δ(9)-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea in rat models of conditioned gaping. The potential of intragastric (i.g.) administration of THC, CBDA, or combined doses, to interfere with acute nausea-induced conditioned gaping (acute nausea) or the expression of contextually elicited conditioned gaping (anticipatory nausea), was evaluated. For acute nausea, i.g. administration of subthreshold doses of THC (0.5 and 1 mg/kg) or CBDA (0.5 and 1 μg/kg) significantly suppressed acute nausea-induced gaping, whereas higher individual doses of both THC and CBDA were maximally effective. Combined i.g. administration of higher doses of THC and CBDA (2.5 mg/kg THC-2.5 μg/kg CBDA; 10 mg/kg THC-10 μg/kg CBDA; 20 mg/kg THC-20 μg/kg CBDA) also enhanced positive hedonic reactions elicited by saccharin solution during conditioning. For anticipatory nausea, combined subthreshold i.g. doses of THC (0.1 mg/kg) and CBDA (0.1 μg/kg) suppressed contextually elicited conditioned gaping. When administered i.g., THC was effective on its own at doses ranging from 1 to 10 mg/kg, but CBDA was only effective at 10 μg/kg. THC alone was equally effective by intraperitoneal (i.p.) and i.g. administration, whereas CBDA alone was more effective by i.p. administration (Rock et al. in Psychopharmacol (Berl) 232:4445-4454, 2015) than by i.g. administration. Oral administration of subthreshold doses of THC and CBDA may be an effective new treatment for acute nausea and anticipatory nausea and appetite enhancement in chemotherapy patients.

  20. A vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) delivery system part II: comparison of behavioural effects of pulmonary versus parenteral cannabinoid exposure in rodents.

    Science.gov (United States)

    Manwell, Laurie A; Ford, Brittany; Matthews, Brittany A; Heipel, Heather; Mallet, Paul E

    2014-01-01

    Studies of the rewarding and addictive properties of cannabinoids using rodents as animal models of human behaviour often fail to replicate findings from human studies. Animal studies typically employ parenteral routes of administration, whereas humans typically smoke cannabis, thus discrepancies may be related to different pharmacokinetics of parenteral and pulmonary routes of administration. Accordingly, a novel delivery system of vapourized Δ(9)-tetrahydrocannabinol (Δ(9)-THC) was developed and assessed for its pharmacokinetic, pharmacodynamic, and behavioural effects in rodents. A commercially available vapourizer was used to assess the effects of pulmonary (vapourized) administration of Δ(9)-THC and directly compared to parenteral (intraperitoneal, IP) administration of Δ(9)-THC. Sprague-Dawley rats were exposed to pure Δ(9)-THC vapour (1, 2, 5, 10, and 20mg/pad), using a Volcano® vapourizing device (Storz and Bickel, Germany) or IP-administered Δ(9)-THC (0.1, 0.3, 0.5, 1.0mg/kg), and drug effects on locomotor activity, food and water consumption, and cross-sensitization to morphine (5mg/kg) were measured. Vapourized Δ(9)-THC significantly increased feeding during the first hour following exposure, whereas IP-administered Δ(9)-THC failed to produce a reliable increase in feeding at all doses tested. Acute administration of 10mg of vapourized Δ(9)-THC induced a short-lasting stimulation in locomotor activity compared to control in the first of four hours of testing over 7days of repeated exposure; this chronic exposure to 10mg of vapourized Δ(9)-THC did not induce behavioural sensitization to morphine. These results suggest vapourized Δ(9)-THC administration produces behavioural effects qualitatively different from those induced by IP administration in rodents. Furthermore, vapourized Δ(9)-THC delivery in rodents may produce behavioural effects more comparable to those observed in humans. We conclude that some of the conflicting findings in animal

  1. Micro-pulverized extraction pretreatment for highly sensitive analysis of 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol in hair by liquid chromatography/tandem mass spectrometry.

    Science.gov (United States)

    Kuwayama, Kenji; Miyaguchi, Hajime; Yamamuro, Tadashi; Tsujikawa, Kenji; Kanamori, Tatsuyuki; Iwata, Yuko T; Inoue, Hiroyuki

    2015-11-30

    A primary metabolite of Δ(9) -tetrahydrocannabinol, 11-nor-9-carboxytetrahydrocannabinol (THC-COOH), serves as an effective indicator for cannabis intake. According to the recommendations of the Society of Hair Testing, at least 0.2 pg/mg of THC-COOH (cut-off level) must be present in a hair sample to constitute a positive result in a drug test. Typically, hair is digested with an alkaline solution and is subjected to gas chromatography/tandem mass spectrometry (GC/MS/MS) with negative ion chemical ionization (NICI). It is difficult to quantify THC-COOH at the cut-off level using liquid chromatography/tandem mass spectrometry (LC/MS/MS) without acquisition of second-generation product ions in triple quadrupole-ion trap mass spectrometers, because large amounts of matrix components in the low-mass range produced by digestion interfere with the THC-COOH peak. Using the typical pretreatment method (alkaline dissolution) and micro-pulverized extraction (MPE) with a stainless bullet, we compared the quantification of THC-COOH using GC/MS/MS and LC/MS/MS. MPE reduced the amount of matrix components in the low-mass range and enabled the quantification of THC-COOH at 0.2 pg/mg using a conventional triple quadrupole liquid chromatograph coupled to a mass spectrometer. On the other hand, the MPE pretreatment was unsuitable for GC/MS/MS, probably due to matrix components in the high-mass range. The proper combination of pretreatments and instrumental analyses was shown to be important for detecting trace amounts of THC-COOH in hair. In MPE, samples can be prepared rapidly, and LC/MS/MS is readily available, unlike GC/MS/MS with NICI. The combination of MPE and LC/MS/MS might therefore be used in the initial screening for THC-COOH in hair prior to confirmatory analysis using GC/MS/MS with NICI. Copyright © 2015 John Wiley & Sons, Ltd.

  2. Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility of the prepubescent animal.

    Science.gov (United States)

    Silva, Lindsay; Black, Rita; Michaelides, Michael; Hurd, Yasmin L; Dow-Edwards, Diana

    Adolescents who use marijuana are more likely to exhibit anxiety, depression, and other mood disorders, including psychotic-like symptoms. Additionally, the age at onset of use and the stress history of the individual can affect responses to cannabis. To examine the effect of early life experience on adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we exposed adolescent (postnatal day (P) 29-38) male and female rats, either shipped from a supplier or born in our vivarium, to once daily injections of 3mg/kg THC. Our findings suggest that males are more sensitive to the anxiolytic and antidepressant effects of THC, as measured by the elevated plus maze (EPM) and forced swim test (FST), respectively, than females. Exposure to the FST increased plasma corticosterone levels, regardless of drug treatment or origin and females had higher levels than males overall. Shipping increased THC responses in females (acoustic startle habituation) and in males (latency to immobility in FST). No significant effects of THC or shipping on pre-pulse inhibition were observed. Due to differences in timing of puberty in males and females during the P29-38 period of THC treatment, we also dosed female rats between P21-30 (pre-puberty) and male rats between P39-48 (puberty). Pre-pubertal animals showed reductions in anxiety on the EPM, an effect that was not seen in animals treated during puberty. These results suggest that both sexes are more susceptible to changes in emotional behavior when THC exposure occurs just prior to the onset of puberty. Within the animals dosed from P29-38, THC increased cannabinoid receptor 1 (CB1R) mRNA expression and tended to decrease CP55,940 stimulated [35S]GTPγS binding in the central amygdala only of females. Therefore, early stress enhances THC responses in males (in FST) and females (ASR habituation), THC alters CB1R expression and function in females only and prepubescent rats are generally more responsive to THC than pubertal rats. In summary

  3. Highly sensitive quantification of unconjugated 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol in a cannabis user's hair using micropulverized extraction.

    Science.gov (United States)

    Kuwayama, Kenji; Miyaguchi, Hajime; Yamamuro, Tadashi; Tsujikawa, Kenji; Kanamori, Tatsuyuki; Iwata, Yuko T; Inoue, Hiroyuki

    2016-05-01

    We previously developed a simple and highly sensitive analytical method for 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol (THC-COOH) in spiked hair using micropulverized extraction (MPE) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Using this method, we were able to quantify THC-COOH at 0.2pg/mg, which is the cut-off level recommended by the Society of Hair Testing. However, it was impossible to prove the validity of the method and the presence of THC-COOH conjugated with glucuronide in hair because we did not have authentic hair containing THC-COOH at the cut-off levels at that time. In this study, the previously developed method was verified using recently obtained hair from a cannabis user. The concentrations of THC-COOH quantified using the method were 0.36±0.01pg/mg without hydrolyzation for glucuronide and 0.49±0.05pg/mg with hydrolyzation after MPE, whereas the concentration quantified using the conventional alkaline dissolution and gas chromatography/tandem mass spectrometry with negative ion chemical ionization was 0.50±0.02pg/mg. The results proved that THC-COOH could be extracted completely from authentic hair containing THC-COOH at the recommended cut-off level using MPE. In addition, MPE with and without hydrolyzation, unlike alkaline dissolution of hair, enabled the measurement of the percentage of the conjugate form in total THC-COOH. The percentage of conjugated THC-COOH in hair measured using the MPE was approximately 26%, which was greatly different from previously reported data (>75%). The discrimination between conjugated and unconjugated compounds in hair is important to understand the mechanism of drug uptakes into hair. More data obtained with our simple and highly sensitive method from the hair of cannabis users would help to understand the relationship of concentrations between THC-COOH and its conjugate in hair. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Quantification of anandamide and 2-arachidonoylglycerol plasma levels to examine potential influences of tetrahydrocannabinol application on the endocannabinoid system in humans.

    Science.gov (United States)

    Thieme, Ulrike; Schelling, Gustav; Hauer, Daniela; Greif, Robert; Dame, Torsten; Laubender, Ruediger Paul; Bernhard, Werner; Thieme, Detlef; Campolongo, Patrizia; Theiler, Lorenz

    2014-01-01

    The effects of tetrahydrocannabinol (THC) and endogenous cannabinoids (endocannabinoids, ECs) are both mediated by activation of the cannabinoid receptors CB1 and CB2. Exogenous activation of these receptors by THC could therefore alter EC levels. We tested this hypothesis in healthy volunteers (n = 25) who received a large intravenous dose of THC (0.10 mg/kg). Effects on the EC system were quantified by serial measurements of plasma ECs after THC administration. Eleven blood samples were drawn during the first 5 h after THC administration and two more samples after 24 and 48 h. THC, its metabolites THC-OH (biologically active) and THC-COOH (non-active), and the ECs anandamide and 2-arachidonoylglycerol (2-AG) were quantified by liquid chromatography-mass spectrometry. EC-plasma levels showed a biphasic response after THC injection reaching maximal values at 30 min. Anandamide increased slightly from 0.58 ± 0.21 ng/ml at baseline to 0.64 ± 0.24 ng/ml (p < 0.05) and 2-AG from 7.60 ± 4.30 ng/ml to 9.50 ± 5.90 ng/ml (p < 0.05). After reaching maximal concentrations, EC plasma levels decreased markedly to a nadir of 300 min after THC administration (to 0.32 ± 0.15 ng/ml for anandamide and to 5.50 ± 3.01 ng/ml for 2-AG, p < 0.05). EC plasma concentrations returned to near baseline levels until 48 h after the experiment. THC (0.76 ± 0.16 ng/ml) and THC-OH (0.36 ± 0.17 ng/ml) were still measurable at 24 h and remained detectible until 48 h after THC administration. Although the underlying mechanism is not clear, high doses of intravenous THC appear to influence endogenous cannabinoid concentrations and presumably EC-signalling. Copyright © 2013 John Wiley & Sons, Ltd.

  5. Chronic Δ(9)-Tetrahydrocannabinol Administration Reduces IgE(+)B Cells but Unlikely Enhances Pathogenic SIVmac251 Infection in Male Rhesus Macaques of Chinese Origin.

    Science.gov (United States)

    Wei, Qiang; Liu, Li; Cong, Zhe; Wu, Xiaoxian; Wang, Hui; Qin, Chuan; Molina, Patricia; Chen, Zhiwei

    2016-09-01

    Delta9-tetrahydrocannabinol (Δ(9)-THC) is the major psychoactive component of the cannabis plant. Δ(9)-THC has been used in the active ingredient of Marinol as an appetite stimulant for AIDS patients. Its impact on progression of HIV-1 infection, however, remains debatable. Previous studies indicated that Δ(9)-THC administration enhanced HIV-1 infection in huPBL-SCID mice but seemingly decreased early mortality in simian immunodeficiency virus (SIV) infected male Indian-derived rhesus macaques. Here, we determine the chronic effect of Δ(9)-THC administration using 0.32 mg/kg or placebo (PBO), i.m., twice daily for 428 days on SIVmac251 infected male Chinese-derived rhesus macaques. Sixteen animals were divided into four study groups: Δ(9)-THC(+)SIV(+), Δ(9)-THC(+)SIV(-), PBO/SIV(+) and PBO/SIV(-) (n = 4/group). One-month after daily Δ(9)-THC or PBO administrations, macaques in groups one and three were challenged intravenously with pathogenic SIVmac251/CNS, which was isolated from the brain of a Chinese macaque with end-staged neuroAIDS. No significant differences in peak and steady state plasma viral loads were seen between Δ(9)-THC(+)SIV(+) and PBO/SIV(+) macaques. Regardless of Δ(9)-THC, all infected macaques displayed significant drop of CD4/CD8 T cell ratio, loss of CD4(+) T cells and higher persistent levels of Ki67(+)CD8(+) T cells compared with uninfected animals. Moreover, long-term Δ(9)-THC treatment reduced significantly the frequency of circulating IgE(+)B cells. Only one Δ(9)-THC(+)SIV(+) macaque died of simian AIDS with paralyzed limbs compared with two deaths in the PBO/SIV(+) group during the study period. These findings indicate that chronic Δ(9)-THC administration resulted in reduction of IgE(+)B cells, yet it unlikely enhanced pathogenic SIVmac251/CNS infection in male Rhesus macaques of Chinese origin.

  6. Chronic Δ9-tetrahydrocannabinol administration reduces IgE+B cells but unlikely enhances pathogenic SIVmac251 infection in male Rhesus macaques of Chinese origin

    Science.gov (United States)

    Wu, Xiaoxian; Wang, Hui; Qin, Chuan; Molina, Patricia; Chen, Zhiwei

    2016-01-01

    Delta9-tetrahydrocannabinol (Δ9-THC) is the major psychoactive component of the cannabis plant. Δ9-THC has been used in the active ingredient of Marinol as an appetite stimulant for AIDS patients. Its impact on progression of HIV-1 infection, however, remains debatable. Previous studies indicated that Δ9-THC administration enhanced HIV-1 infection in huPBL-SCID mice but seemingly decreased early mortality in simian immunodeficiency virus (SIV) infected male Indian-derived rhesus macaques. Here, we determine the chronic effect of Δ9-THC administration (0.32mg/kg or placebo-PBO, i.m., twice daily for 428 days) on SIVmac251 infected male Chinese-derived rhesus macaques. Sixteen animals were divided into four study groups: Δ9-THC+SIV+, Δ9-THC+SIV−, placebo (PBO)/SIV+ and PBO/SIV− (n=4/group). One-month after daily Δ9-THC or PBO administrations, macaques in groups one and three were challenged intravenously with pathogenic SIVmac251/CNS, which was isolated from the brain of a Chinese macaque with end-staged neuroAIDS. No significant differences in peak and steady state plasma viral loads were seen between Δ9-THC and PBO infected macaques. Regardless of Δ9-THC, all infected macaques displayed significant drop of CD4/CD8 T cell ratio, loss of CD4+ T cells and higher persistent levels of Ki67+CD8+ T cells when compared to uninfected animals. Moreover, long-term Δ9-THC treatment reduced significantly the frequency of circulating IgE+B cells. Only one infected macaque in the Δ9-THC+SIV+ group died of simian AIDS with paralyzed limbs as compared with two deaths in the PBO/SIV+ group during the study period. These findings indicate that chronic Δ9-THC administration resulted in reduction of IgE+B cells, yet it unlikely enhanced pathogenic SIVmac251/CNS infection in male Rhesus macaques of Chinese origin. PMID:27109234

  7. Accurate identification and quantification of 11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid in urine drug testing: evaluation of a direct high efficiency liquid chromatographic-mass spectrometric method.

    Science.gov (United States)

    Stephanson, Nikolai; Josefsson, Martin; Kronstrand, Robert; Beck, Olof

    2008-08-01

    A direct liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for measurement of urinary Delta(9)-tetrahydrocannabinol carboxylic acid (THCA) was developed. The method involved dilution of the urine sample with water containing (2)H(9)-deuterated analogue as internal standard, hydrolysis with ammonia, reversed phase chromatography using a Waters ultra-performance liquid chromatography (UPLC) equipment with gradient elution, negative electrospray ionization, and monitoring of two product ions in selected reaction monitoring mode. The measuring range was 2-1000 ng/mL for THCA, and the intra- and inter-assay imprecision, expressed as the coefficient of variation, was below 5%. Influence from urine matrix on ionization efficiency was noted in infusion experiments, but was compensated for by the internal standard. Comparison with established gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry methods in authentic patient samples demonstrated accuracy in both qualitative and quantitative results. A small difference in mean ratios (~15%) may be explained by the use of different hydrolysis procedures between methods. In conclusion, the high efficiency LC-MS/MS method was capable of accurately identify and quantify THCA in urine with a capacity of 14 samples per hour.

  8. Genetic moderation of the effects of cannabis: catechol-O-methyltransferase (COMT) affects the impact of Δ9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences.

    Science.gov (United States)

    Tunbridge, Elizabeth M; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Stumpenhorst, Katharina; Harrison, Paul J; Morrison, Paul D; Freeman, Daniel

    2015-11-01

    Cannabis use can induce cognitive impairments and psychotic experiences. A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val(158)Met) appears to influence the immediate cognitive and psychotic effects of cannabis, or ∆(9)-tetrahydrocannabinol (THC), its primary psychoactive ingredient. This study investigated the moderation of the impact of experimentally administered THC by COMT. Cognitive performance and psychotic experiences were studied in participants without a psychiatric diagnosis, using a between-subjects design (THC vs. placebo). The effect of COMT Val(158)Met genotype on the cognitive and psychotic effects of THC, administered intravenously in a double-blind, placebo-controlled manner to 78 participants who were vulnerable to paranoia, was examined. The results showed interactive effects of genotype and drug group (THC or placebo) on working memory, assayed using the Digit Span Backwards task. Specifically, THC impaired performance in COMT Val/Val, but not Met, carriers. In contrast, the effect of THC on psychotic experiences, measured using the Community Assessment of Psychic Experiences (CAPE) positive dimension, was unaffected by COMT genotype. This study is the largest to date examining the impact of COMT genotype on response to experimentally administered THC, and the first using a purely non-clinical cohort. The data suggest that COMT genotype moderates the cognitive, but not the psychotic, effects of acutely administered THC. © The Author(s) 2015.

  9. Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and [INCREMENT]9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats.

    Science.gov (United States)

    Leitl, Michael D; Negus, S Stevens

    2016-06-01

    Neuropathic pain is often associated with behavioral depression. Intraplantar formalin produces sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) in rats. This study evaluated pharmacological modulation of formalin-induced ICSS depression. Rats with intracranial electrodes targeting the medial forebrain bundle responded for electrical brain stimulation in an ICSS procedure. Bilateral intraplantar formalin administration depressed ICSS for 14 days. Morphine (0.32-3.2 mg/kg), ketoprofen (0.1-10 mg/kg), bupropion (3.2-32 mg/kg), and [INCREMENT]9-tetrahydrocannabinol (THC; 0.32-3.2 mg/kg) were evaluated for their effectiveness to reverse formalin-induced depression of ICSS. Drug effects on formalin-induced mechanical allodynia were evaluated for comparison. Morphine and bupropion reversed both formalin-induced ICSS depression and mechanical allodynia, and effects on ICSS were sustained during repeated treatment. Ketoprofen failed to reverse either formalin effect. THC blocked mechanical allodynia, but decreased ICSS in control rats and exacerbated formalin-induced depression of ICSS. The failure of ketoprofen to alter formalin effects suggests that formalin effects result from neuropathy rather than inflammation. The effectiveness of morphine and bupropion to reverse formalin effects agrees with other evidence that these drugs block pain-depressed behavior in rats and relieve neuropathic pain in humans. The effects of THC suggest general behavioral suppression and do not support the use of THC to treat neuropathic pain.

  10. Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in Δ9-Tetrahydrocannabinol-Mediated Induction of ΔFosB in the Mouse Forebrain.

    Science.gov (United States)

    Lazenka, Matthew F; Tomarchio, Aaron J; Lichtman, Aron H; Greengard, Paul; Flajolet, Marc; Selley, Dana E; Sim-Selley, Laura J

    2015-09-01

    Δ(9)-Tetrahydrocannabinol (THC), the main psychoactive component of marijuana, produces motor and motivational effects via interactions with the dopaminergic system in the caudate-putamen and nucleus accumbens. However, the molecular events that underlie these interactions after THC treatment are not well understood. Our study shows that pretreatment with dopamine D1 receptor (D1R) antagonists before repeated administration of THC attenuated induction of Δ FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB) in the nucleus accumbens, caudate-putamen, amygdala, and prefrontal cortex. Anatomical studies showed that repeated THC administration induced ΔFosB in D1R-containing striatal neurons. Dopamine signaling in the striatum involves phosphorylation-specific effects of the dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa (DARPP-32), which regulates protein kinase A signaling. Genetic deletion of DARPP-32 attenuated ΔFosB expression measured after acute, but not repeated, THC administration in both the caudate-putamen and nucleus accumbens. THC was then acutely or repeatedly administered to wild-type (WT) and DARPP-32 knockout (KO) mice, and in vivo responses were measured. DARPP-32 KO mice exhibited enhanced acute THC-mediated hypolocomotion and developed greater tolerance to this response relative to the WT mice. Agonist-stimulated guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding showed that cannabinoid-stimulated G-protein activity did not differ between DARPP-32 KO and WT mice treated with vehicle or repeated THC. These results indicate that D1Rs play a major role in THC-mediated ΔFosB induction in the forebrain, whereas the role of DARPP-32 in THC-mediated ΔFosB induction and modulation of motor activity appears to be more complex. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  11. Explorative Placebo-Controlled Double-Blind Intervention Study with Low Doses of Inhaled Δ9-Tetrahydrocannabinol and Cannabidiol Reveals No Effect on Sweet Taste Intensity Perception and Liking in Humans.

    Science.gov (United States)

    de Bruijn, Suzanne E M; de Graaf, Cees; Witkamp, Renger F; Jager, Gerry

    2017-01-01

    Introduction: The endocannabinoid system (ECS) plays an important role in food reward. For example, in humans, liking of palatable foods is assumed to be modulated by endocannabinoid activity. Studies in rodents suggest that the ECS also plays a role in sweet taste intensity perception, but it is unknown to what extent this can be extrapolated to humans. Therefore, this study aimed at elucidating whether Δ9-tetrahydrocannabinol (THC) or cannabidiol (CBD) affects sweet taste intensity perception and liking in humans, potentially resulting in alterations in food preferences. Materials and Methods: In a randomized placebo-controlled, double-blind crossover study, 10 healthy males participated in three test sessions that were 2 weeks apart. During the test sessions, participants received THC-rich, CBD-rich, or placebo Cannabis by inhalation divided over two doses (4 + 1 mg THC; 25 + 10 mg CBD). Participants tasted seven chocolate milk-like drinks that differed in sugar concentration and they rated sweet taste intensity and liking of the drinks. They were then asked to rank the seven drinks according to how much they liked the drinks and were offered ad libitum access to their favorite drink. In addition, they completed a computerized food preference task and completed an appetite questionnaire at the start, midway, and end of the test sessions. Results: Inhalation of the Cannabis preparations did not affect sweet taste intensity perception and liking, ranking order, or ad libitum consumption of the favorite drink. In addition, food preferences were not influenced by the interventions. Reported fullness was lower, whereas desire to eat was higher throughout the THC compared to the CBD condition. Conclusions: These results suggest that administration of Cannabis preparations at the low doses tested does not affect sweet taste intensity perception and liking, nor does it influence food preferences in humans.

  12. Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and Evaluation of Oral Fluid Screening Devices for Predicting Δ9-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis Brownie Administration.

    Science.gov (United States)

    Newmeyer, Matthew N; Swortwood, Madeleine J; Andersson, Maria; Abulseoud, Osama A; Scheidweiler, Karl B; Huestis, Marilyn A

    2017-03-01

    Roadside oral fluid (OF) Δ9-tetrahydrocannabinol (THC) detection indicates recent cannabis intake. OF and blood THC pharmacokinetic data are limited and there are no on-site OF screening performance evaluations after controlled edible cannabis. We reviewed OF and blood cannabinoid pharmacokinetics and performance evaluations of the Draeger DrugTest®5000 (DT5000) and Alere™ DDS®2 (DDS2) on-site OF screening devices. We also present data from a controlled oral cannabis administration session. OF THC maximum concentrations (Cmax) were similar in frequent as compared to occasional smokers, while blood THC Cmax were higher in frequent [mean (range) 17.7 (8.0-36.1) μg/L] smokers compared to occasional [8.2 (3.2-14.3) μg/L] smokers. Minor cannabinoids Δ9-tetrahydrocannabivarin and cannabigerol were never detected in blood, and not in OF by 5 or 8 h, respectively, with 0.3 μg/L cutoffs. Recommended performance (analytical sensitivity, specificity, and efficiency) criteria for screening devices of ≥80% are difficult to meet when maximizing true positive (TP) results with confirmation cutoffs below the screening cutoff. TPs were greatest with OF confirmation cutoffs of THC ≥1 and ≥2 μg/L, but analytical sensitivities were 80% with an OF THC ≥5 μg/L cutoff. Performance criteria also were >80% with a blood THC ≥5 μg/L confirmation cutoff; however, positive OF screening results might not confirm due to the time required to collect blood after a crash or police stop. OF confirmation is recommended for roadside OF screening.ClinicalTrials.gov identification number: NCT02177513. © 2016 American Association for Clinical Chemistry.

  13. Impaired NFAT and NFκB activation are involved in suppression of CD40 ligand expression by Δ{sup 9}-tetrahydrocannabinol in human CD4{sup +} T cells

    Energy Technology Data Exchange (ETDEWEB)

    Ngaotepprutaram, Thitirat [Department of Pharmacology and Toxicology, Michigan State University (United States); Center for Integrative Toxicology, Michigan State University (United States); Kaplan, Barbara L.F. [Department of Pharmacology and Toxicology, Michigan State University (United States); Center for Integrative Toxicology, Michigan State University (United States); Neuroscience Program, Michigan State University (United States); Kaminski, Norbert E., E-mail: kamins11@msu.edu [Department of Pharmacology and Toxicology, Michigan State University (United States); Center for Integrative Toxicology, Michigan State University (United States)

    2013-11-15

    We have previously reported that Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), the main psychoactive cannabinoid in marijuana, suppresses CD40 ligand (CD40L) expression by activated mouse CD4{sup +} T cells. CD40L is involved in pathogenesis of many autoimmune and inflammatory diseases. In the present study, we investigated the molecular mechanism of Δ{sup 9}-THC-mediated suppression of CD40L expression using peripheral blood human T cells. Pretreatment with Δ{sup 9}-THC attenuated CD40L expression in human CD4{sup +} T cells activated by anti-CD3/CD28 at both the protein and mRNA level, as determined by flow cytometry and quantitative real-time PCR, respectively. Electrophoretic mobility shift assays revealed that Δ{sup 9}-THC suppressed the DNA-binding activity of both NFAT and NFκB to their respective response elements within the CD40L promoter. An assessment of the effect of Δ{sup 9}-THC on proximal T cell-receptor (TCR) signaling induced by anti-CD3/CD28 showed significant impairment in the rise of intracellular calcium, but no significant effect on the phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β. Collectively, these findings identify perturbation of the calcium-NFAT and NFκB signaling cascade as a key mechanistic event by which Δ{sup 9}-THC suppresses human T cell function. - Highlights: • Δ{sup 9}-THC attenuated CD40L expression in activated human CD4+ T cells. • Δ{sup 9}-THC suppressed DNA-binding activity of NFAT and NFκB. • Δ{sup 9}-THC impaired elevation of intracellular Ca2+. • Δ{sup 9}-THC did not affect phosphorylation of ZAP70, PLCγ1/2, Akt, and GSK3β.

  14. In vitro effect of. Delta. sup 9 -tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E sub 2

    Energy Technology Data Exchange (ETDEWEB)

    Rettori, V.; Aguila, M.C.; McCann, S.M. (Univ. of Texas Southwestern Medical Center at Dallas (United States)); Gimeno, M.F.; Franchi, A.M. (Centro de Estudios Farmacologicos y de Principios Naturales, Buenos Aires (Argentina))

    1990-12-01

    Previous in vivo studies have shown that {Delta}{sup 9}-tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were deigned to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or nonrepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E{sub 2} (PGE{sub 2}) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE{sub 2} suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE{sub 2} synthesis and release. The authors speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release.

  15. Correlations and agreement between delta-9-tetrahydrocannabinol (THC) in blood plasma and timeline follow-back (TLFB)-assisted self-reported use of cannabis of patients with cannabis use disorder and psychotic illness attending the CapOpus randomized clinical trial.

    Science.gov (United States)

    Hjorthøj, Carsten Rygaard; Fohlmann, Allan; Larsen, Anne-Mette; Arendt, Mikkel; Nordentoft, Merete

    2012-06-01

    To assess correlations and agreement between timeline follow-back (TLFB)-assisted self-report and blood samples for cannabis use. Secondary analysis of a randomized trial. Copenhagen, Denmark. One hundred and three patients from the CapOpus trial with cannabis use disorder and psychosis, providing 239 self-reports of cannabis use and 88 valid blood samples. Delta-9-tetrahydrocannabinol (THC), 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) detected in plasma using high-performance liquid chromatography with tandem mass spectrometry detection. Self-report of cannabis-use last month by TLFB. Pearson's r, sensitivity and specificity calculated as measures of correlation or agreement. Correlations were strong; r = 0.75 for number of days and r = 0.83 for number of standard joints in the preceding month when excluding outliers. Including outliers, coefficients were moderate to strong (r = 0.49). There were differences in subgroups, mainly inconsistent, depending on inclusion or exclusion of outliers. Sensitivity and specificity for TLFB detecting the presence or absence of cannabis use were 95.7% [95% confidence interval (CI) 88.0-99.1%) and 72.2% (95% CI 46.5-90.3%), respectively. Using 19 days as cut-off on TLFB, they were 94.3% (95% CI 86.0-98.4%) and 94.4% (95% CI 72.2-99.9%), respectively. Area under the receiver operating characteristic (ROC) curve was 0.96. Timeline follow-back (TLFB)-assisted self-report of cannabis use correlates highly with plasma-delta-9-tetrahydrocannabinol in patients with comorbid cannabis use disorder and psychosis. Sensitivity and specificity of timeline follow-back appear to be optimized with 19 days as the cut-off point. As such, timeline follow-back may be superior to analysis of blood when going beyond 19 days of recall. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

  16. The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model.

    Science.gov (United States)

    Cherniakov, Irina; Izgelov, Dvora; Domb, Abraham J; Hoffman, Amnon

    2017-11-15

    The lipophilic phytocannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold increase in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL which resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized

  17. Evaluation of Δ(9) -tetrahydrocannabinol detection using DrugWipe5S(®) screening and oral fluid quantification after Quantisal™ collection for roadside drug detection via a controlled study with chronic cannabis users.

    Science.gov (United States)

    Wille, Sarah M R; Di Fazio, Vincent; Toennes, Stefan W; van Wel, Janelle H P; Ramaekers, Johannes G; Samyn, Nele

    2015-03-01

    Oral fluid (OF) is potentially useful to detect driving under the influence of drugs because of its ease of sampling. While cannabis is the most prevalent drug in Europe, sensitivity issues for Δ(9) -tetrahydrocannabinol (THC) screening and problems during OF collection are observed. The ability of a recently improved OF screening device - the DrugWipe5S(®) , to detect recent THC use in chronic cannabis smokers, was studied. Ten subjects participated in a double-blind placebo-controlled study. The subjects smoked two subsequent doses of THC; 300 µg/kg and 150 µg/kg with a pause of 75 min using a Volcano vapourizer. DrugWipe5S(®) screening and OF collection using the Quantisal™ device were performed at baseline, 5 min after each administration and 80 min after the last inhalation. Blood samples were drawn simultaneously. The screening devices (n = 80) were evaluated visually after 8 min, while the corresponding OF and serum samples were analyzed respectively with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) or gas chromatography-mass spectrometry (GC-MS). Neat OF THC concentrations ranged from 12 361 ng/g 5 min after smoking down to 34 ng/g 80 min later. Under placebo conditions, a median THC concentration of 8 ng/g OF (0-746 ng/g) and < 1 ng/ mL serum (0-7.8 ng/mL) was observed. The DrugWipe5S(®) was positive just after smoking (90%); however, sensitivity rapidly decreased within 1.5 h (50%). Sensitivity of DrugWipe5S(®) should be improved. As chronic cannabis users have high residual THC concentrations in their serum and OF, confirmation cut-offs should be set according to the aim of detecting recent drug use or establishing zero tolerance. Copyright © 2014 John Wiley & Sons, Ltd.

  18. Development of a simple and sensitive liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) method for the determination of cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) and its metabolites in rat whole blood after oral administration of a single high dose of CBD.

    Science.gov (United States)

    Palazzoli, Federica; Citti, Cinzia; Licata, Manuela; Vilella, Antonietta; Manca, Letizia; Zoli, Michele; Vandelli, Maria Angela; Forni, Flavio; Cannazza, Giuseppe

    2018-02-20

    The investigation of the possible conversion of cannabidiol (CBD) into Δ 9 -tetrahydrocannabinol (THC) in vivo after oral administration of CBD is reported herein since recent publications suggested a rapid conversion in simulated gastric fluid. To this end, single high dose of CBD (50mg/kg) was administered orally to rats and their blood was collected after 3 and 6h. A highly sensitive and selective LC-MS/MS method was developed and fully validated in compliance with the Scientific Working Group of Forensic Toxicology (SWGTOX) standard practices for method validation in forensic toxicology. This method also involved the optimization of cannabinoids and their metabolites extraction in order to remove co-eluting phospholipids and increase the sensitivity of the MS detection. Neither THC nor its metabolites were detected in rat whole blood after 3 or 6h from CBD administration. After oral administration, the amount of CBD dissolved in olive oil was higher than that absorbed from an ethanolic solution. This could be explained by the protection of lipid excipients towards CBD from acidic gastric juice. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. A comparison of the validity of gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry analysis of urine samples II: amphetamine, methamphetamine, (±)-3,4-methylenedioxyamphetamine, (±)-3,4-methylenedioxymethamphetamine, (±)-3,4-methylenedioxyethylamphetamine, phencyclidine, and (±)-11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol.

    Science.gov (United States)

    Stout, Peter R; Bynum, Nichole D; Lewallen, Cynthia M; Mitchell, John M; Baylor, Michael R; Ropero-Miller, Jeri D

    2010-10-01

    On November 25, 2008, the U.S. Department of Health and Human Services posted a final notice in the Federal Register authorizing the use of liquid chromatography-tandem mass spectrometry (LC-MS-MS) and other technologies in federally regulated workplace drug testing (WPDT) programs. To support this change, it is essential to explicitly demonstrate that LC-MS-MS, as a technology, can produce results at least as valid as gas chromatography (GC)-MS, the long-accepted standard in confirmatory analytical technologies for drugs of abuse. A series of manufactured control urine samples (n = 10 for each analyte) containing amphetamine, methamphetamine, (±)-3,4-methylenedioxyamphetamine, (±)-3,4-methylenedioxymethamphetamine, (±)-3,4-methylenedioxyethylamphetamine, phencyclidine, and (±)-11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol at concentrations ranging from 10% to 2000% of federal cutoffs were analyzed with replication by five federally regulated laboratories using GC-MS and at RTI International using LC-MS-MS. Interference samples as described in the National Laboratory Certification Program 2009 Manual were analyzed by GC-MS and LC-MS-MS as well as previously confirmed urine specimens of WPDT origin. Matrix effects were assessed for LC-MS-MS. Results indicated that LC-MS-MS analysis produced results at least as precise, accurate, and specific as GC-MS for the analytes investigated in this study. Matrix effects, while evident, could be controlled by the use of matrix-matched controls and calibrators with deuterated internal standards.

  20. Effects of ¿9-Tetrahydrocannabinol on human working memory function

    NARCIS (Netherlands)

    Bossong, M.G.; Jansma, J.M.; Hell, van H.H.; Jager, G.; Oudman, E.; Saliasi, E.; Kahn, R.S.; Ramsey, N.F.

    2012-01-01

    Background Evidence indicates involvement of the endocannabinoid (eCB) system in both the pathophysiology of schizophrenia and working memory (WM) function. Additionally, schizophrenia patients exhibit relatively strong WM deficits. These findings suggest the possibility that the eCB system is also

  1. Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia.

    Science.gov (United States)

    Walther, Sebastian; Mahlberg, Richard; Eichmann, Uta; Kunz, Dieter

    2006-05-01

    Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today. Current treatment options are few and limited due to substantial side effects. The aim of the study was to measure the effect of the cannabinoid dronabinol on nocturnal motor activity. In an open-label pilot study, six consecutive patients in the late stages of dementia and suffering from circadian and behavioral disturbances-five patients with Alzheimer's disease and one patient with vascular dementia-were treated with 2.5 mg dronabinol daily for 2 weeks. Motor activity was measured objectively using actigraphy. Compared to baseline, dronabinol led to a reduction in nocturnal motor activity (P=0.028). These findings were corroborated by improvements in Neuropsychiatric Inventory total score (P=0.027) as well as in subscores for agitation, aberrant motor, and nighttime behaviors (P<0.05). No side effects were observed. The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia.

  2. Orthostatic hypotension after delta 9-tetrahydrocannabinol marihuana inhalation.

    Science.gov (United States)

    Merritt, J C; Cook, C E; Davis, K H

    1982-01-01

    3 male glaucoma subjects experienced orthostatic hypotension within 10 min after completing 2% delta 9-THC ranging from 57 to 233 ng/ml were found 5 min after smoking. Peripheral venodilation appeared responsible for the precipitous decrease in systolic blood pressure in all 3 subjects. These orthostatic episodes which clinically simulated the typical 'faint' were characterized by the absence of tachycardia and their relief by assuming a reclining position. The postural hypotension occurred despite differences in inhalation technique, level of delta (9)-THC present in plasma, previous marihuana experience of body habitus.

  3. A urinary metabolite of {Delta}{sup 1}-tetrahydrocannabinol. The first synthesis of 4``-hydroxy-{Delta}{sup 1}-tetrahydrocannabinol-7-oic acid labelled with deuterium

    Energy Technology Data Exchange (ETDEWEB)

    Szirmai, Maria; Odqvist, Helena [Uppsala Univ. (Sweden). Dept. of Pharmacognosy; Halldin, M.M. [Karolinska Inst., Stockholm (Sweden). Dept. of Pharmacology

    1996-04-01

    The first synthesis of 4``-hydroxy-{Delta}-{sup 1}-THC-7-oic acid, one of the three major metabolites of {Delta}{sup 1}-THC identified in human urine is discussed. Methyl 4-(3,5-dihydroxyphenyl)butanoate was prepared from 3,5-diydroxybenzoic acid in an overall yield of 15% was condensed with a terpene synthon under acidic conditions followed by hydrolysis and conversion of the 4``-carboxylic acid function to the corresponding methyl ketone using methyllithium. Reduction with NaBH{sub 4} afforded the secondary alcohol in the side-chain. Acetylation and removal of the 1,3-dithiane masking group gave the aldehyde in C-7-position which was further oxidized using NaClO{sub 2} followed by deacetylation to give the desired metabolite. The same procedure may be used for the synthesis of unlabelled 4``-hydroxy-{Delta}{sup 1}-THC-7-oic acid. (author).

  4. Distribution of Delta 9-Tetrahydrocannabinol and 11-Nor-9-Carboxy-Delta 9-Tetrahydrocannabinol Acid in Postmortem Biological Fluids and Tissues From Pilots Fatally Injured in Aviation Accidents

    Science.gov (United States)

    2013-12-01

    Schoor M. Letter: effects of marihuana on flying ability. JAMA 230(9):1258 (1974). 8. Janowsky DS, Meacham MP, Blaine JD, Schoor M, Bozzetti LP...Simulated flying performance after marihuana intoxication. Aviat Space Environ Med 47(2):124-128 (1976a). 9. Janowsky DS, Meacham MP, Blaine JD, Schoor M

  5. Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice.

    Science.gov (United States)

    Harris, Hannah M; Sufka, Kenneth J; Gul, Waseem; ElSohly, Mahmoud A

    2016-08-01

    Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy. Georg Thieme Verlag KG Stuttgart · New York.

  6. Characteristics of the stimulus produced by the mixture of cannabidiol with delta 9-tetrahydrocannabinol.

    Science.gov (United States)

    Zuardi, A W; Finkelfarb, E; Bueno, O F; Musty, R E; Karniol, I G

    1981-01-01

    Rats, trained to discriminate between delta 9-THC (5 mg/kg) and a control solution, using a T-maze, were submitted to generalization tests wih delta 9-THC (2.5 and 1.25 mg/kg), CBD (40 mg/kg) and the mixtures of delta 9-THC (5 and 1.25 mg/kg) with CBD (40 mg/kg). Doses of delta 9-THC smaller than the training dose, produced a progressive reduction in the number of correct responses together with a decrease in the running time. The choice made by the animals under the effect of CBD (40 mg/kg) did not differ from that of the animals given the control solution but their running time was significantly longer. The mixtures of CBD (40 mg/kg) with delta 9-THC (5 and 1.25 mg/kg) produced approximately 50% response to both sides of the maze, and with run times greater than those observed with delta 9-THC (5 mg/kg). The results suggest that the simultaneous administration of the two cannabinoids might produce a qualitative stimulus different from that produced by delta 9-THC alone.

  7. Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L.

    Science.gov (United States)

    El-Alfy, Abir T; Ivey, Kelly; Robinson, Keisha; Ahmed, Safwat; Radwan, Mohamed; Slade, Desmond; Khan, Ikhlas; ElSohly, Mahmoud; Ross, Samir

    2010-06-01

    The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Delta(9)-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Delta(9)-THC and Delta(8)-THC showed a U-shaped dose response with only Delta(9)-THC showing significant antidepressant-like effects at 2.5 mg/kg (pcannabidiol (CBD) exhibited significant effect at 20 and 200mg/kg, respectively (p<0.01). The antidepressant-like action of Delta(9)-THC and CBC was further confirmed in the TST. Delta(9)-THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p<0.05) while CBC resulted in a significant dose-dependent decrease in immobility at 40 and 80 mg/kg doses (p<0.01). Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis. Published by Elsevier Inc.

  8. Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L

    OpenAIRE

    El-Alfy, Abir T.; Ivey, Kelly; Robinson, Keisha; Ahmed, Safwat; Radwan, Mohamed; Slade, Desmond; Khan, Ikhlas; ElSohly, Mahmoud; Ross, Samir

    2010-01-01

    The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Δ9-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lac...

  9. Bornyl- and isobornyl-Delta8-tetrahydrocannabinols: a novel class of cannabinergic ligands.

    Science.gov (United States)

    Lu, Dai; Guo, Jianxin; Duclos, Richard I; Bowman, Anna L; Makriyannis, Alexandros

    2008-10-23

    Structure-activity relationship studies of classical cannabinoid analogues have established that the C3 aliphatic side chain plays a pivotal role in determining cannabinergic potency. In earlier work, we provided evidence for the presence of subsites within the CB1 and CB2 cannabinoid receptor binding domains that can accommodate bulky conformationally defined substituents at the C3 alkyl side chain pharmacophore of classical cannabinoids. We have now extended this work with the synthesis of a series of Delta (8)-THC analogues in which bornyl substituents are introduced at the C3 position. Our results indicate that, for optimal interactions with both CB1 and CB2 receptors, the bornyl substituents need to be within close proximity of the tricyclic core of Delta (8)-THC and that the conformational space occupied by the C3 substituents influences CB1/CB2 receptor subtype selectivity.

  10. Bornyl- and Isobornyl-Δ8-tetrahydrocannabinols: A Novel Class of Cannabinergic Ligands

    Science.gov (United States)

    Lu, Dai; Guo, Jianxian; Duclos, Richard I.; Bowman, Anna L.; Makriyannis, Alexandros

    2013-01-01

    Structure-activity relationship studies of classical cannabinoid analogs have established that the C3 aliphatic side chain plays a pivotal role in determining cannabinergic potency. In earlier work we provided evidence for the presence of subsites within the CB1 and CB2 cannabinoid receptor binding domains that can accommodate bulky conformationally defined substituents at the C3 alkyl side chain pharmacophore of classical cannabinoids. We have now extended this work with the synthesis of a series of Δ8-THC analogs in which bornyl substituents are introduced at the C3 position. Our results indicate that for optimal interactions with both CB1 and CB2 receptors, the bornyl substituents need to be within close proximity of the tricyclic core of Δ8-THC and that the conformational space occupied by the C3 substituents influences CB1/CB2 receptor subtype selectivity. PMID:18826296

  11. Is THC-COOH-glucuronide a useful marker for Tetrahydrocannabinol (THC) in DUID cases?

    DEFF Research Database (Denmark)

    Telving, Rasmus; Hasselstrøm, Jørgen Bo; Andreasen, Mette Findal

    ). Introduction The physical and chemical nature of THC makes it difficult to include in traditional screening procedures along with other common legal and illegal drugs. Development of multi-component toxicological screening procedures that include THC is therefore a challenge but also highly desirable in high...... from Bruker. The Screening for THC-COOH-glucuronide included 1608 DUID whole blood samples from 2013 and 2014 already quantified on an existing validated LC-MS/MS method using Multiple Reaction Monitoring (MRM). The Danish per se limit for THC in DUID cases is 1.0 µg/kg blood and to compensate...

  12. Consumption and quantitation of delta9-tetrahydrocannabinol in commercially available hemp seed oil products.

    Science.gov (United States)

    Bosy, T Z; Cole, K A

    2000-10-01

    There has been a recent and significant increase in the use and availability of hemp seed oil products. These products are being marketed as a healthy source of essential omega fatty acids when taken orally. Although the health aspects of these oils is open to debate, the probability that oils derived from the hemp seed will contain delta9-tetrahyrdocannabinol (THC) is noteworthy. Recent additions to the literature cite a number of studies illustrating that the ingestion of these products results in urinary levels of the THC metabolite, delta9-tetrahyrdocannabinol carboxylic acid (THCA), well above the administrative cutoff (50 ng/mL) used during random drug screens. Testing performed by our laboratory found that the concentration of THC in hemp oil products has been reduced considerably since the publication of earlier studies. The purpose of this study is to quantitate the THC levels in commercially available hemp oils and to administer those oils tested to THC-free volunteers to determine urine metabolite levels following several 15-g doses. Two extraction protocols were evaluated for removing THC from the oil matrix: a single step liquid-liquid extraction was compared to a two-phase process using both liquid-liquid and solid-phase techniques. Gas chromatography-mass spectrometry was used to determine THC levels in several products: four from Spectrum Essentials (3 bottled oils and 1-g capsules), two from Health from the Sun (1-g capsules and bottled oil) oils, and single samples of both Hempstead and Hempola hemp oils. These hemp oil products contained THC concentrations of 36.0, 36.4, 117.5, 79.5, 48.6, 45.7, 21.0, and 11.5 mg/g, respectively. The Abbott AxSYM FPIA and Roche On-Line KIMS immunoassays were used to screen the urine samples, and GC-MS was used to determine the amount of THC in each oil as well as confirm and quantitate THCA in the urine of study participants immediately before and 6 h after each dose. Peak THCA levels in the participants' urine ranged from 1 to 49 ng/mL. All volunteers were below positive screen and confirmation cutoffs within 48 h after cessation of ingestion.

  13. The endocannabinoid system and emotional processing: A pharmacological fMRI study with Delta 9-tetrahydrocannabinol

    NARCIS (Netherlands)

    Bossong, M.G.; Hell, van H.H.; Jager, G.; Kahn, R.S.; Ramsey, N.F.; Jansma, J.M.

    2013-01-01

    Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the

  14. Disposition of smoked cannabis with high [Delta]9-tetrahydrocannabinol content: A kinetic model.

    NARCIS (Netherlands)

    Hunault, C.C.; van Eijkeren, J.C.; Mensinga, T.T.; de Vries, I.; Leenders, M.E.C.; Meulenbelt, J.|info:eu-repo/dai/nl/079479227

    2010-01-01

    Introduction No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69 mg THC).Methods

  15. Detection of Δ9-tetrahydrocannabinol (THC in hair using GC–MS

    Directory of Open Access Journals (Sweden)

    Himanshu Khajuria

    2014-03-01

    Full Text Available Detection of drugs from hair samples has become an imperative technique in forensic toxicological analysis. In this study, hair samples were collected from 20 cannabis users undergoing treatment at a rehabilitation center at different time intervals. Hair samples were cleaned and digested, followed by extraction and quantification of THC by GC–MS. At LOD of 0.1 ng/mg of THC, the concentration ranged from 0.16 to 2.3 ng/mg (mean, 0.95 ng/mg. Results indicate that THC is detectable after 3 months of last drug intake.

  16. Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability.

    Science.gov (United States)

    de Vries, Marjan; Van Rijckevorsel, Dagmar C M; Vissers, Kris C P; Wilder-Smith, Oliver H G; Van Goor, Harry

    2016-03-01

    We aimed to assess the analgesic efficacy, pharmacokinetics, tolerability and safety of a single dose of Δ9-THC in patients with chronic abdominal pain resulting from chronic pancreatitis (CP). This was a randomized, single dose, double-blinded, placebo-controlled, two way crossover study in patients suffering from abdominal pain as result of CP (n = 24), post hoc subdivided into opioid and non-opioid users. Δ9-THC (8 mg) or active placebo (5 mg/10 mg diazepam) was administered orally in a double dummy design. No treatment effect was shown for delta VAS pain scores after Δ9-THC compared with diazepam. Δ9-THC was well absorbed with a mean tmax of 123 min. No significant differences were found between Δ9-THC vs. diazepam for alertness, mood, calmness or balance. Feeling anxious and heart rate were significantly increased after Δ9-THC compared with diazepam. The most frequently reported adverse events (AEs) after Δ9-THC administration were somnolence, dry mouth, dizziness and euphoric mood. A single dose of Δ9-THC was not efficacious in reducing chronic pain resulting from CP, but was well tolerated with only mild or moderate AEs. The PK results in CP patients showed delayed absorption and an increased variability compared with healthy volunteers. © 2015 The British Pharmacological Society.

  17. Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: a randomized controlled trial.

    Science.gov (United States)

    Ahmed, Amir I A; van den Elsen, Geke A H; Colbers, Angela; van der Marck, Marjolein A; Burger, David M; Feuth, Ton B; Rikkert, Marcel G M Olde; Kramers, Cornelis

    2014-09-01

    There is a great concern about the safety of THC-based drugs in older people (≥65 years), as most of THC-trials did not include such group. In this phase 1, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial, we evaluated the safety and pharmacokinetics of three oral doses of Namisol(®), a novel THC in tablet form, in older subjects. Twelve healthy older subjects (6 male; mean age 72±5 years) randomly received a single oral dose of 3mg, 5mg, or 6.5mg of THC or matching placebo, in a crossover manner, on each intervention day. The data for 11 subjects were included in the analysis. The data of 1 subject were excluded due to non-compliance to study medication. THC was safe and well tolerated. The most frequently reported adverse events (AEs) were drowsiness (27%) and dry mouth (11%). Subjects reported more AEs with THC 6.5mg than with 3mg (p=0.048), 5mg (p=0.034) and placebo (p=0.013). There was a wide inter-individual variability in plasma concentrations of THC. Subjects for whom the Cmax fell within the sampling period (over 2h), Cmax was 1.42-4.57ng/mL and Tmax was 67-92min. The AUC0-2h (n=11) was 1.67-3.51ng/mL. Overall, the pharmacodynamic effects of THC were smaller than effects previously reported in young adults. In conclusion, THC appeared to be safe and well tolerated by healthy older individuals. Data on safety and effectiveness of THC in frail older persons are urgently required, as this population could benefit from the therapeutic applications of THC. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  18. Mother-Infant Interaction in Rhesus Monkeys Treated Chronically with Delta-9-Tetrahydrocannabinol.

    Science.gov (United States)

    Golub, Mari S.; And Others

    1981-01-01

    Drug-exposed mother-infant rhesus monkey pairs were similar to nontreated controls in the amount and types of activity displayed at the infant's tenth and ninetieth day of age. At about 3 months of age drug-exposed pairs increased in interaction, signaling mother-infant independence. This finding suggests that mother-infant attachment may be…

  19. Alterations in serum lipids and peptides of insulin, glucagon in diabetic rats by Δ9- tetrahydrocannabinol

    OpenAIRE

    Coşkun, Zeynep Mine; Bolkent, Sema

    2012-01-01

    Diabetes mellitus insuline bağımlı olmayan, insulin direnci ile karakterize kronik bir hastalıktır. Diabetes mellitus’da genellikle hiperglisemi ile birlikte hiperlipidemi de gelişir. Cannabis sativa’nın ana psikoaktif bileşeni olan Δ9- tetrahidrokannabinol (Δ9-THC) kannabinoid reseptör agonistlerinden biridir. Non-insulin-dependent diabetes mellitus, a chronic disease which is characterized by insulin resistance. Hyperglycemia is frequently accompanied by hyperlipidemia. Δ9-tetra...

  20. Tetrahydrocannabinolic acid synthase, the enzyme controlling marijuana psychoactivity, is secreted into the storage cavity of the glandular trichomes

    National Research Council Canada - National Science Library

    Sirikantaramas, Supaart; Taura, Futoshi; Tanaka, Yumi; Ishikawa, Yu; Morimoto, Satoshi; Shoyama, Yukihiro

    2005-01-01

    ...), the psychoactive component of marijuana (Cannabis sativa L.). We suggest herein that THCA is biosynthesized in the storage cavity of the glandular trichomes based on the following observations...

  1. Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

    NARCIS (Netherlands)

    Bossong, MG; Mehta, Mitul; van Berckel, Bart; Howes, Oliver; Kahn, RS; Stokes, Paul

    2015-01-01

    RATIONALE: Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human

  2. Interactions between delta 9-tetrahydrocannabinol and cannabidiol as evaluated by drug discrimination procedures in rats and pigeons.

    Science.gov (United States)

    Hiltunen, A J; Järbe, T U

    1986-02-01

    Animals (rats and pigeons) were trained to discriminate between the presence and absence of delta 9-THC; the training doses were, respectively: 0.56 mg/kg (pigeons) and 3.0 mg/kg (rats). Once the drug discrimination was mastered, the pigeons were tested repeatedly after a single intramuscular (i.m.) injection of delta 9-THC (0.56 mg/kg) at the following intervals 0.5, 1.5, 4.5 and 9 hr after the injection. These results were compared with data from a separate procedure, i.e. where the various intervals after injection were examined only once per injection and both procedures yielded essentially the same outcome. Thus, less than 50% appropriate responding to THC was observed at 0.5 and 9 hr after injection, whereas greater than 90% responding to THC occurred at 1.5 and 4.5 hr. The two procedures have previously been compared in rats (Järbe, Swedberg and Mechoulam, 1981). The repeated tests procedure was then used to evaluate combinations of delta 9-THC and cannabidiol in both species. Cannabidiol prolonged the cue effects of 1 mg/kg of delta 9-THC (intraperitoneal route of administration) in rats but did not change the time-effect curve for delta 9-THC in pigeons (dose range examined: 0.10--0.56 mg/kg); the challenge doses of cannabidiol were, respectively: 30.0 mg/kg (i.p.) and 17.5 mg/kg (i.m.). The rate of responding did not differ in tests with combinations of delta 9-THC and cannabidiol as compared to delta 9-THC given alone in pigeons. Subcutaneously administered 3-PPP, a dopamine pre-synaptic blocker, did not induce responding appropriate for delta 9-THC in rats.

  3. Tolerance to Chronic Delta-9-Tetrahydrocannabinol (Δ9-THC) in Rhesus Macaques Infected With Simian Immunodeficiency Virus

    OpenAIRE

    Winsauer, Peter J.; Molina, Patricia E.; Amedee, Angela M.; Filipeanu, Catalin M; McGoey, Robin R.; Troxclair, Dana A.; Walker, Edith M.; Birke, Leslie L; Stouwe, Curtis Vande; Howard, Jessica M.; Leonard, Stuart T.; Moerschbaecher, Joseph M.; Lewis, Peter B.

    2011-01-01

    Although Δ9-THC has been approved to treat anorexia and weight loss associated with AIDS, it may also reduce well-being by disrupting complex behavioral processes or enhancing HIV replication. To investigate these possibilities, four groups of male rhesus macaques were trained to respond under an operant acquisition and performance procedure, and administered vehicle or Δ9-THC before and after inoculation with simian immunodeficiency virus(SIVmac251, 100 TCID50/ml, i.v.). Prior to chronic Δ9-...

  4. Chronic Adolescent Exposure to Δ-9-Tetrahydrocannabinol in COMT Mutant Mice: Impact on Psychosis-Related and Other Phenotypes

    National Research Council Canada - National Science Library

    O'Tuathaigh, Colm M P; Hryniewiecka, Magdalena; Behan, Aine; Tighe, Orna; Coughlan, Catherine; Desbonnet, Lieve; Cannon, Mary; Karayiorgou, Maria; Gogos, Joseph A; Cotter, David R; Waddington, John L

    2010-01-01

    ... and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32-52) or adulthood (PDs 70-90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis...

  5. Tolerance to Chronic Delta-9-Tetrahydrocannabinol (Δ9-THC) in Rhesus Macaques Infected With Simian Immunodeficiency Virus

    Science.gov (United States)

    Winsauer, Peter J.; Molina, Patricia E.; Amedee, Angela M.; Filipeanu, Catalin M.; McGoey, Robin R.; Troxclair, Dana A.; Walker, Edith M.; Birke, Leslie L.; Stouwe, Curtis Vande; Howard, Jessica M.; Leonard, Stuart T.; Moerschbaecher, Joseph M.; Lewis, Peter B.

    2011-01-01

    Although Δ9-THC has been approved to treat anorexia and weight loss associated with AIDS, it may also reduce well-being by disrupting complex behavioral processes or enhancing HIV replication. To investigate these possibilities, four groups of male rhesus macaques were trained to respond under an operant acquisition and performance procedure, and administered vehicle or Δ9-THC before and after inoculation with simian immunodeficiency virus(SIVmac251, 100 TCID50/ml, i.v.). Prior to chronic Δ9-THC and SIV inoculation, 0.032– 0.32 mg/kg of Δ9-THC produced dose-dependent rate-decreasing effects and small, sporadic error-increasing effects in the acquisition and performance components in each subject. Following 28 days of chronic Δ9-THC (0.32 mg/kg, i.m.) or vehicle twice daily, delta-9-THC-treated subjects developed tolerance to the rate-decreasing effects, and this tolerance was maintained during the initial 7–12 months irrespective of SIV infection (i.e., +THC/−SIV, +THC/+SIV). Full necropsy was performed on all SIV subjects an average of 329 days post-SIV inoculation, with postmortem histopathology suggestive of a reduced frequency of CNS pathology as well as opportunistic infections in delta-9-THC-treated subjects. Chronic Δ9-THC also significantly reduced CB-1 and CB-2 receptor levels in the hippocampus, attenuated the expression of a proinflammatory cytokine (MCP-1), and did not increase viral load in plasma, cerebrospinal fluid, or brain tissue compared to vehicle-treated subjects with SIV. Together, these data indicate that chronic Δ9-THC produces tolerance to its behaviorally disruptive effects on complex tasks while not adversely affecting viral load or other markers of disease progression during the early stages of infection. PMID:21463073

  6. Adolescent delta-9-tetrahydrocannabinol (THC) exposure fails to affect THC-induced place and taste conditioning in adult male rats.

    Science.gov (United States)

    Wakeford, Alison G P; Flax, Shaun M; Pomfrey, Rebecca L; Riley, Anthony L

    2016-01-01

    Adolescent initiation of drug use has been linked to problematic drug taking later in life and may represent an important variable that changes the balance of the rewarding and/or aversive effects of abused drugs which may contribute to abuse vulnerability. The current study examined the effects of adolescent THC exposure on THC-induced place preference (rewarding effects) and taste avoidance (aversive effects) conditioning in adulthood. Forty-six male Sprague-Dawley adolescent rats received eight injections of an intermediate dose of THC (3.2mg/kg) or vehicle. After these injections, animals were allowed to mature and then trained in a combined CTA/CPP procedure in adulthood (PND ~90). Animals were given four trials of conditioning with intervening water-recovery days, a final CPP test and then a one-bottle taste avoidance test. THC induced dose-dependent taste avoidance but did not produce place conditioning. None of these effects was impacted by adolescent THC exposure. Adolescent exposure to THC had no effect on THC taste and place conditioning in adulthood. The failure to see an effect of adolescent exposure was addressed in the context of other research that has assessed exposure of drugs of abuse during adolescence on drug reactivity in adulthood. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. The effect of delta 9-tetrahydrocannabinol and LSD on the acquisition of an active avoidance response in the rat.

    Science.gov (United States)

    Waser, P G; Martin, A; Heer-Carcano, L

    1976-04-15

    The course of active avoidance learning of rats in a symmetrical Y-maze under the influence of 1, 3, and 9 mg/kg of delta 9-THC i.p., and 5, 20, and mug/kg of LSD was investigated. Delta-THC in a dosage of 1 mg/kg had no effect on avoidance learning. Three to a lesser extent 9 mg/kg produced more rapid learning with a significantly better performance. Learning under delta 9-THC proved to be state-dependent. The withdrawal of delta 9-THC caused a decrease in the avoidance rate, which was dependent on the dosage. Upon renewal of the THC doses, the animals reattained their earlier preformance. In the course of the experiment there was rapid tolerance development, especially of the sedative properties of THC. LSD retarded the rate of acquisition of the active avoidance response. Whereas the control animals displayed over 80% successful active avoidance from the 14th session onwards, this was achieved by the LSD groups only after the 20th session. However, in contrast to the control group the LSD animals were able to increase their avoidance rate to over 90%, and this was maintained to the end of the experiment (a total of 24 sessions with LSD). The sudden withdrawal of LSD produced a fall in avoidance rate, which was dependent on the pervious training dosage; as with delta 9-THC state-dependent learning can also be assumed for LSD.

  8. Synthesis of a labelled terpene synthon, useful in the preparation of metabolites of [Delta][sup 1]-tetrahydrocannabinol

    Energy Technology Data Exchange (ETDEWEB)

    Szirmai, M. (Uppsala Univ. (Sweden)); Halldin, M.M.; Ohlsson, A. (Karolinska Inst., Stockholm (Sweden))

    1992-02-01

    The synthesis of an isotopically labelled terpene synthon (4) is described. The usefulness of this terpene synthon in the synthesis of [delta][sup 1]-THC metabolites is shown by preparation of ([+-])-[[sup 2]H[sub 10

  9. Electrochemical Study of Delta-9-Tetrahydrocannabinol by Cyclic Voltammetry Using Screen Printed Electrode, Improvements in Forensic Analysis

    Directory of Open Access Journals (Sweden)

    Marco Antonio BALBINO

    2016-12-01

    Full Text Available Rapid screening of seized drugs is a continuing problem for governmental laboratories and customs agents. Recently new and cheaper methods based on electrochemical sensing have been developed for the detection of illicit drugs. Screen printed electrodes are particularly useful in this regard and can provide excellent sensitivity. In this study, a carbon screen printed electrode for the voltammetric analysis of D9-THC was developed. The analysis was performed using cyclic voltammetry with 0.15 mol×L-1 potassium nitrate as a supporting electrolyte. In the analysis, a D9-THC standard solution was added to the surface electrode by a drop coating method. A study of scan rate, time of pre-concentration, and concentration influence parameters showed versatility during the investigation. The high sensitivity, quantitative capability and low limit of detection (1.0 µmol×L-1 demonstrate that this electrochemical method should be an attractive alternative in forensic investigations of seized samples.

  10. Acute administration of Δ9 tetrahydrocannabinol does not prevent enhancement of sensory gating by clozapine in DBA/2 mice

    Science.gov (United States)

    Smucny, Jason; Stevens, Karen E.; Tregellas, Jason R.

    2014-01-01

    Despite high rates of marijuana abuse in schizophrenia, the physiological interactions between tetrahydrocanabinol (THC) and antipsychotic medications are poorly understood. A well-characterized feature of schizophrenia is poor gating of the P50 auditory-evoked potential. This feature has been translationally modeled by the DBA/2 mouse, which exhibits poor suppression of the P20-N40 AEP, the rodent analogue of the human P50. Previous work has demonstrated that this deficit is reversed by the antipsychotic clozapine. It is unknown, however, if this effect is altered by THC administration. Using a conditioning-testing paradigm with paired auditory stimuli, the effects of clozapine and dronabinol (a pharmaceutical THC formulation) on inhibitory P20-N40 AEP processing were assessed from in vivo hippocampal CA3 recordings in anesthetized DBA/2 mice. The effects of clozapine (0.33 mg/kg) and dronabinol (10 mg/kg) were assessed alone and in combination (0.33, 1, 1.83, or 3.33 mg/kg clozapine with 10 mg/kg dronabinol). Improved P20-N40 AEP gating was observed after acute administration of 0.33 mg/kg clozapine. Co-injection of 0.33 mg/kg clozapine and 10 mg/kg THC, however, did not improve gating relative to baseline. This effect was overcome by higher doses of clozapine (1 and 1.83 mg/kg), as these doses improved gating relative to baseline in the presence of 10 mg/kg THC. 10 mg/kg THC alone did not affect gating. In conclusion, THC does not prevent improvement of P20-N40 gating by clozapine. PMID:24418217

  11. Effects of ¿9-Tetrahydrocannabinol Administration on human encoding and recall memory function: a pharmacological fMRI study

    NARCIS (Netherlands)

    Bossong, M.G.; Jager, G.; Hell, van H.H.; Zuurman, L.; Jansma, J.M.; Mehta, M.A.; Gerven, van J.; Kahn, R.S.; Ramsey, N.F.

    2012-01-01

    Deficits in memory function are an incapacitating aspect of various psychiatric and neurological disorders. Animal studies have recently provided strong evidence for involvement of the endocannabinoid (eCB) system in memory function. Neuropsychological studies in humans have shown less convincing

  12. Novel /sup 125/I radioimmunoassay for the analysis of. delta. /sup 9/-tetrahydrocannabinol and its metabolites in human body fluids

    Energy Technology Data Exchange (ETDEWEB)

    Law, B.; Mason, P.A.; Moffat, A.C.; King, L.J.

    A cannabinoid radioimmunoassay (RIA) that detects some of the major ..delta../sup 9/-THC metabolites is developed and evaluated for use in forensic science. It incorporates a novel /sup 125/I radiotracer, is sensitive, reliable, relatively quick, and simple to use. The RIA uses a commercially available antiserum and detects a number of cannabinoid metabolites, including ..delta../sup 9/-THC-11-oic acid and its glucuronide conjugate in biological fluids. The method was successfully applied to the analysis of blood and urine samples submitted for forensic analysis.

  13. Suppression of polymorphonuclear (PMN) and monocyte-mediated inhibition of Candida albicans growth by delta-9-tetrahydrocannabinol

    Energy Technology Data Exchange (ETDEWEB)

    Djeu, J.Y.; Parapanios, A.; Halkias, D.; Friedman, H.

    1986-03-05

    This study was an in vitro attempt to identify the effector cells responsible for growth inhibition of the opportunistic fungus, candida albicans, and to determine if THC or another marijuana derivatives, 11-hydroxyTHC, would adversely affect their function. Using a 24h radiolabel assay, the authors found that growth inhibition of C. albicans was primarily mediated by PMN and monocytes that could be isolated normal human peripheral blood. Both effector cell types caused almost complete inhibition of Candida growth at effector/target ratio of 300/1 and inhibition was often still seen at 30/1-. Incubation of PMN, PBL, or monocytes for 1 hr at 37C with THC or 11-hydroxyTHC caused a marked suppression of function in all 3 cell populations. Maximal suppression was obtained with 7.5-10..mu..g/ml of the drugs in medium containing 10% fetal bovine serum (FBS) or with 2-4..mu..g/ml in 1% FBS. These drug concentrations did not affect lymphoid cell viability or candida growth in the absence of lymphoid effector cells. Marijuana derivatives, therefore, are doubly dangerous in that opportunistic fungi such as C. albicans can grow in their presence while the effector cells that control fungal growth are readily inactivated.

  14. Comparative effects of phencyclidine (PCP) and. delta. /sup 9/-tetrahydrocannabinol (THC) on glucose oxidation in the rat testis

    Energy Technology Data Exchange (ETDEWEB)

    Husain, S.; Bauer, V.

    1986-03-05

    Glucose and fructose are important fuels of cellular energetics in organs like testis and brain. The previous in-vitro studies indicated that THC may disrupt many gonadal functions by inhibiting energy metabolism in the testis. PCP is sold on the street as any one of a variety of psychoactive drugs. Most commonly it is misrepresented as THC. Therefore, to compare the effects of PCP and THC on glucose utilization, in-vitro radiorespirometric experiments were conducted in rat testicular tissues. The /sup 14/CO/sub 2/ production from 5.5 mM radiolabelled glucose was followed in the presence and absence of 0.2, 0.1, 0.05, 0.01, 0.005, 0.0025 mM PCP. PCP produced a dose-dependent biphasic effect, stimulating /sup 14/CO/sub 2/ production by 6.2, 17 and 5.8% and then inhibiting it by 13.2, 15.4 and 8.9% with respective concentrations of PCP. This is in contrast to THC which produced a dose-related inhibition of 15.2, 18.1, 20.1 and 25.3% in /sup 14/CO/sub 2/ production with 0.1, 0.2, 0.3 and 0.4 mM THC. These observations are significant due to the possible abuse of PCP together with THC either deliberately or by misrepresentation.

  15. Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain

    Energy Technology Data Exchange (ETDEWEB)

    Ali, S.F.; Newport, G.D.; Scallet, A.C.; Gee, K.W.; Paule, M.G.; Brown, R.M.; Slikker, W. Jr. (National Center for Toxicological Research, Jefferson, Arkansas (USA))

    THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains were dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the (35S)TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of (35S)TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects.

  16. Pretreatment with Δ9-tetrahydrocannabinol (THC) increases cocaine-stimulated activity in adolescent but not adult male rats

    OpenAIRE

    Dow-Edwards, Diana; Izenwasser, Sari

    2011-01-01

    Marijuana (cannabis sativa) remains one of the most widely used illegal drugs, with adolescents being particularly vulnerable to its use and abuse. In spite of this, most studies are conducted in adult animals even though the effects might be quite different in adolescents. Additionally, the use of marijuana often precedes the use of other psychoactive drugs including cocaine, especially when marijuana exposure begins during early adolescence. The purpose of this study was to examine the effe...

  17. [Does a positive finding of tetrahydrocannabinol in the blood result from ingestion of Indian frankincense (Boswellia serrata)?].

    Science.gov (United States)

    Skopp, Gisela; Schmitt, Georg

    2012-01-01

    The exculpatory statement that a positive THC finding in the blood is due to the consumption of hemp products or passive exposure to cannabis smoke has been disproved by the monitoring of hemp products and recent passive inhalation studies conducted in social settings, which showed that these conditions are unlikely to produce a positive result in the blood. The defense that the ingestion of Indian olibanum may result in a positive THC concentration in the blood is unusual; it is based on older publications where authors had speculated on a possible association of the synthetic pathways of THC from terpenoid precursors also being present in olibanum and the biogenesis of THC in hemp. It had further been speculated whether chemical or plant-derived pathways may also occur in humans. A thorough understanding of the different pathways and recently published results have outdated these speculations.

  18. Effect of prior foot shock stress and Δ9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats.

    Science.gov (United States)

    Rock, Erin M; Limebeer, Cheryl L; Petrie, Gavin N; Williams, Lauren A; Mechoulam, Raphael; Parker, Linda A

    2017-07-01

    Cannabis is commonly used by humans to relieve stress. Here, we evaluate the potential of intraperitoneally (i.p.) administered Δ 9 -tetrahydrocannabiol (THC) and cannabidiolic acid (CBDA, the precursor of cannabidiol [CBD]) to produce dose-dependent effects on anxiety-like responding in the light-dark (LD) emergence test of anxiety-like responding in rats, when administered acutely or chronically (21 days). As well, we evaluate the potential of THC, CBDA, and CBD to reduce anxiogenic responding produced by foot shock (FS) stress 24 h prior to the LD test. In the absence of the explicit FS stressor, THC (1 and 10 mg/kg) produced anxiogenic-like responding when administered acutely or chronically, but CBDA produced neither anxiogenic- nor anxiolytic-like responding. Administration of FS stress 24 h prior to the LD test enhanced anxiogenic-like responding (reduced time spent and increased latency to enter the light compartment) in rats pretreated with either vehicle (VEH) or THC (1 mg/kg); however, administration of CBDA (0.1-100 μg/kg) or CBD (5 mg/kg) prevented the FS-induced anxiogenic-like responding (an anxiolytic-like effect). The 5-hydroxytryptamine 1A (5-HT 1A ) receptor antagonist, WAY100635, reversed CBDA's anxiolytic effect (1 μg/kg). Combining an anxiolytic dose of CBDA (1 μg/kg) or CBD (5 mg/kg) with an anxiogenic dose of THC (1 mg/kg) did not modify THC's anxiogenic effect. These results suggest the anxiolytic effects of CBDA and CBD may require the presence of a specific stressor.

  19. Hormonal status and age differentially affect tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on learning in female rats

    OpenAIRE

    Peter J. Winsauer; Filipeanu, Catalin M.; Weed, Peter F.; Sutton, Jessie L.

    2015-01-01

    The effects of hormone status and age on the development of tolerance to Δ9-THC were assessed in sham-operated (intact) or ovariectomized (OVX) female rats that received either intraperitoneal saline or 5.6 mg/kg of Δ9-THC daily from postnatal day (PD) 75–180 (early adulthood onward) or PD 35–140 (adolescence onward). During this time, the four groups for each age (i.e., intact/saline, intact/THC, OVX/saline, and OVX/THC) were trained in a learning and performance procedure and dose-effect cu...

  20. Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC

    National Research Council Canada - National Science Library

    Karschner, Erin L; Schwope, David M; Schwilke, Eugene W; Goodwin, Robert S; Kelly, Deanna L; Gorelick, David A; Huestis, Marilyn A

    2012-01-01

    ... 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing...

  1. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults

    OpenAIRE

    Kollins, Scott H.; Schoenfelder, Erin N.; English, Joseph S.; Holdaway, Alex; Van Voorhees, Elizabeth; O’Brien, Benjamin R.; Dew, Rachel; Chrisman, Allan K.

    2014-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 ...

  2. Chronic administration during early adulthood does not alter the hormonally-dependent disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on complex behavior in female rats.

    Science.gov (United States)

    Winsauer, Peter J; Sutton, Jessie L

    2014-02-01

    This study examined whether chronic Δ(9)-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ(9)-THC during adolescence. To do this, either sham-operated (intact) or ovariectomized (OVX) female rats received daily saline or 5.6 mg/kg of Δ(9)-THC i.p. for 40 days during early adulthood. Following chronic administration, and a drug-free period to train both a learning and performance task, acute dose-effect curves for Δ(9)-THC (0.56-10 mg/kg) were established in each of the four groups (intact/saline, intact/THC, OVX/saline and OVX/THC). The dependent measures of responding under the learning and performance tasks were the overall response rate and the percentage of errors. Although the history of OVX and chronic Δ(9)-THC in early adulthood did not significantly affect non-drug or baseline behavior under the tasks, acute administration of Δ(9)-THC produced both rate-decreasing and error-increasing effects on learning and performance behavior, and these effects were dependent on their hormone condition. More specifically, both intact groups were more sensitive to the rate-decreasing and error-increasing effects of Δ(9)-THC than the OVX groups irrespective of chronic Δ(9)-THC administration, as there was no significant main effect of chronic treatment and no significant interaction between chronic treatment (saline or Δ(9)-THC) and the dose of Δ(9)-THC administered as an adult. Post mortem examination of 10 brain regions also indicated there were significant differences in agonist-stimulated GTPγS binding across brain regions, but no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ(9)-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we and others have shown for chronic administration during adolescence. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults.

    Science.gov (United States)

    Kollins, Scott H; Schoenfelder, Erin N; English, Joseph S; Holdaway, Alex; Van Voorhees, Elizabeth; O'Brien, Benjamin R; Dew, Rachel; Chrisman, Allan K

    2015-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10mg oral doses of delta-9-tetrahydocannibinol (THC); and 0mg, 10mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10mg THC+0mg, 10mg, and 40 mg MPH=89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of "Feel Drug," "Good Effects," and "Take Drug Again." THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper

    Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of

  5. Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol.

    Science.gov (United States)

    Cluny, Nina L; Keenan, Catherine M; Reimer, Raylene A; Le Foll, Bernard; Sharkey, Keith A

    2015-01-01

    Acute administration of cannabinoid CB1 receptor agonists, or the ingestion of cannabis, induces short-term hyperphagia. However, the incidence of obesity is lower in frequent cannabis users compared to non-users. Gut microbiota affects host metabolism and altered microbial profiles are observed in obese states. Gut microbiota modifies adipogenesis through actions on the endocannabinoid system. This study investigated the effect of chronic THC administration on body weight and gut microbiota in diet-induced obese (DIO) and lean mice. Adult male DIO and lean mice were treated daily with vehicle or THC (2mg/kg for 3 weeks and 4 mg/kg for 1 additional week). Body weight, fat mass, energy intake, locomotor activity, whole gut transit and gut microbiota were measured longitudinally. THC reduced weight gain, fat mass gain and energy intake in DIO but not lean mice. DIO-induced changes in select gut microbiota were prevented in mice chronically administered THC. THC had no effect on locomotor activity or whole gut transit in either lean or DIO mice. Chronic THC treatment reduced energy intake and prevented high fat diet-induced increases in body weight and adiposity; effects that were unlikely to be a result of sedation or altered gastrointestinal transit. Changes in gut microbiota potentially contribute to chronic THC-induced actions on body weight in obesity.

  6. Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis

    NARCIS (Netherlands)

    Aizpurua-Olaizola, Oier; Zarandona, Iratxe; Ortiz, Laura; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, Aresatz

    A high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) method for simultaneous quantification of Δ9-tetrahydrocannabinol (THC), its two metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH), and four

  7. 76 FR 35243 - Manufacturer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2011-06-16

    ... of controlled substances: Drug Schedule Gamma Hydroxybutyric Acid (2010) I Ibogaine (7260) I Lysergic acid diethylamide (7315) I Tetrahydrocannabinols (7370) I Dimethyltryptamine (7435) I 1- piperidine I...

  8. 76 FR 5830 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-02-02

    ... controlled substances: Drug Schedule Gamma Hydroxybutyric Acid (2010) I Ibogaine (7260) I Lysergic acid diethylamide (7315) I Tetrahydrocannabinols (7370) I Dimethyltryptamine (7435) I 1- piperidine I (7470...

  9. Beyond THC: The New Generation of Cannabinoid Designer Drugs

    National Research Council Canada - National Science Library

    Fattore, Liana; Fratta, Walter

    2011-01-01

    Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC), the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs...

  10. 77 FR 2324 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2012-01-17

    ... controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to... drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol as a synthetic...

  11. 75 FR 53720 - Manufacturer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2010-09-01

    ...: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I Alphamethadol (9605) I Nabilone (7379... code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol as a synthetic intermediate...

  12. 77 FR 47114 - Manufacturer of Controlled Substances; Notice of Application; AMRI Rensselaer, Inc.

    Science.gov (United States)

    2012-08-07

    ... following basic classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols... distribution to its customers. In reference to drug code 7360 (Marihuana), the company plans to bulk...

  13. 76 FR 17968 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-03-31

    ... controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I Alphamethadol (9605) I... code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol as a synthetic intermediate...

  14. Cannabinoids in oral fluid following passive exposure to marijuana smoke

    NARCIS (Netherlands)

    Moore, Christine; Coulter, Cynthia; Uges, Donald; Tuyay, James; van der Linde, Susanne; van Leeuwen, Arthur; Garnier, Margaux; Orbita, Jonathan

    2011-01-01

    The concentration of tetrahydrocannabinol (THC) and its main metabolite 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) as well as cannabinol (CBN), and cannabidiol (CBD) were measured in oral fluid following realistic exposure to marijuana in a Dutch coffee-shop. Ten healthy

  15. The effects of cannabinoids on body temperature and brain catecholamine synthesis.

    Science.gov (United States)

    Bloom, A S; Johnson, K M; Dewey, W L

    1978-04-01

    delta9-Tetrahydrocannabinol, 11-OH-delta9-tetrahydrocannabinol and 9-nor-9beta-OH-hexahydrocannabinol produced hypothermia and increased catecholamine synthesis in mouse brain. The potencies of the effects of these compounds were correlated. Cannabinol and cannabidiol were inactive in both tests.

  16. 75 FR 14188 - Importer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2010-03-24

    ... Hydroxybutyric Acid (2010) I Methaqualone (2565) I Alpha-ethyltryptamine (7249) I Ibogaine (7260) I Lysergic acid diethylamide (7315) I Marihuana (7360) I Tetrahydrocannabinols (7370) I Mescaline (7381) I 4-Bromo-2,5...

  17. Cannabidiol

    Science.gov (United States)

    Cannabidiol is a chemical in the Cannabis sativa plant, also known as marijuana. Over 80 chemicals, known ... 9-tetrahydrocannabinol (THC) is the major active ingredient, cannabidiol makes up about 40% of cannabis extracts and ...

  18. Medical Marijuana in Certain Neurological Disorders

    Science.gov (United States)

    ... two main types of chemicals in the plant: cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD and THC are ... least one year · Might lead to improvement on tests for spasticity a doctor performs, but only if ...

  19. Risks associated with the non-medicinal use of cannabis

    National Research Council Canada - National Science Library

    Hoch, Eva; Bonnetn, Udo; Thomasius, Rainer; Ganzer, Florian; Havemann-Reinecke, Ursula; Preuss, Ulrich W

    2015-01-01

    ...), case-control studies, and treatment guidelines. The delta-9-tetrahydrocannabinol content of cannabis products is rising around the world as a result of plant breeding, while cannabidiol, in contrast, is often no longer detectable...

  20. Dronabinol and chronic pain: importance of mechanistic considerations

    NARCIS (Netherlands)

    Vries, M. de; Rijckevorsel, D.C.M. van; Wilder-Smith, O.H.G.; Goor, H. van

    2014-01-01

    INTRODUCTION: Although medicinal cannabis has been used for many centuries, the therapeutic potential of delta-9-tetrahydrocannabinol (Delta9-THC; international non-proprietary name = dronabinol) in current pain management remains unclear. Several pharmaceutical products with defined natural or

  1. Marijuana, alcohol and actual driving performance

    Science.gov (United States)

    1999-07-01

    The purpose of this study was to empirically determine the separate and combined effects of Delta-9-tetrahydrocannabinol (THC) and alcohol on actual driving performance. This was the first study ever in which the drugs' combined effects were measured...

  2. Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ⁹-THC in humans discriminating Δ⁹-THC

    National Research Council Canada - National Science Library

    Lile, Joshua A; Kelly, Thomas H; Hays, Lon R

    2014-01-01

    ...)-tetrahydrocannabinol (Δ(9)-THC). The aim of the present study was to determine the potential involvement of the GABAA receptor subtype by assessing the separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ(9...

  3. Transformation and sorption of illicit drug biomarkers in sewer systems: understanding the role of suspended solids in raw wastewater

    DEFF Research Database (Denmark)

    Ramin, Pedram; Brock, Andreas Libonati; Polesel, Fabio

    2016-01-01

    substrates (primary metabolic processes) and transformation of illicit drug biomarkers (secondary metabolic processes) by suspended biomass. Sixteen drug biomarkers were targeted, including mephedrone, methadone, cocaine, heroin, codeine and tetrahydrocannabinol (THC) and their major human metabolites. Batch...

  4. Gene duplication and divergence affecting drug content in Cannabis sativa

    National Research Council Canada - National Science Library

    Weiblen, George D; Wenger, Jonathan P; Craft, Kathleen J; ElSohly, Mahmoud A; Mehmedic, Zlatko; Treiber, Erin L; Marks, M. David

    2015-01-01

    ..., and psychoactive drugs but few economic plants are so poorly understood genetically. Marijuana and hemp were crossed to evaluate competing models of cannabinoid inheritance and to explain the predominance of tetrahydrocannabinolic acid ( THCA...

  5. 77 FR 13633 - Manufacturer of Controlled Substances; Notice of Registration; National Center for Natural...

    Science.gov (United States)

    2012-03-07

    ... following basic classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to cultivate marihuana for the National Institute on Drug Abuse for research...

  6. 77 FR 67398 - Manufacturer of Controlled Substances Notice of Application; National Center For Natural Products...

    Science.gov (United States)

    2012-11-09

    ... the following basic classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to cultivate marihuana for the National Institute on Drug Abuse for...

  7. 77 FR 75670 - Manufacturer of Controlled Substances, Notice of Registration, AMRI Rensselaer, Inc.

    Science.gov (United States)

    2012-12-21

    ... basic classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I... reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol as a synthetic...

  8. 75 FR 64745 - Manufacturer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2010-10-20

    ... schedule I: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to cultivate marihuana for the National Institute on Drug Abuse for research approved by the Department of Health and...

  9. 76 FR 51401 - Manufacturer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2011-08-18

    ... classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The... customers. In reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol as...

  10. 77 FR 52368 - Manufacturer of Controlled Substances; Notice of Registration; Austin Pharma, LLC.

    Science.gov (United States)

    2012-08-29

    ... basic classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I... customers. In reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol as...

  11. 75 FR 14187 - Importer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2010-03-24

    ... controlled substances listed in schedules I and II: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols..., laboratory-based research only. In reference to drug code 7360 (Marihuana), the company plans to import...

  12. 78 FR 69132 - Manufacturer of Controlled Substances, Notice of Application, National Center for Natural...

    Science.gov (United States)

    2013-11-18

    ... the following basic classes of controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to cultivate marihuana in support of the National Institute on Drug...

  13. 76 FR 25375 - Importer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-05-04

    ... substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I 4-Bromo-2,5-dimethoxyamphetamine..., laboratory-based research only. In reference to drug code 7360 (Marihuana), the company plans to import...

  14. 76 FR 62449 - Manufacturer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2011-10-07

    ...: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to cultivate marihuana for the National Institute on Drug Abuse for research approved by the Department of Health and...

  15. 76 FR 30970 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-05-27

    ... controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I Amphetamine (1100) II... distribution to its customers. In reference to drug code 7360 (Marihuana), the company plans to bulk...

  16. 76 FR 5829 - Manufacturer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2011-02-02

    ... controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I Amphetamine (1100) II... distribution to its customers. In reference to drug code 7360 (Marihuana), the company plans to bulk...

  17. 78 FR 23597 - Manufacturer of Controlled Substances, Notice of Registration, National Center for Natural...

    Science.gov (United States)

    2013-04-19

    ... classes of controlled substances: Drug Schedule Marihuana (7360) II Tetrahydrocannabinols (7370) II The company plans to cultivate marihuana for the National Institute on Drug Abuse for research approved by the...

  18. 75 FR 6062 - Manufacturer of Controlled Substances Notice of Registration

    Science.gov (United States)

    2010-02-05

    ... schedules I and II: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I Cocaine (9041) I The Institute will manufacture small quantities of cocaine and marihuana derivatives for use by their customers...

  19. Cannabis Use Surveillance by Sweat Analysis.

    Science.gov (United States)

    Gambelunghe, Cristiana; Fucci, Nadia; Aroni, Kyriaki; Bacci, Mauro; Marcelli, Antonio; Rossi, Riccardo

    2016-10-01

    Sweat testing, an alternative matrix for establishing drug abuse, offers additional benefits to the more common biological samples. The authors developed a procedure using gas chromatography-mass spectrometry to test for Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, cannabinol (CBN), and cannabidiol (CBD) in a sweat patch. The results were compared with urine and hair sample results. Urine, hair, and sweat samples were simultaneously collected from 12 patients who were involved, respectively, in forensic case and monitoring abuse. Selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), recovery, intraday and interday imprecision, and inaccuracy of the quantification procedure were validated. LODs in hair were 0.05 ng/mg for Δ9-tetrahydrocannabinol, CBN, and CBD, and 0.005 ng/mg for 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid. The LOD for sweat was 0.30 ng/patch for all substances. The LOQ in hair was 0.1 ng/mg for Δ9-tetrahydrocannabinol, CBN, and CBD, and 0.01 ng/mg for 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid. The LOQ was 0.4 ng/patch in sweat for each analyte. Cannabinoid in urine was determined by means of immunochemical screening (cutoff 11-nor-Δ-tetrahydrocannabinol-9-carboxylic acid 50 ng/mL). All subjects tested positive for 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid and Δ9-tetrahydrocannabinol in urine and hair. In sweat samples, Δ9-tetrahydrocannabinol was found in all patches (0.4-2.0 ng/patch); 6 cases were positive for CBN (0.4-0.5 ng/patch) and 3 for CBD (0.4-0.6 ng/patch); 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid was never detected in patches. Present sweat analysis results integrated the information from hair and urine and showed that sweat analysis is a suitable, noninvasive method for monitoring compliance with rehabilitation therapy and for detecting recent cumulative use of cannabinoids.

  20. Quality Control of Traditional Cannabis Tinctures: Pattern, Markers, and Stability

    OpenAIRE

    Peschel, Wieland

    2016-01-01

    Traditional tinctures of Cannabis sativa L. became obsolete before elucidation of the main cannabinoids and routine quality testing for medicines. In view of increasing medicinal use of cannabinoids and associated safety concerns, tinctures from a ?9-tetrahydrocannabinol (THC)-type chemovar were studied. High-performance liquid chromatography with diode-array detection (HPLC/DAD) was used to determine THC, ?9-tetrahydrocannabinolic acid A (THCA), cannabinol (CBN), cannabidiol (CBD), cannabidi...

  1. Unheated Cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways

    NARCIS (Netherlands)

    Verhoeckx, K.C.M.; Korthout, H.A.A.J.; Meeteren-Kreikamp, A.P. van; Ehlert, K.A.; Wang, M.; Greef, J. van der; Rodenburg, R.J.T.; Witkamp, R.F.

    2006-01-01

    There is a great interest in the pharmacological properties of cannabinoid like compounds that are not linked to the adverse effects of Δ9-tetrahydrocannabinol (THC), e.g. psychoactive properties. The present paper describes the potential immuno-modulating activity of unheated Cannabis sativa

  2. Long term stability of cannabis resin and cannabis extracts

    DEFF Research Database (Denmark)

    Lindholst, Christian

    2010-01-01

      The aim of the present study was to investigate the stability of cannabinoids in cannabis resin slabs and cannabis extracts upon long-term storage. The levels of tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD) and cannabigerol (CBG) on both neutral and acidic form were measured...

  3. Isomeric separation of cannabinoids by UPLC combined with ionic mobility mass spectrometry (TWIM-MS)-Part I

    NARCIS (Netherlands)

    Tose, Lilian V.; Santos, Nayara A.; Rodrigues, Rayza R T; Murgu, Michael; Gomes, Alexandre F.; Vasconcelos, Géssica A.; Souza, Paulo C T; Vaz, Boniek G.; Romão, Wanderson

    The Cannabis sativa L. plant is rich in a wide variety of cannabinoids. δ9-tetrahydrocannabinol (δ9-THC) is the main chemical compound responsible for its psychoactive effect, and it can be identified as [M+H]+ and [M-H]- ions at m/z 315 and 313, respectively, where M=C21H30O2. However, six other

  4. The adverse health effects of synthetic cannabinoids with emphasis on psychosis-like effects

    NARCIS (Netherlands)

    van Amsterdam, Jan; Brunt, Tibor; van den Brink, Wim

    2015-01-01

    Cannabis use is associated with an increased risk of psychosis in vulnerable individuals. Cannabis containing high levels of the partial cannabinoid receptor subtype 1 (CB1) agonist tetrahydrocannabinol (THC) is associated with the induction of psychosis in susceptible subjects and with the

  5. Prenatal Cannabis Exposure and Infant Development: “A Tolerated Matter”

    NARCIS (Netherlands)

    H. El Marroun (Hanan)

    2010-01-01

    textabstractSince centuries, cannabis is used for recreational, spiritual and medicinal purposes. Today, cannabis is one of the most commonly used illicit substances, also among pregnant women. In the last decades, levels of Δ9-tetrahydrocannabinol in cannabis products have increased, and

  6. An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine.

    Science.gov (United States)

    Klawitter, Jelena; Sempio, Cristina; Mörlein, Sophie; De Bloois, Erik; Klepacki, Jacek; Henthorn, Thomas; Leehey, Maureen A; Hoffenberg, Edward J; Knupp, Kelly; Wang, George S; Hopfer, Christian; Kinney, Greg; Bowler, Russell; Foreman, Nicholas; Galinkin, Jeffrey; Christians, Uwe; Klawitter, Jost

    2017-10-01

    Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids. To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma. In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (marijuana research and clinical practice.

  7. The Endocannabinoid Anandamide : Metabolism & Neuroprotection

    NARCIS (Netherlands)

    Stelt, Marcelis van der

    2002-01-01

    Marijuana is an extract of the Cannabis sativa and is the most used illegal drug in the world. Public debate centres upon the possible legalization of marijuana for recreational and therapeutic uses. DELTA-exp.9-Tetrahydrocannabinol (THC), the main psychoactive compound in marijuana, exerts its

  8. Medicinal cannabis (Bedrolite) substitution therapy in inpatients with a psychotic disorder and a comorbid cannabis use disorder: A case series.

    Science.gov (United States)

    Schipper, Regi; Dekker, Mathilde; de Haan, Lieuwe; van den Brink, Wim

    2017-10-01

    Cannabis use disorders are frequently comorbid in patients with a psychotic disorder and are associated with worse outcomes. To date there are no proven effective strategies to achieve cannabis abstinence in this population. An alternative for abstinence might be harm reduction, i.e. replacing the use of street cannabis with high tetrahydrocannabinol and low cannabidiol levels by medicinal cannabis variants with relatively low tetrahydrocannabinol and relatively high cannabidiol levels, thereby reducing the psychosis inducing effects of cannabis and enhancing the antipsychotic effects of cannabis. Here we present the data of a case series with seven inpatients diagnosed with a psychotic disorder and a treatment-resistant cannabis use disorder who received substitution therapy with a low tetrahydrocannabinol medicinal cannabis variant (Bedrolite). The results suggest that the low tetrahydrocannabinol medicinal cannabis variant Bedrolite is not effective in the treatment of inpatients with a psychotic disorder and comorbid cannabis use disorder. Bedrolite is thus not very likely to become an effective harm reduction strategy in these patients.

  9. Showing Its Colors. Thin-Layer Chromatographic Detection of Cannabinoid Metabolites.

    Science.gov (United States)

    Bonicamp, Judith M.

    1986-01-01

    Describes a chemistry laboratory experiment in which thin-layer chromatography (TLC) is used to analyze urine specimens containing metabolites of the drug tetrahydro-cannabinol, which comes from the marijuana plant. The materials needed to conduct the experiment are listed, and the procedure and expected results are outlined. (TW)

  10. 21 CFR 1308.35 - Exemption of certain cannabis plant material, and products made therefrom, that contain...

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Exemption of certain cannabis plant material, and... ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE SCHEDULES OF CONTROLLED SUBSTANCES Exempt Cannabis Plant... cannabis plant material, and products made therefrom, that contain tetrahydrocannabinols. (a) Any processed...

  11. Safety of hemp used as animal feed

    OpenAIRE

    Scientific Committee on Animal Nutrition

    2010-01-01

    The Statement reacts to the EFSA "Information request on the use of hemp-derived products as animal feed, the transfer of tetrahydrocannabinol (THC, and related compounds) from hemp in food products and on the maximum tolerable levels of those compounds in humans’ food“.

  12. The science of marijuana

    National Research Council Canada - National Science Library

    Iversen, Leslie L

    2008-01-01

    ... 1930s, which essentially eliminated all medical research in the field for almost 30 years. This action was tragic for science, as chemists were extremely close to isolating the active chemical ingredient of marijuana prior to World War II. The identification of delta-9tetrahydrocannabinol (THC) had to wait for the elegant efforts of Raphael ...

  13. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects

    OpenAIRE

    Russo, Ethan B

    2011-01-01

    Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expres...

  14. NMR assignments of the major cannabinoids and cannabiflavonoids isolated from flowers of Cannabis sativa.

    Science.gov (United States)

    Choi, Young Hae; Hazekamp, Arno; Peltenburg-Looman, Anja M G; Frédérich, Michel; Erkelens, Cornelis; Lefeber, Alfons W M; Verpoorte, Robert

    2004-01-01

    The complete 1H- and 13C-NMR assignments of the major Cannabis constituents, delta9-tetrahydrocannabinol, tetrahydrocannabinolic acid, delta8-tetrahydrocannabinol, cannabigerol, cannabinol, cannabidiol, cannabidiolic acid, cannflavin A and cannflavin B have been determined on the basis of one- and two-dimensional NMR spectra including 1H- and 13C-NMR, 1H-1H-COSY, HMQC and HMBC. The substitution of carboxylic acid on the cannabinoid nucleus (as in tetrahydrocannabinolic acid and cannabidiolic acid) has a large effect on the chemical shift of H-1" of the C5 side chain and 2'-OH. It was also observed that carboxylic acid substitution reduces intermolecular hydrogen bonding resulting in a sharpening of the H-5' signal in cannabinolic acid in deuterated chloroform. The additional aromaticity of cannabinol causes the two angular methyl groups (H-8 and H-9) to show identical 1H-NMR shifts, which indicates that the two aromatic rings are in one plane in contrast to the other cannabinoids. For the cannabiflavonoids, the unambiguous assignments of C-3' and C-4' of cannflavin A and B were determined by HMBC spectra.

  15. Drug: D00306 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 246 314.4617 D00306.gif Cannabis sativa [TAX:3483] Anti-emetic Same as: C06972 ATC code: A04AD10 cannabinoid...D00306 Drug Dronabinol (USP/INN); Tetrahydrocannabinol; Marinol (TN) C21H30O2 314.2

  16. Incorporation of lipophilic drugs in sugar glasses by lyophilization using a mixture of water and tertiary butyl alcohol as solvent

    NARCIS (Netherlands)

    Van Drooge, D.J.; Hinrichs, W.L.J.; Frijlink, H.W.

    2004-01-01

    In this study, anew and robust method was evaluated to prepare physically stable solid dispersions. Trehalose, sucrose, and two inulins having different chain lengths were used as carrier. Diazepam, nifedipine, Delta(9)-tetrahydrocannabinol, and cyclosporine A were used as model drugs. The sugar was

  17. Validation of self-reported cannabis dose and potency: an ecological study

    NARCIS (Netherlands)

    van der Pol, Peggy; Liebregts, Nienke; de Graaf, Ron; Korf, Dirk J.; van den Brink, Wim; van Laar, Margriet

    2013-01-01

    To assess the reliability and validity of self-reported cannabis dose and potency measures. Cross-sectional study comparing self-reports with objective measures of amount of cannabis and delta-9-tetrahydrocannabinol (THC) concentration. Ecological study with assessments at participants' homes or in

  18. Validation of self-reported cannabis dose and potency: an ecological study

    NARCIS (Netherlands)

    van der Pol, P.; Liebregts, N.; de Graaf, R.; Korf, D.J.; van den Brink, W.; van Laar, M.

    2013-01-01

    Aims To assess the reliability and validity of self-reported cannabis dose and potency measures. Design Cross-sectional study comparing self-reports with objective measures of amount of cannabis and delta-9-tetrahydrocannabinol (THC) concentration. Setting Ecological study with assessments at

  19. Cannabinoids and zebrafish

    NARCIS (Netherlands)

    Akhtar, Muhammad Tayyab

    2013-01-01

    Cannabinoids are a group of terpenophenolic compounds and are naturally found in the cannabis plant (Cannabis sativa L). Δ9-Tetrahydrocannabinol (Δ9-THC) is the psychoactive cannabinoid. The high lipophilicity of Δ9-THC is a hindering factor in the further development of this compound into a large

  20. Cannabinoid and Cholinergic Systems Interact during Performance of a Short-Term Memory Task in the Rat

    Science.gov (United States)

    Goonawardena, Anushka V.; Robinson, Lianne; Hampson, Robert E.; Riedel, Gernot

    2010-01-01

    It is now well established that cannabinoid agonists such as [delta][superscript 9]-tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such…

  1. Acute psychomotor, memory and subjective effects of MDMA and THC (co-) administration over time in healthy volunteers

    NARCIS (Netherlands)

    Dumont, G.; Van Hasselt, J.; De Kam, M.; Van Gerven, J.; Touw, D.; Buitelaar, J.; Verkes, R.

    Introduction: In Western societies a considerable percentage of young people expose themselves to the combination of 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”). Cannabis (main active compound D9-tetrahydrocannabinol or THC) is frequently co-used with ecstasy (Parrott et al., 2007).

  2. Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study

    NARCIS (Netherlands)

    Hell, van H.H.; Bossong, M.G.; Jager, G.; Kristo, G.; Osch, M.J.P.; Zelaya, F.; Kahn, R.S.; Ramsey, N.F.

    2011-01-01

    The main reason for recreational use of cannabis is the ‘high’, the primary psychotropic effect of ¿9-tetrahydrocannabinol (THC). This psychoactive compound of cannabis induces a range of subjective, physical and mental reactions. The effect on heart rate is pronounced and complicates

  3. Smoked Cannabis' Psychomotor and Neurocognitive Effects in Occasional and Frequent Smokers

    OpenAIRE

    Desrosiers, Nathalie A.; Ramaekers, Johannes G.; Chauchard, Emeline; Gorelick, David A.; Huestis, Marilyn A.

    2015-01-01

    Δ9-Tetrahydrocannabinol (THC), the primary psychoactive constituent in cannabis, impairs psychomotor performance, cognition and driving ability; thus, driving under the influence of cannabis is a public safety concern. We documented cannabis' psychomotor, neurocognitive, subjective and physiological effects in occasional and frequent smokers to investigate potential differences between these smokers. Fourteen frequent (≥4x/week) and 11 occasional (

  4. THC-concentraties in wiet, nederwiet en hasj in Nederlandse coffeeshops (2001 - 2002)

    NARCIS (Netherlands)

    Niesink, R.J.M.; Pijlman, F.T.A.; Rigter, S.; Hoek, J.; Mostert, L.

    2002-01-01

    THC (tetrahydrocannabinol) is de belangrijkste psychoactieve verbinding in de cannabisplant. In 1999 is door de ministeries van VWS en Justitie een onafhankelijke monitor geëntameerd naar de THC-gehaltes in cannabisproducten zoals die in de Nederlandse coffeeshops worden verkocht, als input voor het

  5. 76 FR 21917 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2011-04-19

    ... controlled substances: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to manufacture small quantities of marihuana derivatives for research purposes. In reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol. In reference to drug code 7370...

  6. 75 FR 9614 - Manufacturer of Controlled Substances; Notice of Registration

    Science.gov (United States)

    2010-03-03

    ... controlled substances listed in schedule I: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to manufacture small quantities of marihuana derivatives for research purposes. In reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol. In reference to...

  7. Evaluation of a radioimmunoassay (/sup 125/I) kit for cannabinoid metabolites in urine and whole blood

    Energy Technology Data Exchange (ETDEWEB)

    Childs, P.S.; McCurdy, H.H.

    The Abuscreen kit (Roche Diagnostics) for the analysis of 11-nor-..delta../sup 9/-tetrahydrocannabinol-9-carboxylic acid and other cannabinoids in urine was evaluated in terms of its accuracy, reproducibility, and sensitivity. A procedure is also presented for the analysis of total cannabinoids in whole blood using the RIA kit.

  8. 75 FR 64744 - Manufacturer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2010-10-20

    ... controlled substances listed in schedule I: Drug Schedule Marihuana (7360) I Tetrahydrocannabinols (7370) I The company plans to manufacture small quantities of marihuana derivatives for research purposes. In reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidiol. In reference to...

  9. 76 FR 39127 - Manufacturer of Controlled Substances; Notice of Application

    Science.gov (United States)

    2011-07-05

    ...). Marihuana (7360) I Tetrahydrocannabinols (7370) I 3,4,5-Trimethoxyamphetamine (7390) I 4-Bromo-2,5... plans to manufacture small quantities of marihuana derivatives for research purposes. In reference to drug code 7360 (Marihuana), the company plans to bulk manufacture cannabidol. In reference to drug code...

  10. 78 FR 55099 - Established Aggregate Production Quotas for Schedule I and II Controlled Substances and...

    Science.gov (United States)

    2013-09-09

    ..., tetrahydrocannabinol, and thebaine were insufficient to provide for the estimated medical, scientific, research, and... (for conversion) was insufficient to provide for the estimated medical, scientific, research, and... assessment of annual needs are sufficient to meet the current 2014 estimated medical, scientific, research...

  11. Pharmacological Foundations of Cannabis Chemovars.

    Science.gov (United States)

    Lewis, Mark A; Russo, Ethan B; Smith, Kevin M

    2017-11-21

    An advanced Mendelian Cannabis breeding program has been developed utilizing chemical markers to maximize the yield of phytocannabinoids and terpenoids with the aim to improve therapeutic efficacy and safety. Cannabis is often divided into several categories based on cannabinoid content. Type I, Δ(9)-tetrahydrocannabinol-predominant, is the prevalent offering in both medical and recreational marketplaces. In recent years, the therapeutic benefits of cannabidiol have been better recognized, leading to the promotion of additional chemovars: Type II, Cannabis that contains both Δ(9)-tetrahydrocannabinol and cannabidiol, and cannabidiol-predominant Type III Cannabis. While high-Δ(9)-tetrahydrocannabinol and high-myrcene chemovars dominate markets, these may not be optimal for patients who require distinct chemical profiles to achieve symptomatic relief. Type II Cannabis chemovars that display cannabidiol- and terpenoid-rich profiles have the potential to improve both efficacy and minimize adverse events associated with Δ(9)-tetrahydrocannabinol exposure. Cannabis samples were analyzed for cannabinoid and terpenoid content, and analytical results are presented via PhytoFacts, a patent-pending method of graphically displaying phytocannabinoid and terpenoid content, as well as scent, taste, and subjective therapeutic effect data. Examples from the breeding program are highlighted and include Type I, II, and III Cannabis chemovars, those highly potent in terpenoids in general, or single components, for example, limonene, pinene, terpinolene, and linalool. Additionally, it is demonstrated how Type I - III chemovars have been developed with conserved terpenoid proportions. Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ(9)-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment. Georg Thieme Verlag KG Stuttgart

  12. Molecular Pharmacology of Phytocannabinoids.

    Science.gov (United States)

    Turner, Sarah E; Williams, Claire M; Iversen, Leslie; Whalley, Benjamin J

    Cannabis sativa has been used for recreational, therapeutic and other uses for thousands of years. The plant contains more than 120 C21 terpenophenolic constituents named phytocannabinoids. The Δ9-tetrahydrocannabinol type class of phytocannabinoids comprises the largest proportion of the phytocannabinoid content. Δ9-tetrahydrocannabinol was first discovered in 1971. This led to the discovery of the endocannabinoid system in mammals, including the cannabinoid receptors CB1 and CB2. Δ9-Tetrahydrocannabinol exerts its well-known psychotropic effects through the CB1 receptor but this effect of Δ9-tetrahydrocannabinol has limited the use of cannabis medicinally, despite the therapeutic benefits of this phytocannabinoid. This has driven research into other targets outside the endocannabinoid system and has also driven research into the other non-psychotropic phytocannabinoids present in cannabis. This chapter presents an overview of the molecular pharmacology of the seven most thoroughly investigated phytocannabinoids, namely Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabivarin, cannabinol, cannabidiol, cannabidivarin, cannabigerol, and cannabichromene. The targets of these phytocannabinoids are defined both within the endocannabinoid system and beyond. The pharmacological effect of each individual phytocannabinoid is important in the overall therapeutic and recreational effect of cannabis and slight structural differences can elicit diverse and competing physiological effects. The proportion of each phytocannabinoid can be influenced by various factors such as growing conditions and extraction methods. It is therefore important to investigate the pharmacology of these seven phytocannabinoids further, and characterise the large number of other phytocannabinoids in order to better understand their contributions to the therapeutic and recreational effects claimed for the whole cannabis plant and its extracts.

  13. CB1-Dependent Long-Term Depression in Ventral Tegmental Area GABA Neurons: A Novel Target for Marijuana.

    Science.gov (United States)

    Friend, Lindsey; Weed, Jared; Sandoval, Philip; Nufer, Teresa; Ostlund, Isaac; Edwards, Jeffrey G

    2017-11-08

    The VTA is necessary for reward behavior with dopamine cells critically involved in reward signaling. Dopamine cells in turn are innervated and regulated by neighboring inhibitory GABA cells. Using whole-cell electrophysiology in juvenile-adolescent GAD67-GFP male mice, we examined excitatory plasticity in fluorescent VTA GABA cells. A novel CB1-dependent LTD was induced in GABA cells that was dependent on metabotropic glutamate receptor 5, and cannabinoid receptor 1 (CB1). LTD was absent in CB1 knock-out mice but preserved in heterozygous littermates. Bath applied Δ 9 -tetrahydrocannabinol depressed GABA cell activity, therefore downstream dopamine cells will be disinhibited; and thus, this could potentially result in increased reward. Chronic injections of Δ 9 -tetrahydrocannabinol occluded LTD compared with vehicle injections; however, a single exposure was insufficient to do so. As synaptic modifications by drugs of abuse are often tied to addiction, these data suggest a possible mechanism for the addictive effects of Δ 9 -tetrahydrocannabinol in juvenile-adolescents, by potentially altering reward behavioral outcomes. SIGNIFICANCE STATEMENT The present study identifies a novel form of glutamatergic synaptic plasticity in VTA GABA neurons, a currently understudied cell type that is critical for the brain's reward circuit, and how Δ 9 -tetrahydrocannabinol occludes this plasticity. This study specifically addresses a potential unifying mechanism whereby marijuana could exert rewarding and addictive/withdrawal effects. Marijuana use and legalization are a pressing issue for many states in the United States. Although marijuana is the most commonly abused illicit drug, the implications of legalized, widespread, or continued usage are speculative. This study in juvenile-adolescent aged mice identifies a novel form of synaptic plasticity in VTA GABA cells, and the synaptic remodeling that can occur after Δ 9 -tetrahydrocannabinol use. Copyright © 2017 the

  14. Analysis of THCA synthase gene expression in cannabis: a preliminary study by real-time quantitative PCR.

    Science.gov (United States)

    Cascini, Fidelia; Passerotti, Stella; Boschi, Ilaria

    2013-09-10

    In this paper we describe analyses performed by Real-Time Reverse-Transcriptase Polymerase Chain Reaction (real-time RT-PCR) on RNA of 12 samples, carried out for forensic purposes to investigate a correlation between tetrahydrocannabinol (THC) concentration in Cannabis and the tetrahydrocannabinol acid synthase (THCAS) gene expression. Samples were obtained from an experimental cultivation of declared potency Cannabis variety seeds and from seizures. The Rubisco gene and the 26S ribosomal RNA gene were used as internal control genes for their constant expression and stability. As results we found minor gene expression in samples from leaves of young plants. Further, grouping results for cannabis samples with similar characteristics, we have found an increased relative expression in samples with the highest percentage of THC coming from seized sample and adult plants. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  15. Establishment of a New Drug Code for Marihuana Extract. Final rule.

    Science.gov (United States)

    2016-12-14

    The Drug Enforcement Administration is creating a new Administration Controlled Substances Code Number for "Marihuana Extract." This code number will allow DEA and DEA-registered entities to track quantities of this material separately from quantities of marihuana. This, in turn, will aid in complying with relevant treaty provisions. Under international drug control treaties administered by the United Nations, some differences exist between the regulatory controls pertaining to marihuana extract versus those for marihuana and tetrahydrocannabinols. The DEA has previously established separate code numbers for marihuana and for tetrahydrocannabinols, but not for marihuana extract. To better track these materials and comply with treaty provisions, DEA is creating a separate code number for marihuana extract with the following definition: "Meaning an extract containing one or more cannabinoids that has been derived from any plant of the genus Cannabis, other than the separated resin (whether crude or purified) obtained from the plant." Extracts of marihuana will continue to be treated as Schedule I controlled substances.

  16. Cannabidiol as a treatment for epilepsy

    OpenAIRE

    Pickrell, William O.; Robertson, Neil P.

    2017-01-01

    Despite an increasing number of anti-epileptic drugs (AEDs), the proportion of drug-resistant cases of epilepsy has remained fairly static at around 30% and the search for new and improved AEDs continues. Cannabis has been used as a medical treatment for epilepsy for thousands of years; it contains many active compounds, the most important being tetrahydrocannabinol, which has psychoactive properties, and cannabidiol, which does not. Animal models and clinical data to date have suggested that...

  17. The Endocannabinoid System as a Target for Treatment of Breast Cancer

    Science.gov (United States)

    2011-08-01

    WIN55,212-2, but not its stereoisomer WIN55,212-3 or the phytocannabinoids ∆9-tetrahydrocannabinol (THC) or cannabidiol (CBD), significantly enhanced...The primary objective of this project was to test whether increasing levels of endogenous anandamide through deletion of its primary catabolic enzyme...was excised and fixed in a 10% formalin solution. The tissue sections were tested immunohistologically using: Hematoxylin and Eosin stain, p63

  18. Cannabinoids and metabolites in expectorated oral fluid after 8 days of controlled around-the-clock oral THC administration

    OpenAIRE

    Milman, Garry; Barnes, Allan J.; Schwope, David M.; Schwilke, Eugene W.; Goodwin, Robert S.; Kelly, Deana L.; Gorelick, David A.; Huestis, Marilyn A.

    2011-01-01

    Oral fluid (OF) is an increasingly accepted matrix for drug testing programs, but questions remain about its usefulness for monitoring cannabinoids. Expectorated OF specimens (n=360) were obtained from 10 adult daily cannabis smokers before, during, and after 37 20-mg oral Δ9-tetrahydrocannabinol (THC) doses over 9 days to characterize cannabinoid disposition in this matrix. Specimens were extracted and analyzed by gas chromatography– mass spectrometry with electron-impact ionization for THC,...

  19. Subacute cannabinoid treatment: anticonvulsant activity and withdrawal excitability in mice.

    OpenAIRE

    Karler, R.; Turkanis, S. A.

    1980-01-01

    1 The effects of subacute treatment with cannabidiol, delta 9-tetrahydrocannabinol (delta 9-THC), phenytoin and phenobarbitone on anticonvulsant activity and on withdrawal excitability in mice were compared in three electrically induced seizure-threshold tests. 2 In the maximal electroshock-threshold test, subacute treatment did not alter the anticonvulsant activity of cannabidiol, phenytoin or phenobarbitone, but tolerance developed to delta 9-THC. 3 In the 60 Hz electroshock-threshold test,...

  20. Traditional marijuana, high-potency cannabis and synthetic cannabinoids:increasing risk for psychosis

    OpenAIRE

    Murray, Robin M.; Quigley, Harriet; Quattrone, Diego; Englund, Amir; Di Forti, Marta

    2016-01-01

    Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose-response relationship between the level of use and the risk of later psychosis. High-potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co-administration of cannabidiol....

  1. Cannabis and Breastfeeding

    OpenAIRE

    Garry, Aur?lia; Rigourd, Virginie; Amirouche, Ammar; Fauroux, Val?rie; Aubry, Sylvie; Serreau, Rapha?l

    2009-01-01

    Cannabis is a drug derived from hemp plant, Cannabis sativa, used both as a recreational drug or as medicine. It is a widespread illegal substance, generally smoked for its hallucinogenic properties. Little is known about the adverse effects of postnatal cannabis exposure throw breastfeeding because of a lack of studies in lactating women. The active substance of cannabis is the delta 9 TetraHydroCannabinol (THC). Some studies conclude that it could decrease motor development of the child at ...

  2. Overview of the TREC 2009 Chemical IR Track

    Science.gov (United States)

    2009-11-01

    soluble polyvinyl acetal wherein the acetal-group is substutiuted by alkyl - groups only. 12 Diazepam or RN: 439- 14-5 Pharmaceuticals Please identify...all documents on diazepam being used as a muscle relaxant (there are other names see ChemID plus or PubChem) 13 tetrahydrocannabinol as an anti-tumour...chemical company that do custom synthesis for different clients in the pharmaceuticals and fine chemicals communities. One of our customers has asked

  3. The Cannabinoid Type-1 Receptor Carboxyl-Terminus, More Than Just a Tail

    OpenAIRE

    Stadel, Rebecca; Ahn, Kwang H.; Kendall, Debra A.

    2011-01-01

    The cannabinoid type-1 (CB1) receptor is a G protein-coupled receptor (GPCR) that binds the main active ingredient of marijuana, Δ9-tetrahydrocannabinol, and has been implicated in several disease states, including drug addiction, anxiety, depression, obesity, and chronic pain. In the two decades since the discovery of CB1, studies at the molecular level have centered on the transmembrane core. This interest has now expanded as we discover that other regions of CB1, including the CB1 carboxyl...

  4. Conjugation of the Dark Quencher QSY 7 to Various Synthetic Cannabinoids for Use in Fluorescence-Based Detection Platforms

    Science.gov (United States)

    2015-02-01

    bone marrow, and spleen. 7 Originally developed to treat a wide variety of diseases from obesity to cancer therapeutics , SCs have more recently...much more potent than traditional cannabis . 12,17 Cannabis sativa contains tetrahydrocannabinol (THC) as the active psychotropic ingredient and...The cannabinoid receptors. Prostaglandins Other Lipid Mediat. 2002;68–69:619–631. 8. Bhargava HN. Potential therapeutic applications of naturally

  5. Did Cannabis Precipitate an STEMI in a Young Woman?

    OpenAIRE

    Jehangir, Waqas; Stanton, Michael; Khan, Rafay; Sahgal, Puneet; Yousif, Abdalla

    2015-01-01

    Cannabis is a substance that contains compounds that bind cannabinoid receptors, CB1 and CB2. Cannabis also contains substances that do not bind these receptors. Delta-9-tetrahydrocannabinol (THC) is the compound in cannabis responsible for its psychoactive effects and binding to cannabinoid receptors. Despite increasing popularity of the medical and recreational uses of cannabis, little attention has been paid to the adverse effects of the use of the substance. Evidence demonstrating an asso...

  6. Medical Marijuana: Clearing Away the Smoke

    OpenAIRE

    Grant, Igor; Atkinson, J. Hampton; GOUAUX, Ben; Wilsey, Barth

    2012-01-01

    Recent advances in understanding of the mode of action of tetrahydrocannabinol and related cannabinoid in-gredients of marijuana, plus the accumulating anecdotal reports on potential medical benefits have spurred increasing re-search into possible medicinal uses of cannabis. Recent clinical trials with smoked and vaporized marijuana, as well as other botanical extracts indicate the likelihood that the cannabinoids can be useful in the management of neuropathic pain, spasticity due to multiple...

  7. Cannabis hyperemesis syndrome: A case report review of treatment

    OpenAIRE

    Mahmad, Abdul I.; Jehangir, Waqas; Jay M. Littlefield II; John, Sujith; Yousif, Abdalla

    2015-01-01

    Introduction: Cannabis is the most common illegal substance used in the world. The psychoactive nature of cannabis is primarily due to delta-9-tetrahydrocannabinol (THC). Some research suggests that prolonged cannabinoid use increases its half-life and fat solubility in the body, slowing gastric emptying, leading towards feelings of nausea and vomiting. We describe a case where a 32 year old male has excessive nausea and vomiting after prolonged use of daily cannabis. Case Report: A 32 yea...

  8. [18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users

    OpenAIRE

    Ceccarini, Jenny; Kuepper, Rebecca; Kemels, Dieter; van Os, Jim; Henquet, Cécile; Van Laere, Koen

    2015-01-01

    Δ9 -Tetrahydrocannabinol, the main psychoactive component of cannabis, exerts its central effects through activation of the cerebral type 1 cannabinoid (CB1 ) receptor. Pre-clinical studies have provided evidence that chronic cannabis exposure is linked to decreased CB1 receptor expression and this is thought to be a component underlying drug tolerance and dependence. In this study, we make first use of the selective high-affinity positron emission tomography (PET) ligand [18 F]MK-9470 to obt...

  9. Cannabinoid Receptor 1 Gene by Cannabis Use Interaction on CB1 Receptor Density

    OpenAIRE

    Ketcherside, Ariel; Noble, Lindsey J.; McIntyre, Christa K.; Filbey, Francesca M.

    2017-01-01

    Abstract Background: Because delta-9-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, binds to cannabinoid 1 (CB1) receptors, levels of CB1 protein could serve as a potential biomarker for response to THC. To date, available techniques to characterize CB1 expression and function in vivo are limited. In this study, we developed an assay to quantify CB1 in lymphocytes to determine how it relates to cannabis use in 58 daily cannabis users compared with 47 nonusers. Fu...

  10. Cross-sectional and prospective relation of cannabis potency, dosing and smoking behaviour with cannabis dependence: an ecological study.

    Science.gov (United States)

    van der Pol, Peggy; Liebregts, Nienke; Brunt, Tibor; van Amsterdam, Jan; de Graaf, Ron; Korf, Dirk J; van den Brink, Wim; van Laar, Margriet

    2014-07-01

    Increased delta-9-tetrahydrocannabinol (THC) concentrations in cannabis may lead to higher THC exposure, cannabis dependence and treatment need, but users may also adapt the actual intake of THC through reduced inhalation of THC containing smoke (titration). We investigated whether consumers of stronger cannabis use less cannabis per joint or inhale less smoke than those using less potent cannabis and whether these factors predict cannabis dependence severity. Heavy cannabis users (n = 98) brought their own cannabis, rolled a joint and smoked it ad libitum in a naturalistic setting. We analysed the content of the joint, its association with smoking behaviour and the cross-sectional and prospective (1.5-year follow-up) relations between smoking behaviour and cannabis dependence severity (total number of DSM-IV dependence symptoms). THC concentration in cannabis (range 1.10-24.70%) was correlated positively with cannabis dose per joint (b = 0.008, P = 0.01), but the resulting THC concentration per joint (range 0.24-15.72%) was associated negatively with inhalation volume (b = -0.05, P = 0.03). Smoking behaviour measures (number of puffs, inhaled volume, reduction of puff volume and puff duration while smoking) predicted follow-up dependence severity, independently of baseline dependence severity and monthly THC dose (number of joints × cannabis dose × cannabis THC concentration). Monthly THC dose only predicted follow-up dependence severity when unadjusted for baseline severity. Cannabis users titrate their delta-9-tetrahydrocannabinol intake by inhaling lower volumes of smoke when smoking strong joints, but this does not fully compensate for the higher cannabis doses per joint when using strong cannabis. Thus, users of more potent cannabis are generally exposed to more delta-9-tetrahydrocannabinol. Smoking behaviour appears to be a stronger predictor for cannabis dependence severity than monthly delta-9-tetrahydrocannabinol dose.

  11. Marijuana’s Acute Effects on Cognitive Bias for Affective and Marijuana Cues

    OpenAIRE

    Metrik, Jane; Aston, Elizabeth R.; Kahler, Christopher W.; Rohsenow, Damaris J.; McGeary, John E.; Knopik, Valerie S.

    2015-01-01

    Marijuana produces acute increases in positive subjective effects and decreased reactivity to negative affective stimuli, though may also acutely induce anxiety. Implicit attentional and evaluative processes may explicate marijuana’s ability to acutely increase positive and negative emotions. This within-subjects study examined whether smoked marijuana with 2.7–3.0 % delta-9-tetrahydrocannabinol (THC), relative to placebo, acutely changed attentional processing of rewarding and negative affec...

  12. The Role of High Pressure and Inert Gases in the Production and Reversal of the High Pressure Neurological Syndrome.

    Science.gov (United States)

    1982-08-06

    Barbiturates: frequency dependent sodium Philadelphia. 11-17 16). channel block. Fed. Proc. 38: 260A 11979). 2. Metcalfe, J. C.. P. Seeman and A. S... tetrahydrocannabinol ) do so to only a of compressibility 8. For ,,i simple solvents it is limited extentr.’ - u This effect is reversed by pres- found that...pressure (4-6) but a number of bilayer. However, excitable fluxes in nerves problems remain unresolved. First, there is are carried by ion channels , and

  13. Synthèse et évaluations pharmacologiques de nouveaux inhibiteurs β-lactamiques de la Fatty Acid Amide Hydrolase humaine (hFAAH) mise en évidence d’un mécanisme d’inhibition réversible et compétitif

    OpenAIRE

    Feledziak, Marion

    2012-01-01

    Research on cannabis effects has evolved in a medicinal context towards the discovery and the understanding of the endocannabinoid system. Most of the effects, beneficial or psychotropic, produced by the cannabis consumption have been ascribed to the activation of two receptors, called cannabinoid receptors CB1 and CB2, by a liposoluble molecule the tetrahydrocannabinol (THC). Displaying the existence of these two receptors has accelerated the research about an eventual endogenous cannabinoid...

  14. Cannabinoids production in Cannabis sativa L.: An in vitro approach

    OpenAIRE

    Farag, Sayed

    2014-01-01

    Cannabis sativa L. (Cannabaceae) is the oldest known medicinal plant. For millennia, the plant has also been used for fibre and oil production.The most prominent feature of C. sativa is the psychoactive effect ascribed to its secondary metabolites, cannabinoids (mainly to tetrahydrocannabinol, THC). However, many other pharmacological properties of the aforementioned specialized compounds have been described. Currently, the demand for THC for various medical applications is substantial, while...

  15. Impact of enzymatic and alkaline hydrolysis on CBD concentration in urine

    OpenAIRE

    Bergamaschi, Mateus M.; Barnes, Allan; Queiroz, Regina H. C.; Hurd, Yasmin L; Huestis, Marilyn A.

    2013-01-01

    A sensitive and specific analytical method for cannabidiol (CBD) in urine was needed to define urinary CBD pharmacokinetics after controlled CBD administration, and to confirm compliance with CBD medications including Sativex—a cannabis plant extract containing 1:1 Δ9-tetrahydrocannabinol (THC) and CBD. Non-psychoactive CBD has a wide range of therapeutic applications and may also influence psychotropic smoked cannabis effects. Few methods exist for the quantification of CBD excretion in urin...

  16. Medical cannabis ? the Canadian perspective

    OpenAIRE

    Ko, Gordon D; Bober, Sara L; Mindra, Sean; Moreau, Jason M

    2016-01-01

    Cannabis has been widely used as a medicinal agent in Eastern medicine with earliest evidence in ancient Chinese practice dating back to 2700 BC. Over time, the use of medical cannabis has been increasingly adopted by Western medicine and is thus a rapidly emerging field that all pain physicians need to be aware of. Several randomized controlled trials have shown a significant and dose-dependent relationship between neuropathic pain relief and tetrahydrocannabinol ? the principal psychoactive...

  17. Synthetic Cannabinoid Use and Descriptive Norms among Collegiate Student-Athletes

    OpenAIRE

    Egan, Kathleen L.; Erausquin, Jennifer Toller; Milroy, Jeffrey J.; Wyrick, David L.

    2016-01-01

    Synthetic cannabinoids have gained popularity over the past decade, especially among young adults, due to sharing similar psychoactive properties with Tetrahydrocannabinol (THC). A limited number of studies have examined synthetic cannabinoid use among college students but none have examined use exclusively by collegiate student-athletes. The objective of this study was to examine synthetic cannabinoid use among collegiate student-athletes. In the spring of 2013, 3,276 freshmen and transfer c...

  18. Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis.

    Science.gov (United States)

    Aizpurua-Olaizola, Oier; Zarandona, Iratxe; Ortiz, Laura; Navarro, Patricia; Etxebarria, Nestor; Usobiaga, Aresatz

    2017-04-01

    A high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) method for simultaneous quantification of Δ9-tetrahydrocannabinol (THC), its two metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH), and four additional cannabinoids (cannabidiol (CBD), cannabigerol (CBG), tetrahydrocannabivarin (THCV), and cannabinol (CBN)) in 1 mL of human urine and plasma was developed and validated. The hydrolysis process was studied to ensure complete hydrolysis of glucuronide conjugates and the extraction of a total amount of analytes. Initially, urine and plasma blank samples were spiked with THC-COOH-glucuronide and THC-glucuronide, and four different pretreatment methods were compared: hydrolysis-free method, enzymatic hydrolysis with Escherichia Coli β-glucuronidase, alkaline hydrolysis with 10 M NaOH, and enzyme-alkaline tandem hydrolysis. The last approach assured the maximum efficiencies (close to 100%) for both urine and plasma matrices. Regarding the figures of merit, the limits of detection were below 1 ng/mL for all analytes, the accuracy ranged from 84% to 115%, and both within-day and between-day precision were lower than 12%. Finally, the method was successfully applied to real urine and plasma samples from cannabis users. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Bioactive products from singlet oxygen photooxygenation of cannabinoids.

    Science.gov (United States)

    Galal Osman, Ahmed; Elokely, Khaled M; Yadav, Vivek K; Carvalho, Paulo; Radwan, Mohamed; Slade, Desmond; Gul, Waseem; Khan, Shabana; Dale, Olivia R; Husni, Afeef S; Klein, Michael L; Cutler, Stephen J; Ross, Samir A; ElSohly, Mahmoud A

    2018-01-01

    Photooxygenation of Δ8 tetrahydrocannabinol (Δ8-THC), Δ9 tetrahydrocannabinol (Δ9-THC), Δ9 tetrahydrocannabinolic acid (Δ9-THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides. Testing these compounds for their modulatory effect on cannabinoid receptors CB1 and CB2 led to the identification of 7 and 21 as CB1 partial agonists with Ki values of 0.043 μM and 0.048 μM, respectively and 23 as a cannabinoid with high binding affinity for CB2 with Ki value of 0.0095 μM, but much less affinity towards CB1 (Ki 0.467 μM). The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC50 values ranging from 4.2 to 8.5 μg/mL. Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  20. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.

    Science.gov (United States)

    Izzo, Angelo A; Borrelli, Francesca; Capasso, Raffaele; Di Marzo, Vincenzo; Mechoulam, Raphael

    2009-10-01

    Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.

  1. Determination of main tetrahydrocannabinoids by GC-MS: impact of protein precipitation by acetonitrile on solid phase extraction of cannabinoids from human serum.

    Science.gov (United States)

    Hidvégi, E; Somogyi, G P

    2014-06-01

    The analysis of delta9-tetrahydrocannabinol (delta9-THC) and its main metabolites [11-hydroxy-delta9-tetrahydrocannabinol (11-OH-delta9-THC) and 11-nor-9-carboxy-delta9-tetrahydrocannabinol] in serum is a routine assay in forensic toxicology in the case of drivers influenced by Cannabis abuse and in other cases. Analysis of the specimen may involve protein precipitation, although there are authors who do not use this step. In this study we investigated the effect of acetonitrile as protein precipitant added to the serum on the absolute extraction recoveries of the analytes. This is very important not only from a forensic point of view, but also from the aspect of impact of delta9-THC therapy. Our results showed that in the case of spiked serum (2 ml), 80-87% extraction recovery can be achieved if 4 ml of acetonitrile is added before solid phase extraction. The second best result could be reached if no acetonitrile was added (64-73%). However, in the case of physiological sera of Cannabis consumers, no precipitation may be more advantageous in some cases. Matrix effects, which were studied by comparing the detectability and relative intensities of matrix peaks within the corresponding time windows of the analytes, were less influenced if the extraction was achieved with or without acetonitrile.

  2. Qualitative and quantitative analysis of THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC in whole blood by ultra-performance liquid chromatography/tandem mass spectrometry.

    Science.gov (United States)

    Simões, Susana Sadler; Ajenjo, Antonio Castañera; Dias, Mário João

    2011-09-30

    A qualitative and quantitative analytical method was developed for the simultaneous determination of Δ(9) -tetrahydrocannabinol (THC), 11-hydroxy-Δ(9) -tetrahydrocannabinol (11-OH-THC) and l1-nor-9-carboxy-Δ(9) -tetrahydrocannabinol (THC-COOH) in whole blood. The samples were prepared by solid-phase extraction followed by ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) analysis using positive ion electrospray ionization and multiple reaction monitoring. The chromatographic separation was performed with an Acquity UPLC® HSS T3 (50 × 2.1 mm i.d., 1.8 µm) reversed-phase column using a methanol/2 mM ammonium formate (formic acid 0.1%) gradient in a total run time of 9.5 min. MS/MS detection was achieved with two precursor-product ion transitions per substance. The method was fully validated, including selectivity and capacity of identification, according to the identification criteria (two transitions per substance, signal-to-noise ratio, relative retention time and ion ratio) without the presence of interferences, limit of detection (0.2 µg/L for THC and 0.5 µg/L for 11-OH-THC and THC-COOH), limit of quantitation (0.5 µg/L for all cannabinoids), recovery (53-115%), carryover, matrix effect (34-43%), linearity (0.5-100 µg/L), intra-assay precision (CV < 10% for the relative peak area ratios and <0.1% for the relative retention time), inter-assay accuracy (mean relative error <10%) and precision (CV <11%). The method has already been successfully used in proficiency tests and subsequently applied to authentic samples in routine forensic analysis. Copyright © 2011 John Wiley & Sons, Ltd.

  3. Weed or Wheel! fMRI, Behavioural, and Toxicological Investigations of How Cannabis Smoking Affects Skills Necessary for Driving

    Science.gov (United States)

    Thomas, Aurélien; Mall, Jean-Frédéric; Chtioui, Haithem; Appenzeller, Monique; Annoni, Jean-Marie; Favrat, Bernard

    2013-01-01

    Marijuana is the most widely used illicit drug, however its effects on cognitive functions underling safe driving remain mostly unexplored. Our goal was to evaluate the impact of cannabis on the driving ability of occasional smokers, by investigating changes in the brain network involved in a tracking task. The subject characteristics, the percentage of Δ9-Tetrahydrocannabinol in the joint, and the inhaled dose were in accordance with real-life conditions. Thirty-one male volunteers were enrolled in this study that includes clinical and toxicological aspects together with functional magnetic resonance imaging of the brain and measurements of psychomotor skills. The fMRI paradigm was based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. We show that cannabis smoking, even at low Δ9-Tetrahydrocannabinol blood concentrations, decreases psychomotor skills and alters the activity of the brain networks involved in cognition. The relative decrease of Blood Oxygen Level Dependent response (BOLD) after cannabis smoking in the anterior insula, dorsomedial thalamus, and striatum compared to placebo smoking suggests an alteration of the network involved in saliency detection. In addition, the decrease of BOLD response in the right superior parietal cortex and in the dorsolateral prefrontal cortex indicates the involvement of the Control Executive network known to operate once the saliencies are identified. Furthermore, cannabis increases activity in the rostral anterior cingulate cortex and ventromedial prefrontal cortices, suggesting an increase in self-oriented mental activity. Subjects are more attracted by intrapersonal stimuli (“self”) and fail to attend to task performance, leading to an insufficient allocation of task-oriented resources and to sub-optimal performance. These effects correlate with the subjective feeling of confusion rather than with the blood level of Δ9-Tetrahydrocannabinol

  4. Behaviours of psychotropic substances in indoor and outdoor environments of Rome, Italy.

    Science.gov (United States)

    Cecinato, Angelo; Balducci, Catia; Romagnoli, Paola; Perilli, Mattia

    2014-01-01

    The intensive campaign conducted in March 2013 in Rome, Italy, at one coffee bar, one primary school and two homes revealed that in indoor environments, drugs can reach concentration levels exceeding orders of magnitude those recorded outdoors, even when the same substances are not consumed there. At homes, the gross average of cocaine reached 0.13 ng/m3 indoors and 0.09 ng/m3 outdoors (ratio~1.6); Δ9-tetrahydrocannabinol was 6.6 ng/m3 indoors and 1.1 ng/m3 outdoors (ratio~7); cannabidiol reached 0.30 and 0.07 ng/m3, respectively (ratio~6); and cannabinol 2.3 ng/m3 indoors and 0.7 ng/m3 outdoors (ratio~3). At the coffee bar, the average drug burdens were even higher, namely 0.33, 4.7, 14.3 and 2.5 ng/m3, respectively, for cocaine, cannabidiol, tetrahydrocannabinol and cannabinol. The school presented a special behaviour: the indoor/outdoor concentration ratios of cocaine, cannabidiol, tetrahydrocannabinol and cannabinol accounting for ~1.5, ~0, ~4 and ~0.5, in the order. Cocaine was more abundant on weekdays at all sites except one home indoors, whilst total cannabinoids prevailed on weekends at the other home and the school. Using the regional network stations as reference, all indoor locations except one were more contaminated by cocaine by a factor≥1.5, whilst cannabinoids were, aside from the school, up to 100 times higher.

  5. Development and validation of a solid-phase extraction method using anion exchange sorbent for the analysis of cannabinoids in plasma and serum by gas chromatography-mass spectrometry.

    Science.gov (United States)

    Gasse, Angela; Pfeiffer, Heidi; Köhler, Helga; Schürenkamp, Jennifer

    2016-07-01

    The aim of this work was to develop and validate a solid-phase extraction (SPE) method for the analysis of cannabinoids with emphasis on a very extensive and effective matrix reduction in order to ensure constant good results in selectivity and sensitivity regardless of the applied measuring technology. This was obtained by the use of an anion exchange sorbent (AXS) and the purposive ionic interaction between matrix components and this sorbent material. In a first step, the neutral cannabinoids ∆9-tetrahydrocannabinol (THC) and 11-hydroxy-∆9-tetrahydrocannabinol (11-OH-THC) were eluted, leaving 11-nor-9-carboxy-∆9-tetrahydrocannabinol (THC-COOH) and the main interfering matrix components bound to the AXS. In a second step, exploiting differences in pH and polarity, it was possible to separate matrix components and THC-COOH, thereby yielding a clean elution of THC-COOH into the same collecting tube as THC and 11-OH-THC. Even when using a simple measuring technology like gas chromatography with single quadrupole mass spectrometry, this two-step elution allows for an obvious decrease in number and intensity of matrix interference in the chromatogram. Hence, in both plasma and serum, the AXS extracts resulted in very good selectivity. Limits of detection and limits of quantification were below 0.25 and 0.35 ng/mL for the neutral cannabinoids in both matrices, 2.0 and 3.0 ng/mL in plasma and 1.6 and 3.3 ng/mL in serum for THC-COOH. The recoveries were ≥79.8 % for all analytes. Interday and intraday imprecisions ranged from 0.8 to 6.1 % relative standard deviation, and accuracy bias ranged from -12.6 to 3.6 %.

  6. Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving.

    Directory of Open Access Journals (Sweden)

    Giovanni Battistella

    Full Text Available Marijuana is the most widely used illicit drug, however its effects on cognitive functions underlying safe driving remain mostly unexplored. Our goal was to evaluate the impact of cannabis on the driving ability of occasional smokers, by investigating changes in the brain network involved in a tracking task. The subject characteristics, the percentage of Δ(9-Tetrahydrocannabinol in the joint, and the inhaled dose were in accordance with real-life conditions. Thirty-one male volunteers were enrolled in this study that includes clinical and toxicological aspects together with functional magnetic resonance imaging of the brain and measurements of psychomotor skills. The fMRI paradigm was based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. We show that cannabis smoking, even at low Δ(9-Tetrahydrocannabinol blood concentrations, decreases psychomotor skills and alters the activity of the brain networks involved in cognition. The relative decrease of Blood Oxygen Level Dependent response (BOLD after cannabis smoking in the anterior insula, dorsomedial thalamus, and striatum compared to placebo smoking suggests an alteration of the network involved in saliency detection. In addition, the decrease of BOLD response in the right superior parietal cortex and in the dorsolateral prefrontal cortex indicates the involvement of the Control Executive network known to operate once the saliencies are identified. Furthermore, cannabis increases activity in the rostral anterior cingulate cortex and ventromedial prefrontal cortices, suggesting an increase in self-oriented mental activity. Subjects are more attracted by intrapersonal stimuli ("self" and fail to attend to task performance, leading to an insufficient allocation of task-oriented resources and to sub-optimal performance. These effects correlate with the subjective feeling of confusion rather than with the blood level of Δ(9

  7. Weed or wheel! FMRI, behavioural, and toxicological investigations of how cannabis smoking affects skills necessary for driving.

    Science.gov (United States)

    Battistella, Giovanni; Fornari, Eleonora; Thomas, Aurélien; Mall, Jean-Frédéric; Chtioui, Haithem; Appenzeller, Monique; Annoni, Jean-Marie; Favrat, Bernard; Maeder, Philippe; Giroud, Christian

    2013-01-01

    Marijuana is the most widely used illicit drug, however its effects on cognitive functions underlying safe driving remain mostly unexplored. Our goal was to evaluate the impact of cannabis on the driving ability of occasional smokers, by investigating changes in the brain network involved in a tracking task. The subject characteristics, the percentage of Δ(9)-Tetrahydrocannabinol in the joint, and the inhaled dose were in accordance with real-life conditions. Thirty-one male volunteers were enrolled in this study that includes clinical and toxicological aspects together with functional magnetic resonance imaging of the brain and measurements of psychomotor skills. The fMRI paradigm was based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. We show that cannabis smoking, even at low Δ(9)-Tetrahydrocannabinol blood concentrations, decreases psychomotor skills and alters the activity of the brain networks involved in cognition. The relative decrease of Blood Oxygen Level Dependent response (BOLD) after cannabis smoking in the anterior insula, dorsomedial thalamus, and striatum compared to placebo smoking suggests an alteration of the network involved in saliency detection. In addition, the decrease of BOLD response in the right superior parietal cortex and in the dorsolateral prefrontal cortex indicates the involvement of the Control Executive network known to operate once the saliencies are identified. Furthermore, cannabis increases activity in the rostral anterior cingulate cortex and ventromedial prefrontal cortices, suggesting an increase in self-oriented mental activity. Subjects are more attracted by intrapersonal stimuli ("self") and fail to attend to task performance, leading to an insufficient allocation of task-oriented resources and to sub-optimal performance. These effects correlate with the subjective feeling of confusion rather than with the blood level of Δ(9)-Tetrahydrocannabinol

  8. The effects of cannabinoids and cannabispiro compounds on Escherichia coli adhesion to tissue culture cells and on leukocyte functions in vitro.

    Science.gov (United States)

    Molnár, J; Petri, I; Berek, I; Shoyama, Y; Nishioka, I

    1987-01-01

    delta 9-Tetrahydrocannabinol, cannabidiol, cannabidiolic acid, tetrahydrocannabidiolic acid, cannabispirol, acetylcannabispirol, cannabispirone, and cannabispirenone in a low concentration did not affect the adhesion of Escherichia coli on cultured HEp-2 cells. Cannabinoids at 10(-6) M increased the chemiluminescence of human polymorphonuclear leukocytes, while the cannabispiro compounds failed to enhance the oxidative burst of leukocytes. In lymphocyte and granulocyte function tests (E- and EA-rosette formation, blast transformation of T-lymphocytes in the presence of phytohaemagglutinin and concanavalin-A, ADCC and phagocytosis) all compounds displayed immunosuppressive effect at 1.5 X 10(-5) M. Tetrahydrocannabidiolic acid exerted the weakest immunosuppression on human leukocyte functions.

  9. The Cannabis Dilemma: A Review of Its Associated Risks and Clinical Efficacy

    Directory of Open Access Journals (Sweden)

    Melvyn Weibin Zhang

    2015-01-01

    Full Text Available Cannabis, also known as marijuana, has 9-tetrahydrocannabinol as the main constituent. There has been strict legislation governing the utilization of cannabis locally and worldwide. However, there has been an increasing push to make cannabis legalized, in view of its potential medical and therapeutic effects, for various medical disorders ranging from development disorders to cancer treatment, and being an adjunctive medication for various neurological conditions. It is the aim of this review paper to explore the evidence base for its proposed therapeutic efficacy and to compare the evidence base supporting its proposed therapeutic efficacy with its known and well-researched medical and psychiatric side effects.

  10. Activity of cannabis in relation to its delta'-trans-tetrahydro-cannabinol content.

    OpenAIRE

    Fairbairn, J. W.; Pickens, J. T.

    1981-01-01

    1 Conditions have been worked out for a reliable estimation of the cataleptic activity of delta'-trans-tetrahydrocannabinol (THC) after oral administration to mice, using the ring test over a period of 6 h. 2 By this method, the activity of cannabis herb and 5 crude fractions were measured against THC; at the same time the THC contents were determined chemically. 3 The B/C ratio (biological activity divided by chemical assay) was calculated for each. With cannabis herb the value was 3.3 and w...

  11. Intermolecular Interactions between Eosin Y and Caffeine Using 1H-NMR Spectroscopy

    Directory of Open Access Journals (Sweden)

    Macduff O. Okuom

    2013-01-01

    Full Text Available DETECHIP has been used in testing analytes including caffeine, cocaine, and tetrahydrocannabinol (THC from marijuana, as well as date rape and club drugs such as flunitrazepam, gamma-hydroxybutyric acid (GHB, and methamphetamine. This study investigates the intermolecular interaction between DETECHIP sensor eosin Y (DC1 and the analyte (caffeine that is responsible for the fluorescence and color changes observed in the actual array. Using 1H-NMR, 1H-COSY, and 1H-DOSY NMR methods, a proton exchange from C-8 of caffeine to eosin Y is proposed.

  12. Preclinical Science Regarding Cannabinoids as Analgesics: An Overview

    Directory of Open Access Journals (Sweden)

    ME Lynch

    2005-01-01

    Full Text Available Modern pharmacology of cannabinoids began in 1964 with the isolation and partial synthesis of delta-9-tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics. The present article presents an overview of the preclinical science.

  13. Pregnenolone can protect the brain from cannabis intoxication.

    Science.gov (United States)

    Vallée, Monique; Vitiello, Sergio; Bellocchio, Luigi; Hébert-Chatelain, Etienne; Monlezun, Stéphanie; Martin-Garcia, Elena; Kasanetz, Fernando; Baillie, Gemma L; Panin, Francesca; Cathala, Adeline; Roullot-Lacarrière, Valérie; Fabre, Sandy; Hurst, Dow P; Lynch, Diane L; Shore, Derek M; Deroche-Gamonet, Véronique; Spampinato, Umberto; Revest, Jean-Michel; Maldonado, Rafael; Reggio, Patricia H; Ross, Ruth A; Marsicano, Giovanni; Piazza, Pier Vincenzo

    2014-01-03

    Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.

  14. Endocannabinoids, Related Compounds and Their Metabolic Routes

    Directory of Open Access Journals (Sweden)

    Filomena Fezza

    2014-10-01

    Full Text Available Endocannabinoids are lipid mediators able to bind to and activate cannabinoid receptors, the primary molecular targets responsible for the pharmacological effects of the Δ9-tetrahydrocannabinol. These bioactive lipids belong mainly to two classes of compounds: N-acylethanolamines and acylesters, being N-arachidonoylethanolamine (AEA and 2-arachidonoylglycerol (2-AG, respectively, their main representatives. During the last twenty years, an ever growing number of fatty acid derivatives (endocannabinoids and endocannabinoid-like compounds have been discovered and their activities biological is the subject of intense investigations. Here, the most recent advances, from a therapeutic point of view, on endocannabinoids, related compounds, and their metabolic routes will be reviewed.

  15. Marijuana: medical implications.

    Science.gov (United States)

    Hubbard, J R; Franco, S E; Onaivi, E S

    1999-12-01

    Over 50 percent of people will use marijuana sometime in their life. While intoxication lasts two to three hours, the active ingredient in marijuana, delta-9-tetrahydro-cannabinol, can accumulate in fatty tissues, including the brain and testes. Adverse effects from marijuana use include decreased coordination, epithelial damage to the lungs, increased risk of infection, cardiovascular effects and cognitive deficits. Unexplained behavior changes, altered social relationships and poor performance at school or work can signify a drug problem. Treatment requires a combination of education, social support, drug monitoring and attention to comorbid medical and psychiatric conditions.

  16. Potential Effects of Cannabidiol as a Wake-Promoting Agent

    Science.gov (United States)

    Murillo-Rodríguez, Eric; Sarro-Ramírez, Andrea; Sánchez, Daniel; Mijangos-Moreno, Stephanie; Tejeda-Padrón, Alma; Poot-Aké, Alwin; Guzmán, Khalil; Pacheco-Pantoja, Elda; Arias-Carrión, Oscar

    2014-01-01

    Over the last decades, the scientific interest in chemistry and pharmacology of cannabinoids has increased. Most attention has focused on ∆9-tetrahydrocannabinol (∆9-THC) as it is the psychoactive constituent of Cannabis sativa (C. sativa). However, in previous years, the focus of interest in the second plant constituent with non-psychotropic properties, cannabidiol (CBD) has been enhanced. Recently, several groups have investigated the pharmacological properties of CBD with significant findings; furthermore, this compound has raised promising pharmacological properties as a wake-inducing drug. In the current review, we will provide experimental evidence regarding the potential role of CBD as a wake-inducing drug. PMID:24851090

  17. Cannabis-induced impairment of learning and memory: effect of different nootropic drugs

    OpenAIRE

    Abdel-Salam, Omar M.E.; Salem, Neveen A.; El-Sayed El-Shamarka, Marwa; Al-Said Ahmed, Noha; Seid Hussein, Jihan; El-Khyat, Zakaria A.

    2013-01-01

    Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984[43]) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Δ9-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/ kg), vinpocetine (1.5 mg/kg) ...

  18. Cannabis-induced impairment of learning and memory

    OpenAIRE

    Abdel-Salam, Omar M.E.; Ahmed, Noha Al-Said; El-Khyat, Zakaria A.; El-Shamarka, Marwa El-Sayed; Hussein, Jihan Seid; Salem, Neveen A.

    2013-01-01

    Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Δ^9-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/ kg), vinpocetine (1.5 mg/kg) ...

  19. Toxic Effects of Cannabis and Cannabinoids: Animal Data

    Directory of Open Access Journals (Sweden)

    Pierre Beaulieu

    2005-01-01

    Full Text Available The present article reviews the main toxic effects of cannabis and cannabinoids in animals. Toxic effects can be separated into acute and chronic classifications. Acute toxicity studies show that it is virtually impossible to die from acute administration of marijuana or tetrahydrocannabinol, the main psychoactive component of cannabis. Chronic toxicity involves lesions of airway and lung tissues, as well as problems of neurotoxicity, tolerance and dependence, and dysregulations in the immune and hormonal systems. Animal toxicity data, however, are difficult to extrapolate to humans.

  20. Cannabinoids – a new weapon against cancer?

    OpenAIRE

    Małgorzata Pokrywka; Joanna Góralska; Bogdan Solnica

    2016-01-01

    Cannabis has been cultivated by man since Neolithic times. It was used, among others for fiber and rope production, recreational purposes and as an excellent therapeutic agent. The isolation and characterization of the structure of one of the main active ingredients of cannabis – Δ9 – tetrahydrocannabinol as well the discovery of its cannabinoid binding receptors CB1 and CB2, has been a milestone in the study of the possibilities of the uses of Cannabis sativa and related products in modern m...

  1. Cannabinoids: the separation of central from peripheral effects on a structural basis.

    Science.gov (United States)

    Evans, F J

    1991-10-01

    A brief history of the therapeutic uses and legal problems of cannabis as well as the component cannabinoids is given. This is followed by a discussion of drug development from delta 1-tetrahydrocannabinol and its synthetic analogues. The controversy of whether the pharmacological effects are of central or peripheral origin is included. Then, the potentials for the development of new drugs based on the cannabinoid structure for the treatment of pain, inflammation, and related conditions are outlined. It is concluded that the central activity of cannabinoids is confirmed and that the presence of a C-5 hydroxy group confers potent peripheral activity.

  2. Highly enantioselective access to cannabinoid-type tricyles by organocatalytic Diels–Alder reactions

    Directory of Open Access Journals (Sweden)

    Stefan Bräse

    2012-08-01

    Full Text Available After prosperous domino reactions towards benzopyrans, the products were used as the starting material in Lewis acid catalyzed and organocatalytic Diels–Alder reactions to build up a tricyclic system. Herein, an asymmetric induction up to 96% enantiomeric excess was obtained by the use of imidazolidinone catalysts. This approach can be utilized to construct the tricyclic system in numerous natural products, in particular the scaffold of tetrahydrocannabinol (THC being the most representative one. Compared with other published methods, condensation with a preexisting cyclohexane moiety in the precursor is needed to gain the heterogenic tricycle systems, whereas we present a novel strategy towards cannabinoid derivatives based on a flexible modular synthesis.

  3. The Cannabis Dilemma: A Review of Its Associated Risks and Clinical Efficacy

    Science.gov (United States)

    Zhang, Melvyn Weibin; Ho, Roger C. M.

    2015-01-01

    Cannabis, also known as marijuana, has 9-tetrahydrocannabinol as the main constituent. There has been strict legislation governing the utilization of cannabis locally and worldwide. However, there has been an increasing push to make cannabis legalized, in view of its potential medical and therapeutic effects, for various medical disorders ranging from development disorders to cancer treatment, and being an adjunctive medication for various neurological conditions. It is the aim of this review paper to explore the evidence base for its proposed therapeutic efficacy and to compare the evidence base supporting its proposed therapeutic efficacy with its known and well-researched medical and psychiatric side effects. PMID:26539302

  4. Analysis and Toxicological Evaluation of Cannabinoids in Hemp Food Products - a review

    OpenAIRE

    Lachenmeier, Dirk W.; Walch, Stephan G.

    2005-01-01

    After having abolished the prohibition of the cultivation of the species Cannabis sativa L. (so-called fibre hemp) with minor content of the psychoactive Δ9-tetrahydrocannabinol (THC), a wide variety of hemp food products is currently offered on the market. In this review, an introduction to the botany of the hemp plant and the current law situation in Germany and the European Union is presented. A survey of the analytic techniques used to verify compliance with the guidance values is given a...

  5. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug

    Directory of Open Access Journals (Sweden)

    Zuardi A.W.

    2006-01-01

    Full Text Available A high dose of delta9-tetrahydrocannabinol, the main Cannabis sativa (cannabis component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of delta9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD, a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.

  6. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.

    Science.gov (United States)

    Laprairie, R B; Bagher, A M; Kelly, M E M; Denovan-Wright, E M

    2015-10-01

    Cannabidiol has been reported to act as an antagonist at cannabinoid CB1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 receptors. Internalization of CB1 receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 receptors and in the STHdh(Q7/Q7) cell model of striatal neurons endogenously expressing CB1 receptors. Cells were treated with 2-arachidonylglycerol or Δ(9)-tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol. Cannabidiol reduced the efficacy and potency of 2-arachidonylglycerol and Δ(9)-tetrahydrocannabinol on PLCβ3- and ERK1/2-dependent signalling in cells heterologously (HEK 293A) or endogenously (STHdh(Q7/Q7)) expressing CB1 receptors. By reducing arrestin2 recruitment to CB1 receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB1 receptor. Cannabidiol behaved as a non-competitive negative allosteric modulator of CB1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB1 receptors, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors. © 2015 The British Pharmacological Society.

  7. [Chemical composition of Brazilian marihuana samples and the importance of several constituents to the pharmacological activity of the plant].

    Science.gov (United States)

    Takahashi, R N; Zuardi, A W; Karniol, I G

    1977-12-01

    The gas chromatographic analysis of marihuana samples seized by the São Paulo State Police showed high levels of delta9-trans-tetrahydrocannabinol (delta9-THC) the most active of cannabis constituents. The cannabiol (CBN) levels were also high and probably able of interfering with delta9-THC actions in some samples. The cannabidiol (CBD) and delta8-trans-tetrahydrocannabinol (delta8THC) levels were generally low. When compared to marihuanas used in other countries the amount of delta9-THC in our samples was in average higher. When the pharmacological activity of one of those marihuana extracts, called natural extract containing a high delta9-THC to the others cannabinoid ratio (CBD, CBN and delta8-THC) was compared to a synthetic extract with the same proportions of those cannabinoids, the activity was not identical in all animals tests used. The possibility of others substances present in the plant, besides those cannabinoids listed before, of interfering with the plant's pharmacological activity is discussed.

  8. Psychoactive constituents of cannabis and their clinical implications: a systematic review.

    Science.gov (United States)

    Casajuana, Cristina; López-Pelayo, Hugo; Balcells, Mª Mercedes; Colom, Joan; Gual, Antoni

    2017-07-14

    Objective This systematic review aims to summarize current evidence on which naturally present cannabinoids contribute to cannabis psychoactivity, considering their reported concentrations and pharmacodynamics in humans. Design Following PRISMA guidelines, papers published before March 2016 in Medline, Scopus-Elsevier, Scopus, ISI-Web of Knowledge and COCHRANE, and fulfilling established a-priori selection criteria have been included. Results In 40 original papers, three naturally present cannabinoids (∆-9-Tetrahydrocannabinol, ∆-8-Tetrahydrocannabinol and Cannabinol) and one human metabolite (11-OH-THC) had clinical relevance. Of these, the metabolite produces the greatest psychoactive effects. Cannabidiol (CBD) is not psychoactive but plays a modulating role on cannabis psychoactive effects. The proportion of 9-THC in plant material is higher (up to 40%) than in other cannabinoids (up to 9%). Pharmacodynamic reports vary due to differences in methodological aspects (doses, administration route and volunteers’ previous experience with cannabis). Conclusions Findings reveal that 9-THC contributes the most to cannabis psychoactivity. Due to lower psychoactive potency and smaller proportions in plant material, other psychoactive cannabinoids have a weak influence on cannabis final effects. Current lack of standard methodology hinders homogenized research on cannabis health effects. Working on a standard cannabis unit considering 9-THC is recommended.

  9. Cell-specific STORM superresolution imaging reveals nanoscale organization of cannabinoid signaling

    Science.gov (United States)

    Szabó, Szilárd I.; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G.; Henstridge, Christopher M.; Balla, Gyula Y.; Nyilas, Rita; Varga, Csaba; Lee, Sang-Hun; Matolcsi, Máté; Cervenak, Judit; Kacskovics, Imre; Watanabe, Masahiko; Sagheddu, Claudia; Melis, Miriam; Pistis, Marco; Soltesz, Ivan; Katona, István

    2014-01-01

    A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell-type-, and subcellular compartment-specific manner. We therefore developed a novel approach combining cell-specific physiological and anatomical characterization with superresolution imaging, and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically-projecting GABAergic interneurons possess increased CB1 receptor number, active-zone complexity, and receptor/effector ratio compared to dendritically-projecting interneurons, in agreement with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ9-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked dramatic CB1-downregulation in a dose-dependent manner. Full receptor recovery required several weeks after cessation of Δ9-tetrahydrocannabinol treatment. These findings demonstrate that cell-type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits, and identify novel molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction. PMID:25485758

  10. Crystal structures of agonist-bound human cannabinoid receptor CB1.

    Science.gov (United States)

    Hua, Tian; Vemuri, Kiran; Nikas, Spyros P; Laprairie, Robert B; Wu, Yiran; Qu, Lu; Pu, Mengchen; Korde, Anisha; Jiang, Shan; Ho, Jo-Hao; Han, Gye Won; Ding, Kang; Li, Xuanxuan; Liu, Haiguang; Hanson, Michael A; Zhao, Suwen; Bohn, Laura M; Makriyannis, Alexandros; Stevens, Raymond C; Liu, Zhi-Jie

    2017-07-27

    The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200(3.36) and Trp356(6.48) (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ(9)-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

  11. Role of cannabis in digestive disorders.

    Science.gov (United States)

    Goyal, Hemant; Singla, Umesh; Gupta, Urvashi; May, Elizabeth

    2017-02-01

    Cannabis sativa, a subspecies of the Cannabis plant, contains aromatic hydrocarbon compounds called cannabinoids. [INCREMENT]-Tetrahydrocannabinol is the most abundant cannabinoid and is the main psychotropic constituent. Cannabinoids activate two types of G-protein-coupled cannabinoid receptors: cannabinoid type 1 receptor and cannabinoid type 2 receptor. There has been ongoing interest and development in research to explore the therapeutic potential of cannabis. [INCREMENT]-Tetrahydrocannabinol exerts biological functions on the gastrointestinal (GI) tract. Cannabis has been used for the treatment of GI disorders such as abdominal pain and diarrhea. The endocannabinoid system (i.e. endogenous circulating cannabinoids) performs protective activities in the GI tract and presents a promising therapeutic target against various GI conditions such as inflammatory bowel disease (especially Crohn's disease), irritable bowel syndrome, and secretion and motility-related disorders. The present review sheds light on the role of cannabis in the gut, liver, and pancreas and also on other GI symptoms, such as nausea and vomiting, cannabinoid hyperemesis syndrome, anorexia, weight loss, and chronic abdominal pain. Although the current literature supports the use of marijuana for the treatment of digestive disorders, the clinical efficacy of cannabis and its constituents for various GI disorders remains unclear.

  12. Impact of cannabis sativa (marijuana) smoke on alveolar bone loss: a histometric study in rats.

    Science.gov (United States)

    Nogueira-Filho, Getulio R; Todescan, Sylvia; Shah, Adnan; Rosa, Bruno T; Tunes, Urbino da R; Cesar Neto, Joao B

    2011-11-01

    Cannabis sativa (marijuana) can interfere with bone physiopathology because of its effect on osteoblast and osteoclast activity. However, its impact on periodontal tissues is still controversial. The present study evaluates whether marijuana smoke affects bone loss (BL) on ligature-induced periodontitis in rats. Thirty male Wistar rats were used in the study. A ligature was placed around one of the mandible first molars (ligated teeth) of each animal, and they were then randomly assigned to one of two groups: control (n = 15) or marijuana smoke inhalation ([MSI] for 8 minutes per day; n = 15). Urine samples were obtained to detect the presence of tetrahydrocannabinol. After 30 days, the animals were sacrificed and decalcified sections of the furcation area were obtained and evaluated according to the following histometric parameters: bone area (BA), bone density (BD), and BL. Tetrahydrocannabinol was positive in urine samples only for the rats of the MSI group. Non-significant differences were observed for unligated teeth from both groups regarding BL, BA, and BD (P >0.05). However, intragroup analysis showed that all ligated teeth presented BL and a lower BA and BD compared to unligated teeth (P <0.05). The intergroup evaluation of the ligated teeth showed that the MSI group presented higher BL and lower BD (P <0.05) compared to ligated teeth from the control group. Considering the limitations of this animal study, cannabis smoke may impact alveolar bone by increasing BL resulting from ligature-induced periodontitis.

  13. Analysis of cannabinoids in commercial hemp seed oil and decarboxylation kinetics studies of cannabidiolic acid (CBDA).

    Science.gov (United States)

    Citti, Cinzia; Pacchetti, Barbara; Vandelli, Maria Angela; Forni, Flavio; Cannazza, Giuseppe

    2017-11-20

    Hemp seed oil from Cannabis sativa L. is a very rich natural source of important nutrients, not only polyunsaturated fatty acids and proteins, but also terpenes and cannabinoids, which contribute to the overall beneficial effects of the oil. Hence, it is important to have an analytical method for the determination of these components in commercial samples. At the same time, it is also important to assess the safety of the product in terms of amount of any psychoactive cannabinoid present therein. This work presents the development and validation of a highly sensitive, selective and rapid HPLC-UV method for the qualitative and quantitative determination of the main cannabinoids, namely cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN), cannabigerol (CBG) and cannabidivarin (CBDV), present in 13 commercial hemp seed oils. Moreover, since decomposition of cannabinoid acids generally occurs with light, air and heat, decarboxylation studies of the most abundant acid (CBDA) were carried out in both open and closed reactor and the kinetics parameters were evaluated at different temperatures in order to evaluate the stability of hemp seed oil in different storage conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. The current status of artisanal cannabis for the treatment of epilepsy in the United States.

    Science.gov (United States)

    Sulak, Dustin; Saneto, Russell; Goldstein, Bonni

    2017-05-01

    The widespread patient use of artisanal cannabis preparations has preceded quality validation of cannabis use for epilepsy. Neurologists and cannabinoid specialists are increasingly in a position to monitor and guide the use of herbal cannabis in epilepsy patients. We report the retrospective data on efficacy and adverse effects of artisanal cannabis in Patients with medically refractory epilepsy with mixed etiologies in Washington State, California, and Maine. Clinical considerations, including potential risks and benefits, challenges related to artisanal preparations, and cannabinoid dosing, are discussed. Of 272 combined patients from Washington State and California, 37 (14%) found cannabis ineffective at reducing seizures, 29 (15%) experienced a 1-25% reduction in seizures, 60 (18%) experienced a 26-50% reduction in seizures, 45 (17%) experienced a 51-75% reduction in seizures, 75 (28%) experienced a 76-99% reduction in seizures, and 26 (10%) experienced a complete clinical response. Overall, adverse effects were mild and infrequent, and beneficial side effects such as increased alertness were reported. The majority of patients used cannabidiol (CBD)-enriched artisanal formulas, some with the addition of delta-9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA). Four case reports are included that illustrate clinical responses at doses <0.1mg/kg/day, biphasic dose-response effects, the use of THCA for seizure prevention, the use of THC for seizure rescue, and the synergy of cannabinoids and terpenoids in artisanal preparations. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy". Copyright © 2017 Elsevier Inc. All rights reserved.

  15. [Outlines of interdisciplinary addiction research given by the example of medical imaging with PET, SPECT and fMRI regarding effects of psychotropic substances].

    Science.gov (United States)

    Giacomuzzi, Salvatore M; Golaszewski, Stefan; Ertl, Markus; Riemer, Yvonne; Brandauer, Elisabeth; Ennemoser, Oswald; Rössler, Haimo; Hinterhuber, Hartmann

    2010-01-01

    The addiction phenomenon provides a fertile ground for the application of the tools of medical imaging which contribute to the development of scientific conceptualization of the effect of psychotropic substances. Medical imaging as for instance PET (Positron Emission Tomography), SPECT (Single Photon Emission Tomography) or functional Magnetic Resonance Imaging (fMRI) are well established for the examination of functional activity in the living brain. Medical imaging permits the development of functional activation maps during perceptual, cognitive or emotional efforts with a high temporal and spatial resolution. Medical imaging devices have therefore also been used to help our understanding of many aspects of the pharmacokinetics and pharmacodynamics of abused drugs. Because Delta-9-Tetrahydrocannabinol and cocaine continue to be the most commonly used illicit drugs, their effects on the brain function are of major interest. The cannabinoid CB(1) receptor agonist Delta(9)-THC as for instance has also been suggested for treatment of Tourette syndrome (TS). This article provides an overview of present applications of medical imaging with PET, SPECT, and fMRI and its results regarding addiction-related research on Delta-9-Tetrahydrocannabinol and cocaine.

  16. Engineering yeasts as platform organisms for cannabinoid biosynthesis.

    Science.gov (United States)

    Zirpel, Bastian; Degenhardt, Friederike; Martin, Chantale; Kayser, Oliver; Stehle, Felix

    2017-10-10

    Δ9-tetrahydrocannabinolic acid (THCA) is a plant derived secondary natural product from the plant Cannabis satival. The discovery of the human endocannabinoid system in the late 1980s resulted in a growing number of known physiological functions of both synthetic and plant derived cannabinoids. Thus, manifold therapeutic indications of cannabinoids currently comprise a significant area of research. Here we reconstituted the final biosynthetic cannabinoid pathway in yeasts. The use of the soluble prenyltransferase NphB from Streptomyces sp. strain CL190 enables the replacement of the native transmembrane prenyltransferase cannabigerolic acid synthase from C. sativa. In addition to the desired product cannabigerolic acid, NphB catalyzes an O-prenylation leading to 2-O-geranyl olivetolic acid. We show for the first time that the bacterial prenyltransferase and the final enzyme of the cannabinoid pathway tetrahydrocannabinolic acid synthase can both be actively expressed in the yeasts Saccharomyces cerevisiae and Komagataella phaffii simultaneously. While enzyme activities in S. cerevisiae were insufficient to produce THCA from olivetolic acid and geranyl diphosphate, genomic multi-copy integrations of the enzyme's coding sequences in K. phaffii resulted in successful synthesis of THCA from olivetolic acid and geranyl diphosphate. This study is an important step toward total biosynthesis of valuable cannabinoids and derivatives and demonstrates the potential for developing a sustainable and secure yeast bio-manufacturing platform. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa.

    Science.gov (United States)

    Ruhaak, Lucia Renee; Felth, Jenny; Karlsson, Pernilla Christina; Rafter, Joseph James; Verpoorte, Robert; Bohlin, Lars

    2011-01-01

    Cyclooxygenase enzymes (COX-1 and COX-2) catalyse the production of prostaglandins from arachidonic acid. Prostaglandins are important mediators in the inflammatory process and their production can be reduced by COX-inhibitors. Endocannabinoids, endogenous analogues of the plant derived cannabinoids, occur normally in the human body. The Endocannabinoids are structurally similar to arachidonic acid and have been suggested to interfere with the inflammatory process. They have also been shown to inhibit cancer cell proliferation. Anti-inflammatory effects of cannabinoids and endocannabinoids have been observed, however the mode of action is not yet clarified. Anti-inflammatory activity (i.e., inhibition of COX-2) is proposed to play an important role in the development of colon cancer, which makes this subject interesting to study further. In the present work, the six cannabinoids tetrahydrocannabinol (Δ⁹-THC), tetrahydrocannabinolic acid (Δ⁹-THC-A), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG) and cannabigerolic acid (CBGA), isolated from Cannabis sativa, were evaluated for their effects on prostaglandin production. For this purpose an in vitro enzyme based COX-1/COX-2 inhibition assay and a cell based prostaglandin production radioimmunoassay were used. Cannabinoids inhibited cyclooxygenase enzyme activity with IC₅₀ values ranging from 1.7·10⁻³ to 2.0·10⁻⁴ M.

  18. Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents.

    Science.gov (United States)

    Rong, Carola; Carmona, Nicole E; Lee, Yena L; Ragguett, Renee-Marie; Pan, Zihang; Rosenblat, Joshua D; Subramaniapillai, Mehala; Shekotikhina, Margarita; Almatham, Fahad; Alageel, Asem; Mansur, Rodrigo; Ho, Roger C; McIntyre, Roger S

    2018-01-01

    To determine, via narrative, non-systematic review of pre-clinical and clinical studies, whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents. Areas covered: A non-systematic literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabis was cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), both in vitro and in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper. Expert opinion: Δ9-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

  19. Cannabinoids inhibit cellular respiration of human oral cancer cells.

    Science.gov (United States)

    Whyte, Donna A; Al-Hammadi, Suleiman; Balhaj, Ghazala; Brown, Oliver M; Penefsky, Harvey S; Souid, Abdul-Kader

    2010-01-01

    The primary cannabinoids, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and Delta(8)-tetrahydrocannabinol (Delta(8)-THC) are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted us to investigate their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183). This epithelial cell line overexpresses bcl-2 and is highly resistant to anticancer drugs. A phosphorescence analyzer that measures the time-dependence of O(2) concentration in cellular or mitochondrial suspensions was used for this purpose. A rapid decline in the rate of respiration was observed when Delta(9)-THC or Delta(8)-THC was added to the cells. The inhibition was concentration-dependent, and Delta(9)-THC was the more potent of the two compounds. Anandamide (an endocannabinoid) was ineffective; suggesting the effects of Delta(9)-THC and Delta(8)-THC were not mediated by the cannabinoidreceptors. Inhibition of O(2) consumption by cyanide confirmed the oxidations occurred in the mitochondrial respiratory chain. Delta(9)-THC inhibited the respiration of isolated mitochondria from beef heart. These results show the cannabinoids are potent inhibitors of Tu183 cellular respiration and are toxic to this highly malignant tumor.

  20. Immune response of shrimp (Penaeus monodon against Vibrios furnissii pathogen

    Directory of Open Access Journals (Sweden)

    Kumaran Subramanian

    2014-04-01

    Full Text Available Objective: To analyse experimental infection and immune system of shrimp (Penaeus monodon against Vibrios furnissii (V. furnissii. Methods: Experimental animals were collected and acclimatized by maintaining specific temperature, pH and salinity to avoid mortality. Shrimps were experimentally infected with V. furnissii and their immune responses were monitored. After the infection all the shrimps were monitored for any symptoms, death rate in 0, 12, 24, 36, 48 h. Then haemolymph were collected and tetrahydrocannabinol, phenol oxidase, nitroblue tetrazolium and lysozyme were monitored in every 12 h at the interval of 48 h. Results: Shrimps infected by live V. furnissii had showed gradual increase in tetrahydrocannabinol, phenol oxidase activity, nitro-blue-tetrazolium and lysozyme activity comparing with the killed and control. Conclusions: The live V. furnissii had showed infection in the shrimp immune system. The live V. furnissii shows infection in experimental shrimps comparing with killed V. furnissii. So the V. furnissii in nature cause the infection in shrimp Penaeus monodon immune system. This report could be applied to control of the infection in shrimp hatchery.

  1. Cannabis sativa and the endogenous cannabinoid system: therapeutic potential for appetite regulation.

    Science.gov (United States)

    Farrimond, Jonathan A; Mercier, Marion S; Whalley, Benjamin J; Williams, Claire M

    2011-02-01

    The herb Cannabis sativa (C. sativa) has been used in China and on the Indian subcontinent for thousands of years as a medicine. However, since it was brought to the UK and then the rest of the western world in the late 19th century, its use has been a source of controversy. Indeed, its psychotropic side effects are well reported but only relatively recently has scientific endeavour begun to find valuable uses for either the whole plant or its individual components. Here, we discuss evidence describing the endocannabinoid system, its endogenous and exogenous ligands and their varied effects on feeding cycles and meal patterns. Furthermore we also critically consider the mounting evidence which suggests non-Δ(9) tetrahydrocannabinol phytocannabinoids play a vital role in C. sativa-induced feeding pattern changes. Indeed, given the wide range of phytocannabinoids present in C. sativa and their equally wide range of intra-, inter- and extra-cellular mechanisms of action, we demonstrate that non-Δ(9) tetrahydrocannabinol phytocannabinoids retain an important and, as yet, untapped clinical potential. Copyright © 2011 John Wiley & Sons, Ltd.

  2. [Therapeutical use of the cannabinoids in psychiatry].

    Science.gov (United States)

    Crippa, José Alexandre S; Zuardi, Antonio Waldo; Hallak, Jaime E C

    2010-05-01

    To review the main advances related to the potential therapeutic use of cannabinoid compounds in psychiatry. A search was performed in the online databases PubMed, ScieELO, and Lilacs for studies and literature reviews concerning therapeutic applications of cannabinoids in psychiatry, especially cannabidiol, rimonabant, Delta(9)-tetrahydrocannabinol, and their analogues. Cannabidiol was found to have therapeutic potential with antipsychotic, anxiolytic, and antidepressant properties, in addition to being effective in other conditions. Delta(9)-tetrahydrocannabinol and its analogues were shown to have anxiolytic effects in the treatment of cannabis dependence and to function as an adjuvant in the treatment of schizophrenia, although additional studies are necessary to support this finding. Rimonabant was effective in the treatment of the subjective and physiological symptoms of cannabis intoxication and functioned as an adjuvant in the treatment of tobacco addiction. The potential to induce adverse reactions such as depression and anxiety restrained the clinical use of this CB(1) antagonist. Cannabinoids may be of great therapeutic interest to psychiatry; however, further controlled trials are necessary to confirm the existing findings and to establish the safety of such compounds.

  3. Cannabis, possible cardiac deaths and the coroner in Ireland.

    LENUS (Irish Health Repository)

    Tormey, W P

    2012-01-10

    BACKGROUND: The elevated risk of triggering a myocardial infarction by smoking cannabis is limited to the first 2 h after smoking. AIM: To examine the possible role of cannabis in cardiac deaths. CASES AND RESULTS: From 3,193 coroners\\' cases over 2 years, there were 13 cases where the clinical information was compatible with a primary cardiac cause of death. An inquest was held in three cases. Myocardial infarction was the primary cause of death in 54%. Other causes were sudden adult death syndrome, sudden death in epilepsy, and poisoning by alcohol and diazepam. Cannabis was mentioned once only on a death certificate, but not as a cause of death. Blood delta9-tetrahydrocannabinol-carboxylic acid was recorded in one case and in no case was plasma tetrahydrocannabinol (THC) measured. CONCLUSIONS: To attribute sudden cardiac death to cannabis, plasma THC should be measured in the toxicology screen in coroners\\' cases where urine cannabinoids are positive. A positive urine cannabinoids immunoassay alone is insufficient evidence in the linkage of acute cardiac death and cannabis.

  4. Detection of THCCOOH in hair by MSD-NCI after HPLC clean-up.

    Science.gov (United States)

    Sachs, H; Dressler, U

    2000-01-10

    Regular consumption of cannabis can easily be detected by examination of hair for tetrahydrocannabinol, cannabinol, and cannabidiol. Although several studies have demonstrated that after contamination with smoke or treatment with THC containing shampoos THC is not detectable, or only in small traces, the detection of 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH) should be offered to prove the consumption and metabolisation of THC. Up to now this confirmation was only available using tandem MS techniques combined with negative chemical ionisation. A new method using a normal quadrupole GC/MS is described. The lack of expensive instruments has to be paid for by a costly and time consuming extraction and clean-up. After the sample has been digested by 2 M NaOH at 95 degrees C and the neutralised liquid has been extracted with a mixture of n-hexane and ethyl acetate the dried residue is reconstituted in acetonitrile-methanol-0.01 M sulfuric acid (49:21:30, v/v/v) and the cannabinoids separated by HPLC. Each fraction is collected over 1 min. Another extraction with n-hexane-ethyl acetate is followed by evaporation, derivatisation, and GC/MS determination. The calibration with THCCOOH spiked hair led to a LOD of 0.3 pg/mg and a LOQ of 1.1 pg/mg.

  5. Analysis of a Commercial Marijuana e-Cigarette Formulation.

    Science.gov (United States)

    Peace, Michelle R; Stone, Joseph W; Poklis, Justin L; Turner, Joseph B M; Poklis, Alphonse

    2016-06-01

    Personal battery-powered vaporizers or electronic cigarettes were developed to deliver a nicotine vapor such that smokers could simulate smoking tobacco without the inherent pathology of inhaled tobacco smoke. With four states within the USA having legalized the cultivation, distribution and recreational use of marijuana and an additional 23 states plus the District of Columbia with laws that legalize marijuana in some form, it was inevitable that suppliers of legal marijuana would develop marijuana products for use in these electronic cigarettes. Presented is the analysis of one such marijuana electronic cigarette formulation sold under the brand name Liberty Reach. The cannabinoid concentrations in Liberty Reach as determined by high-performance liquid chromatography-triple quadrapole mass spectrometry (HPLC-MS-MS) were Δ9-tetrahydrocannabinol, 42.6% (w/v) and cannabidiol 0.5% (w/v). These concentrations were significantly lower than the labeled 69% Δ9-tetrahydrocannabinol and 1% cannabidiol. Furthermore, 4 cannabinoids, 13 marijuana terpenes, and propylene glycol were identified by a combination of Direct Analysis in Real Time-AccuTOF™ mass spectrometry (DART-MS), HPLC-MS-MS and gas chromatography-MS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Death by self-mutilation after oral cannabis consumption.

    Science.gov (United States)

    Delteil, Clemence; Sastre, Caroline; Piercecchi, Marie-Dominique; Faget-Agius, Catherine; Deveaux, Marc; Kintz, Pascal; Devooght, Marc-Antoine; Leonetti, George; Bartoli, Christophe; Pélissier-Alicot, Anne-Laure

    2018-01-01

    Major self-mutilation (amputation, castration, self-inflicted eye injuries) is frequently associated with psychiatric disorders and/or substance abuse. A 35-year-old man presented with behavioral disturbances of sudden onset after oral cannabis consumption and major self-mutilation (attempted amputation of the right arm, self-enucleation of both eyes and impalement) which resulted in death. During the enquiry, four fragments of a substance resembling cannabis resin were seized at the victim's home. Autopsy confirmed that death was related to hemorrhage following the mutilations. Toxicological findings showed cannabinoids in femoral blood (tetrahydrocannabinol (THC) 13.5 ng/mL, 11-hydroxy-tetrahydrocannabinol (11-OH-THC) 4.1 ng/mL, 11-nor-9-carboxy-THC (THC-COOH) 14.7 ng/mL, cannabidiol (CBD) 1.3 ng/mL, cannabinol (CBN) 0.7 ng/mL). Cannabinoid concentrations in hair (1.5 cm brown hair strand/1 segment) were consistent with concentrations measured in chronic users (THC 137 pg/mg, 11-OH-THC 1 pg/mg, CBD 9 pg/mg, CBN 94 pg/mg). Analysis of the fragments seized confirmed that this was cannabis resin with high levels of THC (31-35%). We discuss the implications of oral consumption of cannabis with a very high THC content. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Glycolytic pathway (GP), kreb's cycle (KC), and hexose monophosphate shunt (HMS) activity in myocardial subcellular fractions exposed to cannabinoids

    Energy Technology Data Exchange (ETDEWEB)

    Watson, A.T.; Manno, B.R.; King, J.W.; Fowler, M.R.; Dempsey, C.A.; Manno, J.E.

    1986-03-05

    Delta-9-tetrahydrocannabinol (..delta../sup 9/-THC), the primary psychoactive component of marihuana, and its active metabolite 11-hydroxy-..delta../sup 9/-tetrahydrocannabinol (11-OH-..delta../sup 9/-THC) have been reported to produce a direct cardiac depressant effect. Studies in isolated perfused rat hearts have indicated a decreased force of contraction (inotropic response) when ..delta../sup 9/-THC or 11-OH-..delta../sup 9/-THC was administered in microgram amounts. The mechanism and site of action have not been explained or correlated with associated metabolic pathways. The purpose of this study was to investigate the effects of cannabinoids on major myocardial energy producing pathways, GP and KC, and a non-energy producing pathway, HMS. Cardiac ventricular tissue from male Sprague-Dawley rats (250-300 g) was excised and homogenized for subcellular fractionation. KC, GP and HMS activity was assayed in the appropriate fractions by measuring /sup 14/CO/sub 2/ generation from /sup 14/C-2-pyruvate, /sup 14/C-6-glucose and /sup 14/C-1-glucose respectively. Duplicate assays (n=8) were performed on tissue exposed to saline (control), empty liposomes (vehicle) and four doses each of ..delta../sup 9/-THC and 11-OH-..delta../sup 9/-THC. Changes in metabolic activity and decreases in cardiac contractile performance may be associated.

  8. Cannabinoid receptor localization in brain

    Energy Technology Data Exchange (ETDEWEB)

    Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. (National Institute of Mental Health, Bethesda, MD (USA))

    1990-03-01

    (3H)CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of (3H)CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

  9. Suppression of lymphocyte proliferation by marijuana components is related to cell number and cell source

    Energy Technology Data Exchange (ETDEWEB)

    Klein, T.; Pross, S.; Newton, C.; Friedman, H.

    1986-03-05

    Conflicting reports have appeared concerning the effect of marijuana components on immune responsiveness. The authors have observed that the effect of cannabinoids on lymphocyte proliferation varied with both the concentration of the drug and the mitogen used. They now report that at a constant concentration of drug, the cannabinoid effect varied from no effect to suppression depending upon the number of cells in culture and the organ source of the cells. Dispersed cell suspensions of mouse lymph node, spleen, and thymus were prepared and cultured at varying cell numbers with either delta-9-tetrahydrocannabinol or 11-hydroxy-delta-9-tetrahydrocannabinol and various mitogens. Lymphocyte proliferation was analyzed by /sup 3/H-thymidine incorporation. T-lymphocyte mitogen responses in cultures containing high cell numbers were unaffected by the cannabinoids but as cell numbers were reduced a suppression of the response was observed. Furthermore, thymus cells were considerably more susceptible to cannabinoid suppression than cells from either lymph node or spleen. These results suggest that certain lymphocyte subpopulations are more sensitive to cannabinoid suppression and that in addition to drug concentration other variables such as cell number and cell source must be considered when analyzing cannabinoid effects.

  10. Cannabis and epilepsy: An ancient treatment returns to the fore.

    Science.gov (United States)

    Russo, Ethan B

    2017-05-01

    Cannabis has been associated with the treatment of epilepsy throughout history, and if ancient Assyrian sources referring to "hand of ghost" are considered credible, this relationship may span four millennia. A tradition of usage continued in Arabic medicine and Ayurvedic practice in India, which led, in turn, to early experiments in Europe and North America with "Indian hemp." Lack of standardization, bioavailability issues, and ultimately prohibition were all factors in cannabis-based medicines failing to maintain mainstream usage in seizure treatment, but investigation was resumed in the 1970s with interesting signals noted in both laboratory and clinical settings. Early case studies showed promise, but lacked sufficient rigor. Resumption of research coupled with mass experimentation by families of epilepsy patients has led to intense interest in cannabis-based medicines for its treatment once more, with greatest focus on cannabidiol, but additional investigation of tetrahydrocannabinol, tetrahydrocannabinolic acid, and other phytocannabinoids. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy". Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral administration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Delta9-THC.

    Science.gov (United States)

    Ménétrey, Annick; Augsburger, Marc; Favrat, Bernard; Pin, Marie A; Rothuizen, Laura E; Appenzeller, Monique; Buclin, Thierry; Mangin, Patrice; Giroud, Christian

    2005-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is frequently found in the blood of drivers suspected of driving under the influence of cannabis or involved in traffic crashes. The present study used a double-blind crossover design to compare the effects of medium (16.5 mg THC) and high doses (45.7 mg THC) of hemp milk decoctions or of a medium dose of dronabinol (20 mg synthetic THC, Marinol on several skills required for safe driving. Forensic interpretation of cannabinoids blood concentrations were attempted using the models proposed by Daldrup (cannabis influencing factor or CIF) and Huestis and coworkers. First, the time concentration-profiles of THC, 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) (active metabolite of THC), and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) in whole blood were determined by gas chromatography-mass spectrometry-negative ion chemical ionization. Compared to smoking studies, relatively low concentrations were measured in blood. The highest mean THC concentration (8.4 ng/mL) was achieved 1 h after ingestion of the strongest decoction. Mean maximum 11-OH-THC level (12.3 ng/mL) slightly exceeded that of THC. THCCOOH reached its highest mean concentration (66.2 ng/mL) 2.5-5.5 h after intake. Individual blood levels showed considerable intersubject variability. The willingness to drive was influenced by the importance of the requested task. Under significant cannabinoids influence, the participants refused to drive when they were asked whether they would agree to accomplish several unimportant tasks, (e.g., driving a friend to a party). Most of the participants reported a significant feeling of intoxication and did not appreciate the effects, notably those felt after drinking the strongest decoction. Road sign and tracking testing revealed obvious and statistically significant differences between placebo and treatments. A marked impairment was detected after ingestion of the strongest decoction. A CIF value, which relies on the

  12. Development and validation of an automated liquid-liquid extraction GC/MS method for the determination of THC, 11-OH-THC, and free THC-carboxylic acid (THC-COOH) from blood serum.

    Science.gov (United States)

    Purschke, Kirsten; Heinl, Sonja; Lerch, Oliver; Erdmann, Freidoon; Veit, Florian

    2016-06-01

    The analysis of Δ(9)-tetrahydrocannabinol (THC) and its metabolites 11-hydroxy-Δ(9)-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol (THC-COOH) from blood serum is a routine task in forensic toxicology laboratories. For examination of consumption habits, the concentration of the phase I metabolite THC-COOH is used. Recommendations for interpretation of analysis values in medical-psychological assessments (regranting of driver's licenses, Germany) include threshold values for the free, unconjugated THC-COOH. Using a fully automated two-step liquid-liquid extraction, THC, 11-OH-THC, and free, unconjugated THC-COOH were extracted from blood serum, silylated with N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA), and analyzed by GC/MS. The automation was carried out by an x-y-z sample robot equipped with modules for shaking, centrifugation, and solvent evaporation. This method was based on a previously developed manual sample preparation method. Validation guidelines of the Society of Toxicological and Forensic Chemistry (GTFCh) were fulfilled for both methods, at which the focus of this article is the automated one. Limits of detection and quantification for THC were 0.3 and 0.6 μg/L, for 11-OH-THC were 0.1 and 0.8 μg/L, and for THC-COOH were 0.3 and 1.1 μg/L, when extracting only 0.5 mL of blood serum. Therefore, the required limit of quantification for THC of 1 μg/L in driving under the influence of cannabis cases in Germany (and other countries) can be reached and the method can be employed in that context. Real and external control samples were analyzed, and a round robin test was passed successfully. To date, the method is employed in the Institute of Legal Medicine in Giessen, Germany, in daily routine. Automation helps in avoiding errors during sample preparation and reduces the workload of the laboratory personnel. Due to its flexibility, the analysis system can be employed for other liquid-liquid extractions as

  13. Use of Embryos Extracted from Individual Cannabis sativa Seeds for Genetic Studies and Forensic Applications.

    Science.gov (United States)

    Soler, Salvador; Borràs, Dionís; Vilanova, Santiago; Sifres, Alicia; Andújar, Isabel; Figàs, Maria R; Llosa, Ernesto R; Prohens, Jaime

    2016-03-01

    Legal limits on the psychoactive tetrahydrocannabinol (THC) content in Cannabis sativa plants have complicated genetic and forensic studies in this species. However, Cannabis seeds present very low THC levels. We developed a method for embryo extraction from seeds and an improved protocol for DNA extraction and tested this method in four hemp and six marijuana varieties. This embryo extraction method enabled the recovery of diploid embryos from individual seeds. An improved DNA extraction protocol (CTAB3) was used to obtain DNA from individual embryos at a concentration and quality similar to DNA extracted from leaves. DNA extracted from embryos was used for SSR molecular characterization in individuals from the 10 varieties. A unique molecular profile for each individual was obtained, and a clear differentiation between hemp and marijuana varieties was observed. The combined embryo extraction-DNA extraction methodology and the new highly polymorphic SSR markers facilitate genetic and forensic studies in Cannabis. © 2015 American Academy of Forensic Sciences.

  14. Influence of agroclimatic conditions on content of main cannabinoids in industrial hemp (Cannabis sativa L.

    Directory of Open Access Journals (Sweden)

    Sikora Vladimir

    2011-01-01

    Full Text Available In a six-year field experiment eight industrial hemp varieties were examined for ∆9-tetrahydrocannabinol (THC and cannabidiol (CBD contents. The study analyzed the influence of growing degree days (GDD, soil temperature at 5 cm, air humidity, and growing season precipitation on the levels of the main cannabinoids in this crop. Agroclimatic conditions do not influence THC and CBD contents in industrial hemp in the same way. THC synthesis and accumulation are under the significant positive influence of GDD and air humidity and under the negative influence of precipitation, while soil temperature at 5 cm has no significant effect on it. Soil temperature at 5 cm has a significant positive effect on the CBD content, as do GDD. Precipitation has a negative influence on the CBD content of industrial hemp, while air humidity has no influence on it.

  15. Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation?

    Science.gov (United States)

    Zlebnik, Natalie E; Cheer, Joseph F

    2016-07-08

    The Cannabis sativa plant has been used to treat various physiological and psychiatric conditions for millennia. Current research is focused on isolating potentially therapeutic chemical constituents from the plant for use in the treatment of many central nervous system disorders. Of particular interest is the primary nonpsychoactive constituent cannabidiol (CBD). Unlike Δ(9)-tetrahydrocannabinol (THC), CBD does not act through the cannabinoid type 1 (CB1) receptor but has many other receptor targets that may play a role in psychiatric disorders. Here we review preclinical and clinical data outlining the therapeutic efficacy of CBD for the treatment of motivational disorders such as drug addiction, anxiety, and depression. Across studies, findings suggest promising treatment effects and potentially overlapping mechanisms of action for CBD in these disorders and indicate the need for further systematic investigation of the viability of CBD as a psychiatric pharmacotherapy.

  16. Nonmutagenic action of cannabinoids in vitro.

    Science.gov (United States)

    Zimmerman, A M; Stich, H; San, R

    1978-01-01

    Under the specific conditions reported for the separate tests delta9-tetrahydrocannabinol (THC) did not elicit a mutagenic response in microbial and eukaryotic in vitro test systems. THC treatment to histidine auxotrophs of Salmonella typhimurium strains TA 98 (susceptible to frame shift mutation) and TA 100 (susceptible to base pair substitution) were investigated. Analysis for possible revertance in the presence and absence of S9 microsomal activation system indicated an absence of induction of gene mutation. Cultured fibroblasts from healthy individuals and DNA repair deficient Xeroderma pigmentosum patients display similar survival activity upon exposure to THC. There was no observable increase in the number of chromosome breaks or chromatid exchanges following exposure to THC or THC plus S9 microsomal fraction. THC, 11-OHdelta9-THC, cannabinol, and cannabidiol did not induce unscheduled DNA repair synthesis in cultured human fibroblasts. Moreover, THC did not suppress UV-induced DNA repair synthesis.

  17. Cannabis use in young people: the risk for schizophrenia.

    Science.gov (United States)

    Casadio, Paola; Fernandes, Cathy; Murray, Robin M; Di Forti, Marta

    2011-08-01

    Cannabis is one of the most commonly used illicit drugs, and despite the widely held belief that it is a safe drug, its long-term use has potentially harmful consequences. To date, the research on the impact of its use has largely been epidemiological in nature and has consistently found that cannabis use is associated with schizophrenia outcomes later in life, even after controlling for several confounding factors. While the majority of users can continue their use without adverse effects, it is clear from studies of psychosis that some individuals are more vulnerable to its effects than others. In addiction, evidence from both epidemiological and animal studies indicates that cannabis use during adolescence carries particular risk. Further studies are warranted given the increase in the concentration of the main active ingredient (Δ(9)-tetrahydrocannabinol) in street preparations of cannabis and a decreasing age of first-time exposure to cannabis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands

    DEFF Research Database (Denmark)

    Pertwee, R G; Howlett, A C; Abood, M E

    2010-01-01

    There are at least two types of cannabinoid receptors (CB(1) and CB(2)). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid ¿(9)-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor......-CB(2) established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB(1) and...... deorphanized GPCRs. Also discussed are 1) the ability of CB(1) receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB(1)/CB(2) receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB(1), non-CB(2...

  19. [Stereochemical aspects of narcotic and psychotropic drug action].

    Science.gov (United States)

    Noszál, B; Schiller, Z

    1999-01-01

    Medicinal drugs are predominantly, whereas narcotic and psychotropic drugs are exclusively exogenous compounds. Three further fundamental properties of the narcotic/psychotropic compounds of significant abuse potential is that they all are of natural (plant or microbial) origin, they contain a large number of chiral atoms, and they influence the neurotransmission processes in the central nervous system. For some of them, the existence of corresponding endogenous ligands have recently been reported. Since exogenous compounds and their endogenous ligands are assumed to bind the same target moiety of the receptor, several fundamental questions arise: To what extent can stereochemical relationships be established between the exogenous compound and its endogenous counterpart? Do they have superimposable moieties? Are the corresponding chiral atoms of the same configuration? Is there a chiral-genetic relationship between the exogenous and endogenous compound? Theoretical aspects and answers to all these questions are sought for morphine, cocaine, LSD, tetrahydrocannabinol, amphetamine and related molecules.

  20. Cannabis and Breastfeeding

    Directory of Open Access Journals (Sweden)

    Aurélia Garry

    2009-01-01

    Full Text Available Cannabis is a drug derived from hemp plant, Cannabis sativa, used both as a recreational drug or as medicine. It is a widespread illegal substance, generally smoked for its hallucinogenic properties. Little is known about the adverse effects of postnatal cannabis exposure throw breastfeeding because of a lack of studies in lactating women. The active substance of cannabis is the delta 9 TetraHydroCannabinol (THC. Some studies conclude that it could decrease motor development of the child at one year of age. Therefore, cannabis use and abuse of other drugs like alcohol, tobacco, or cocaine must be contraindicated during breastfeeding. Mothers who use cannabis must stop breastfeeding, or ask for medical assistance to stop cannabis use in order to provide her baby with all the benefits of human milk.

  1. Exploring Butane Hash Oil Use: A Research Note.

    Science.gov (United States)

    Miller, Bryan Lee; Stogner, John M; Miller, J Mitchell

    2016-01-01

    The practice of "dabbing" has seen an apparent upswing in popularity in recent months within American drug subcultures. "Dabbing" refers to the use of butane-extracted marijuana products that offer users much higher tetrahydrocannabinol content than flower cannabis through a single dosage process. Though considerably more potent than most marijuana strains in their traditional form, these butane hash oil products and the practice of dabbing are underexplored in the empirical literature, especially in prohibition states. A mixed-methods evaluation of a federally funded treatment program for drug-involved offenders identified a small sample (n = 6) of butane hash oil users and generated focus group interview data on the nature of butane hash oil, the practice of dabbing, and its effects. Findings inform discussion of additional research needed on butane hash oil and its implications for the ongoing marijuana legalization debate, including the diversity of users, routes of administration, and differences between retail/medical and prohibition states.

  2. Studies on effective atomic numbers for photon energy absorption and electron density of some narcotic drugs in the energy range 1 keV-20 MeV

    Science.gov (United States)

    Gounhalli, Shivraj G.; Shantappa, Anil; Hanagodimath, S. M.

    2013-04-01

    Effective atomic numbers for photon energy absorption ZPEA,eff, photon interaction ZPI,eff and for electron density Nel, have been calculated by a direct method in the photon-energy region from 1 keV to 20 MeV for narcotic drugs, such as Heroin (H), Cocaine (CO), Caffeine (CA), Tetrahydrocannabinol (THC), Cannabinol (CBD), Tetrahydrocannabivarin (THCV). The ZPEA,eff, ZPI,eff and Nel values have been found to change with energy and composition of the narcotic drugs. The energy dependence ZPEA,eff, ZPI,eff and Nel is shown graphically. The maximum difference between the values of ZPEA,eff, and ZPI,eff occurs at 30 keV and the significant difference of 2 to 33% for the energy region 5-100 keV for all drugs. The reason for these differences is discussed.

  3. Effects of amphetamine, morphine, and CP 55, 940 on Go/No-Go task performance in rhesus monkeys.

    Science.gov (United States)

    Koek, Wouter; Gerak, Lisa R; France, Charles P

    2015-08-01

    In humans, impulsivity measured as false alarms in a Go/No-Go task is reportedly decreased by amphetamine and is not affected by oxycodone and delta(9)-tetrahydrocannabinol. To model these findings in animals, three rhesus monkeys were trained to perform a food-reinforced Go/No-Go task. In this task, amphetamine was found to decrease false alarms (i.e. responding during No-Go trials), but only at doses that also decreased hits (i.e. responding during Go trials). Morphine generally decreased hits but not false alarms. The cannabinoid receptor agonist CP 55, 940 decreased both false alarms and hits, but only at doses that also decreased the number of trials completed. Additional studies in animals and humans are necessary to delineate the conditions under which amphetamine and other psychoactive drugs affect impulsivity in Go/No-Go tasks.

  4. Rapid quantification of free and glucuronidated THCCOOH in urine using coated well plates and LC-MS/MS analysis.

    Science.gov (United States)

    Hädener, Marianne; Weinmann, Wolfgang; van Staveren, Dave R; König, Stefan

    2017-03-01

    Generally, urine drug testing for cannabis abuse involves measuring total concentrations of 11-nor-9-carboxy-Δ 9 -tetrahydrocannabinol (THCCOOH) obtained by enzymatic and/or alkaline hydrolysis of THCCOOH-glucuronide. As hydrolysis can be inconsistent and incomplete, direct measurement of the two metabolites is preferable. Methodology & results: We developed a high-throughput LC-MS/MS method for simultaneous quantification of free and glucuronidated THCCOOH in urine using coated 96-well plates for analyte extraction and column-switching chromatography. Excellent separation of the two analytes was achieved within 2.5 min, with linear ranges from 5 to 2000 μg/l for THCCOOH and from 10 to 4000 μg/l for THCCOOH-glucuronide. The method was successfully validated and applied to authentic urine samples from cannabis consumers, demonstrating its applicability for routine cannabinoid testing.

  5. Fluorescence-based lateral flow assays for rapid oral fluid roadside detection of cannabis use.

    Science.gov (United States)

    Plouffe, Brian D; Murthy, Shashi K

    2017-02-01

    With the recent worldwide changes in the legalization of marijuana, there is a significant need for rapid, roadside screening test for driving under the influence of drugs. A robust, sensitive, lateral flow assay has been developed to detect recent use via oral-fluid testing for Δ 9 -tetrahydrocannabinol (THC). This proof-of-concept assay uses a fluorescent-based immunoassay detection of polymeric beads, conjugated to antibodies against native THC. The fluorescent technique allows for significantly lower limits of detection and higher precision determination of recent marijuana use without the use of urine or blood sampling-thus allowing for roadside identification. Detection levels of 0.01 ng/mL were distinguished from background and the lower limit of quantification was determined to approach 1 ng/mL. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Cannabis in palliative medicine: improving care and reducing opioid-related morbidity.

    Science.gov (United States)

    Carter, Gregory T; Flanagan, Aaron M; Earleywine, Mitchell; Abrams, Donald I; Aggarwal, Sunil K; Grinspoon, Lester

    2011-08-01

    Unlike hospice, long-term drug safety is an important issue in palliative medicine. Opioids may produce significant morbidity. Cannabis is a safer alternative with broad applicability for palliative care. Yet the Drug Enforcement Agency (DEA) classifies cannabis as Schedule I (dangerous, without medical uses). Dronabinol, a Schedule III prescription drug, is 100% tetrahydrocannabinol (THC), the most psychoactive ingredient in cannabis. Cannabis contains 20% THC or less but has other therapeutic cannabinoids, all working together to produce therapeutic effects. As palliative medicine grows, so does the need to reclassify cannabis. This article provides an evidence-based overview and comparison of cannabis and opioids. Using this foundation, an argument is made for reclassifying cannabis in the context of improving palliative care and reducing opioid-related morbidity.

  7. Medical marijuana: clearing away the smoke.

    Science.gov (United States)

    Grant, Igor; Atkinson, J Hampton; Gouaux, Ben; Wilsey, Barth

    2012-01-01

    Recent advances in understanding of the mode of action of tetrahydrocannabinol and related cannabinoid in-gredients of marijuana, plus the accumulating anecdotal reports on potential medical benefits have spurred increasing re-search into possible medicinal uses of cannabis. Recent clinical trials with smoked and vaporized marijuana, as well as other botanical extracts indicate the likelihood that the cannabinoids can be useful in the management of neuropathic pain, spasticity due to multiple sclerosis, and possibly other indications. As with all medications, benefits and risks need to be weighed in recommending cannabis to patients. We present an algorithm that may be useful to physicians in determining whether cannabis might be recommended as a treatment in jurisdictions where such use is permitted.

  8. Did Cannabis Precipitate an STEMI in a Young Woman?

    Science.gov (United States)

    Jehangir, Waqas; Stanton, Michael; Khan, Rafay; Sahgal, Puneet; Yousif, Abdalla

    2015-06-01

    Cannabis is a substance that contains compounds that bind cannabinoid receptors, CB1 and CB2. Cannabis also contains substances that do not bind these receptors. Delta-9-tetrahydrocannabinol (THC) is the compound in cannabis responsible for its psychoactive effects and binding to cannabinoid receptors. Despite increasing popularity of the medical and recreational uses of cannabis, little attention has been paid to the adverse effects of the use of the substance. Evidence demonstrating an association between cannabis use and acute coronary syndromes has emerged with case reports and in vitro studies. This case report highlights an ST-segment myocardial infarction in a 27-year-old female with little cardiovascular risk factors, but a significant history of frequent cannabis use.

  9. Cannabidiol as potential anticancer drug

    Science.gov (United States)

    Massi, Paola; Solinas, Marta; Cinquina, Valentina; Parolaro, Daniela

    2013-01-01

    Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ9-tetrahydrocannabinol (Δ9-THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors. Indeed, cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization. However, the clinical use of Δ9-THC and additional cannabinoid agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive cannabinoid compounds with structural affinity for Δ9-THC, such as cannabidiol (CBD), has substantially increased in recent years. The present review will focus on the efficacy of CBD in the modulation of different steps of tumourigenesis in several types of cancer and highlights the importance of exploring CBD/CBD analogues as alternative therapeutic agents. PMID:22506672

  10. Medical Marijuana: Clearing Away the Smoke

    Science.gov (United States)

    Grant, Igor; Atkinson, J. Hampton; Gouaux, Ben; Wilsey, Barth

    2012-01-01

    Recent advances in understanding of the mode of action of tetrahydrocannabinol and related cannabinoid in-gredients of marijuana, plus the accumulating anecdotal reports on potential medical benefits have spurred increasing re-search into possible medicinal uses of cannabis. Recent clinical trials with smoked and vaporized marijuana, as well as other botanical extracts indicate the likelihood that the cannabinoids can be useful in the management of neuropathic pain, spasticity due to multiple sclerosis, and possibly other indications. As with all medications, benefits and risks need to be weighed in recommending cannabis to patients. We present an algorithm that may be useful to physicians in determining whether cannabis might be recommended as a treatment in jurisdictions where such use is permitted. PMID:22629287

  11. The Structure-Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation.

    Science.gov (United States)

    Bow, Eric W; Rimoldi, John M

    2016-01-01

    The cannabinoids are members of a deceptively simple class of terpenophenolic secondary metabolites isolated from Cannabis sativa highlighted by (-)-Δ(9)-tetrahydrocannabinol (THC), eliciting distinct pharmacological effects mediated largely by cannabinoid receptor (CB1 or CB2) signaling. Since the initial discovery of THC and related cannabinoids, synthetic and semisynthetic classical cannabinoid analogs have been evaluated to help define receptor binding modes and structure-CB1/CB2 functional activity relationships. This perspective will examine the classical cannabinoids, with particular emphasis on the structure-activity relationship of five regions: C3 side chain, phenolic hydroxyl, aromatic A-ring, pyran B-ring, and cyclohexenyl C-ring. Cumulative structure-activity relationship studies to date have helped define the critical structural elements required for potency and selectivity toward CB1 and CB2 and, more importantly, ushered the discovery and development of contemporary nonclassical cannabinoid modulators with enhanced physicochemical and pharmacological profiles.

  12. Rod photoreceptors express GPR55 in the adult vervet monkey retina

    DEFF Research Database (Denmark)

    Bouskila, Joseph; Javadi, Pasha; Casanova, Christian

    2013-01-01

    Cannabinoids exert their actions mainly through two receptors, the cannabinoid CB1 receptor (CB1R) and cannabinoid CB2 receptor (CB2R). In recent years, the G-protein coupled receptor 55 (GPR55) was suggested as a cannabinoid receptor based on its activation by anandamide and tetrahydrocannabinol...... components (Müller cells). The aim of this study was to determine the expression pattern of GPR55 in the monkey retina by using confocal microscopy. Our results show that GPR55 is strictly localized in the photoreceptor layer of the extrafoveal portion of the retina. Co-immunolabeling of GPR55 with rhodopsin......, the photosensitive pigment in rods, revealed a clear overlap of expression throughout the rod structure with most prominent staining in the inner segments. Additionally, double-label of GPR55 with calbindin, a specific marker for cone photoreceptors in the primate retina, allowed us to exclude expression of GPR55...

  13. Psychotropic substances in indoor environments.

    Science.gov (United States)

    Cecinato, Angelo; Romagnoli, Paola; Perilli, Mattia; Patriarca, Claudia; Balducci, Catia

    2014-10-01

    The presence of drugs in outdoor air has been established, but few investigations have been conducted indoors. This study focused on psychotropic substances (PSs) at three schools, four homes and one office in Rome, Italy. The indoor drug concentrations and the relationships with the outdoor atmosphere were investigated. The optimised monitoring procedure allowed for the determination of cocaine, cannabinoids and particulate fractions of nicotine and caffeine. In-field experiments were performed during the winter, spring and summer seasons. Psychotropic substances were observed in all indoor locations. The indoor concentrations often exceeded those recorded both outdoors at the same sites and at the atmospheric pollution control network stations, indicating that the drugs were released into the air at the inside sites or were more persistent. During winter, the relative concentrations of cannabinol, cannabidiol and tetrahydrocannabinol depended on site and indoor/outdoor location at the site. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Medical Marijuana in the Workplace

    Science.gov (United States)

    Targino, Marcelo C.; Fanciullo, Gilbert J.; Martin, Douglas W.; Hartenbaum, Natalie P.; White, Jeremy M.; Franklin, Phillip

    2015-01-01

    Although possession and use of marijuana is prohibited by federal law, legalization in four states (Alaska, Colorado, Oregon, and Washington) and allowance for palliation and therapy in 19 others may reposition the drug away from the fringes of society. This evolving legal environment, and growing scientific evidence of its effectiveness for select health conditions, requires assessment of the safety and appropriateness of marijuana within the American workforce. Although studies have suggested that marijuana may be used with reasonable safety in some controlled environments, there are potential consequences to its use that necessitate employer scrutiny and concern. Several drug characteristics must be considered, including Δ9-tetrahydrocannabinol (Δ9-THC, or THC) concentration, route of administration, dose and frequency, and pharmacokinetics, as well as the risks inherent to particular workplace environments. PMID:25951421

  15. Cannabinoid-induced autophagy: Protective or death role?

    Science.gov (United States)

    Costa, Lia; Amaral, Cristina; Teixeira, Natércia; Correia-da-Silva, Georgina; Fonseca, Bruno M

    2016-01-01

    Autophagy, the "self-digestion" mechanism of the cells, is an evolutionary conserved catabolic process that targets portions of cytoplasm, damaged organelles and proteins for lysosomal degradation, which plays a crucial role in development and disease. Cannabinoids are active compounds of Cannabis sativa and the most prevalent psychoactive substance is Δ(9)-tetrahydrocannabinol (THC). Cannabinoid compounds can be divided in three types: the plant-derived natural products (phytocannabinoids), the cannabinoids produced endogenously (endocannabinoids) and the synthesized compounds (synthetic cannabinoids). Various studies reported a cannabinoid-induced autophagy mechanism in cancer and non-cancer cells. In this review we focus on the recent advances in the cannabinoid-induced autophagy and highlight the molecular mechanisms involved in these processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Schedules of Controlled Substances: Placement of FDA-Approved Products of Oral Solutions Containing Dronabinol [(-)-delta-9-transtetrahydrocannabinol (delta-9-THC)] in Schedule II. Interim final rule, with request for comments.

    Science.gov (United States)

    2017-03-23

    On July 1, 2016, the U.S. Food and Drug Administration (FDA) approved a new drug application for Syndros, a drug product consisting of dronabinol [(-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC)] oral solution. Thereafter, the Department of Health and Human Services (HHS) provided the Drug Enforcement Administration (DEA) with a scheduling recommendation that would result in Syndros (and other oral solutions containing dronabinol) being placed in schedule II of the Controlled Substances Act (CSA). In accordance with the CSA, as revised by the Improving Regulatory Transparency for New Medical Therapies Act, DEA is hereby issuing an interim final rule placing FDA-approved products of oral solutions containing dronabinol in schedule II of the CSA.

  17. Drug testing in the workplace: could a positive test for one of the mandated drugs be for reasons other than illicit use of the drug?

    Science.gov (United States)

    elSohly, M A; Jones, A B

    1995-10-01

    This manuscript reviews data available in the scientific literature relative to drug testing for the five mandated drug classes and circumstances other than abuse of the drug itself that could result in a positive test. For marijuana, passive inhalation, unknowing oral ingestion, and the use of Marinol are discussed. Data are presented on the concentration of delta9-tetrahydrocannabinol (THC) and its precursors, acid-A and acid-B, in illicit marijuana and the extent of extraction of THC in boiled (tea) or cooked products. For cocaine, passive inhalation and passive exposure issues are reviewed. For opiates, poppy seed ingestion and guidelines for exclusion of poppy seeds as a cause for a positive test are discussed. For amphetamines, issues such as the presence of other phenethylamines, l-methamphetamine (Vicks' inhalers), and other prescription drugs are discussed. Although passive inhalation of methamphetamine and phencyclidine is theoretically possible, no data were available on these issues.

  18. Simultaneous Screening and Quantification of 29 Drugs of Abuse in Oral Fluid by Solid-Phase Extraction and Ultraperformance LC-MS/MS

    DEFF Research Database (Denmark)

    Linnet, Kristian; Badawi, Nora; Simonsen, Kirsten W.

    2009-01-01

    Background: The European DRUID (Driving under the Influence of Drugs, Alcohol And Medicines) project calls for analysis of oral fluid (OF) samples, collected randomly and anonymously at the roadside from drivers in Denmark throughout 2008–2009. To analyze these samples we developed an ultra...... performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method for detection of 29 drugs and illicit compounds in OF. The drugs detected were opioids, amphetamines, cocaine, benzodiazepines, and {Delta}-9-tetrahydrocannabinol. Method: Solid-phase extraction was performed with a Gilson ASPEC XL......4 system equipped with Bond Elut Certify sample cartridges. OF samples (200 mg) diluted with 5 mL of ammonium acetate/methanol (vol/vol 90:10) buffer were applied to the columns and eluted with 3 mL of acetonitrile with aqueous ammonium hydroxide. Target drugs were quantified by use of a Waters...

  19. Cannabinoid modulations of resting state EEG θ power and working memory are correlated in humans.

    Science.gov (United States)

    Böcker, Koen B E; Hunault, Claudine C; Gerritsen, Jeroen; Kruidenier, Maaike; Mensinga, Tjeert T; Kenemans, J Leon

    2010-09-01

    Object representations in working memory depend on neural firing that is phase-locked to oscillations in the theta band (4-8 Hz). Cannabis intake disrupts synchronicity of theta oscillations and interferes with memory performance. Sixteen participants smoked cigarettes containing 0.0, 29.3, 49.1, or 69.4 mg Delta(9)-tetrahydrocannabinol (THC) in a randomized crossover design and performed working memory and general attention tasks. Dose-dependent effects of THC were observed for resting state EEG theta and beta power, working memory (per-item search time), and attentional performance (percent errors and RT). The THC effects on EEG theta power and memory performance were correlated, whereas other EEG and behavioral effects were not. These findings confirm and extend previous results in rodents and humans, and corroborate a neurocomputational model that postulates that temporal aspects of information processing in working memory depend causally on nested oscillations in the theta and gamma (>30 Hz) bands.

  20. Schizophrenia, ketamine and cannabis: evidence of overlapping memory deficits.

    Science.gov (United States)

    Fletcher, Paul C; Honey, Garry D

    2006-04-01

    Drug models of mental illness are considered useful if they provoke its characteristic symptoms. In this respect, ketamine and tetrahydrocannabinol (cannabis) are coming under increasing scrutiny as models for schizophrenia. However, although both undoubtedly produce psychotic symptoms characteristic of the disorder, we argue here that, because schizophrenia is also accompanied by cognitive deficits, a full understanding of the impact of these drugs on cognition will be crucial in taking these models further. Memory deficits are pronounced in schizophrenia and we focus upon patterns of working and episodic memory impairment produced by ketamine and cannabis, identifying overlaps between drug and illness. We suggest that close attention to these deficits can offer insights into core pathophysiology of schizophrenia.

  1. Pharmacological Treatment of Tourette Disorder

    Directory of Open Access Journals (Sweden)

    Hande Ayraler Taner

    2013-06-01

    Full Text Available Tourette disorder is a chronic neuropsychiatric disorder characterized by vocal and motor tics. The course of the disorder shows waxing and vaning pattern and symptoms adversely affect patients’ quality of life. Patients use psychopharmacologic agents for long periods to control their symptoms during which they also struggle with drug related side effects. Clinicians face serious difficulties in controlling symptoms with psychopharmacological agents. Primarily alpha 2 receptor agonists and antipsychotic drugs have been used in the treatment of Tourette disorder. Risperidone and aripiprazole are the most commonly used new generation antipsychotics in the treatment. In addition there are contradictory findings regarding the use of dopamine agonists, tetrabenazine, topiramate, levatirasetame, and delta-9-tetrahydrocannabinol in these patients

  2. Cannabinoids as treatment for nausea and vomiting

    Directory of Open Access Journals (Sweden)

    Erin M. Rock

    2016-07-01

    Full Text Available Despite the advent of classic anti-emetics, chemotherapy-induced nausea is still problematic, with vomiting being somewhat better managed in the clinic. If post-treatment nausea and vomiting are not properly controlled, anticipatory nausea—a conditioned response to the contextual cues associated with illness-inducing chemotherapy— can develop. Once it develops, anticipatory nausea is refractive to current anti-emetics, highlighting the need for alternative treatment options. One of the first documented medicinal uses of Δ9-tetrahydrocannabinol (Δ9-THC was for the treatment of chemotherapy-induced nausea and vomiting, and recent evidence is accumulating to suggest a role for the endocannabinoid system in modulating chemotherapy-induced nausea and vomiting. Here, we review studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system in human patients and pre-clinical animal models of nausea and vomiting.

  3. Synthesis of deuterium labeled cannabinoids

    Energy Technology Data Exchange (ETDEWEB)

    Banijamali, A.R.; Abou-Taleb, N.; Van der Schyf, C.J.; Charalambous, A.; Makriyannis, A.

    1988-01-01

    Several methods for the specific deuteration of cannabinoids are described. Deuteration of the phenolic ring was accomplished by treatment with BF/sub 3/center dotEt/sub 2/O followed by quenching with a solution of Na/sub 2/ CO/sub 3/ in D/sub 2/ O resulting in deuterium incorporation in both the 2 and 4 positions. Regioselective incorporation of deuterium into either the 2 or 4 position of ..delta../sup 8/-THC was achieved using Florisil spiked with either D/sub 2/O or H/sub 2/O. Deuteration at positions 8, 10 and 11 was achieved by addition of DC1 gas to the appropriate tetrahydrocannabinol to form 9-chlorohexahydrocannabinol labeled at either of the above positions, followed by elimination of hydrogen- or deuterium chloride with potassium-tert-amylate. UV irradiation of specifically labeled ..delta../sup 8/-THC gave the correspondingly labeled ..delta..sup(9,11)-THC.

  4. Acute cannabis intoxication mimicking brugada-like ST segment abnormalities.

    Science.gov (United States)

    Daccarett, Marcos; Freih, Mouhanad; Machado, Christian

    2007-07-10

    A 19 years old male presented with a syncopeal episode after heavy marihuana use. A 12 lead ECG demonstrated Brugada-like ST segment elevation in leads V1 and V2. Urine and blood toxicological studies upon admission demonstrated markedly elevated levels of Tetrahydrocannabinol (THC). A 2D echocardiogram demonstrated normal left ventricular function without the presence of any structural or valvular abnormalities. The ST segments normalized once the acute intoxication resolved. A Procainamide induction test was performed without recurrence of the Brugada-like ST segment abnormalities. Our case exemplifies an otherwise healthy male with a negative work-up for a vasovagal mediated syncope and isolated ST segment changes due to THC. The arrhythmic properties of THC have been related to its effect on action potential shortening and vagal tone hyper-stimulation. The ST segment abnormalities are believed to be related to partial sodium channel agonist activity.

  5. Implication of cannabinoids in neurological diseases.

    Science.gov (United States)

    Alsasua del Valle, Angela

    2006-01-01

    1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally. 2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Delta(9)-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases. 3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB(1) receptor antagonists have therapeutic potential in Parkinson's disease. 4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.

  6. : Cannabinoïdes et hépatopathies chroniques

    OpenAIRE

    Lotersztajn, Sophie; Teixeira-Clerc, Fatima; Hezode, Christophe; Tran Van Nhieu, Jeanne; Deveaux, Vanessa; Mallat, Ariane

    2007-01-01

    (1er paragraphe) Le cannabis (marijuana, Cannabis sativa) est utilisé depuis l'antiquité comme substance psychoactive récréative, mais également en médecine traditionnelle pour ses effets orexigènes et antalgiques (1, 2). Le principal composé actif du cannabis, le Δ9–tetrahydrocannabinol (THC) n'a cependant a été isolé qu'en 1964. La compréhension des mécanismes d'action des phytocannabinoïdes a connu un essor considérable depuis les années quatre-vingt dix, avec le clonage de deux récepteurs...

  7. [Therapeutic applications and biomedical effects of cannabinoids; pharmacological starting points].

    Science.gov (United States)

    Killestein, J; Nelemans, S A

    1997-08-30

    A broad range of therapeutic applications has been suggested for cannabis or its pharmacologically active compound (tetrahydrocannabinol; THC) in many publications. Psychotropic side effects and the anecdotal character of the research have limited the pharmacotherapeutic use of THC until now. Therefore, the Netherlands Health Council recently decided negatively on this matter. Besides several cannabinoid receptor subtypes present in the central nervous system and peripheral tissues endogenous cannabinoids have been detected. These endogenous cannabinoids appear to play an important role in signal transduction, which may be starting points for therapy regarding: cardiovascular diseases, multiple sclerosis and spinal cord disorders. cerebrovascular accident and brain trauma, neurodegenerative diseases, epilepsy, pain management, glaucoma, oncologic and aids-related disorders such as nausea, vomiting and appetite problems.

  8. Psychopharmacology of the endocannabinoids: far beyond anandamide.

    Science.gov (United States)

    Pamplona, F A; Takahashi, R N

    2012-01-01

    The study of endocannabinoid pharmacology has proceeded from the discovery of Δ9-tetrahydrocannabinol, the main psychoactive compound in Cannabis sativa, to the identification of an endogenous endocannabinoid system that is essential for physiological modulation of neuronal functions. We have not yet achieved a complete understanding of the various roles of the endocannabinoids, but this is one of the fastest-growing fields in psychopharmacology. This review starts with a brief historical description of the discovery of the endocannabinoids and then focuses on recent pharmacological advances and recently discovered endocannabinoid mechanisms of action (e.g. functional selectivity, allosterism, and receptor trafficking). Finally, we will discuss the contention that the existence of evidence-based therapeutic applications for cannabinoids and the wide range of physiological functions affected by endocannabinoids suggests that the careful study of the endocannabinoid system may lead to the development of novel therapeutic drugs with higher societal acceptability and lower side effects profiles.

  9. Marijuana-based drugs: innovative therapeutics or designer drugs of abuse?

    Science.gov (United States)

    Seely, Kathryn A; Prather, Paul L; James, Laura P; Moran, Jeffery H

    2011-02-01

    The principal psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), activates CB1 cannabinoid receptors (CB1Rs). Unfortunately, pharmacological research into the design of effective THC analogs has been hampered by psychiatric side effects. THC-based drug design of a less academic nature, however, has led to the marketing of "synthetic marijuana," labeled as K2 or "Spice," among other terms, which elicits psychotropic actions via CB1R activation. Because of structural dissimilarity to THC, the active ingredients of K2/Spice preparations are widely unregulated. The K2/Spice "phenomenon" provides a context for considering whether marijuana-based drugs will truly provide innovative therapeutics or merely perpetuate drug abuse.

  10. Cannabis misinterpretation and misadventure in a coroner's court.

    LENUS (Irish Health Repository)

    Tormey, William Patrick

    2012-10-01

    A 37-year-old, one-pack-per-day tobacco smoker collapsed and died at home. At autopsy, he had an occluded left anterior descending coronary artery. Δ(9)-Tetrahydrocannabinol-carboxylic acid was found in his urine but no cannabinoids were detected in his blood. Misadventure was the inquest verdict on the basis of the urinary cannabis, with acute myocardial infarction as the primary cause and cannabis as the secondary cause of death. Such a conclusion is a misinterpretation of the evidence when the time duration for cannabis as a trigger for myocardial infarction is at most two hours. The absence of cannabis in the blood likely places the time since inhalation at more than two hours. The role of tobacco smoking as a trigger was ignored. Cotinine, the biochemical marker of tobacco smoke, should be added to the standard toxicological screen in the guidelines on autopsy practice of the Royal College of Pathologists.

  11. Maternal marijuana use, adverse pregnancy outcomes, and neonatal morbidity.

    Science.gov (United States)

    Metz, Torri D; Allshouse, Amanda A; Hogue, Carol J; Goldenberg, Robert L; Dudley, Donald J; Varner, Michael W; Conway, Deborah L; Saade, George R; Silver, Robert M

    2017-10-01

    The Eunice Kennedy Shriver National Institute of Child Health and Human Development Stillbirth Collaborative Research Network previously demonstrated an association between stillbirth and maternal marijuana use as defined by the presence of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid in the umbilical cord homogenate. However, the relationship between marijuana use and perinatal complications in live births is uncertain. Our aim was to examine if maternal marijuana use is associated with increased odds of adverse pregnancy outcomes and neonatal morbidity among live-born controls in the Stillbirth Collaborative Research Network cohort. We conducted a secondary analysis of singleton, live-born controls in the Stillbirth Collaborative Research Network data set. Marijuana use was measured by self-report and/or the presence of 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid in umbilical cord homogenate. Tobacco use was measured by self-report and/or presence of any cotinine in maternal serum. Adverse pregnancy outcome was a composite of small for gestational age, spontaneous preterm birth resulting from preterm labor with or without intact membranes, and hypertensive disorders of pregnancy. Neonatal morbidity included neonatal intensive care unit admission and composite neonatal morbidity (pulmonary morbidity, necrotizing enterocolitis, seizures, retinopathy of prematurity, infection morbidity, anemia requiring blood transfusion, neonatal surgery, hyperbilirubinemia, neurological morbidity, or death prior to hospital discharge). Effect of maternal marijuana use on the probability of an adverse outcome was estimated using weighted methodology to account for oversampling in the original study. 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid cord homogenate analysis was performed in the subset of women for whom biospecimens were available. Comparisons using logistic modeling, χ2, and t tests were weighted to account for oversampling of preterm births

  12. “Herbal incense”: Designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays

    Science.gov (United States)

    Järbe, Torbjörn U.C.; Gifford, Roger S.

    2014-01-01

    Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called “Spice”. The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar “subjective high”with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new “designer” cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics. PMID:23891559

  13. "Herbal incense": designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays.

    Science.gov (United States)

    Järbe, Torbjörn U C; Gifford, Roger S

    2014-02-27

    Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called "Spice". The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar "subjective high" with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new "designer" cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics. © 2013 Elsevier Inc. All rights reserved.

  14. Validation of LUCIO-Direct-ELISA kits for the detection of drugs of abuse in urine: application to the new German driving licence re-granting guidelines.

    Science.gov (United States)

    Agius, Ronald; Nadulski, Thomas; Moore, Christine

    2012-02-10

    LUCIO-Direct-enzyme linked immunosorbent assay (ELISA) tests were validated for the screening of drugs of abuse cannabis, opiates, amphetamines and cocaine in urine for the new German medical and psychological assessment (MPA) guidelines with subsequent gas chromatographic-mass spectrometric (GC-MS) confirmation. The screening cut-offs corresponding to 10 ng/mL 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), 50 ng/mL amphetamine, 25 ng/mL morphine and codeine and 30 ng/mL benzoylecgonine were chosen at the point where the number of false negatives was lower than 1%. Due to their accuracy, ease of use and rapid analysis, these ELISA tests are very promising for cases where a large proportion of the tests are expected to be negative such as for abstinence monitoring as part of the driving licence re-granting process. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  15. Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

    Directory of Open Access Journals (Sweden)

    Mauro Maccarrone

    2017-05-01

    Full Text Available Cannabis extracts have been used for centuries, but its main active principle ∆9-tetrahydrocannabinol (THC was identified about 50 years ago. Yet, it is only 25 years ago that the first endogenous ligand of the same receptors engaged by the cannabis agents was discovered. This “endocannabinoid (eCB” was identified as N-arachidonoylethanolamine (or anandamide (AEA, and was shown to have several receptors, metabolic enzymes and transporters that altogether drive its biological activity. Here I report on the latest advances about AEA metabolism, with the aim of focusing open questions still awaiting an answer for a deeper understanding of AEA activity, and for translating AEA-based drugs into novel therapeutics for human diseases.

  16. Passive inhalation of cannabis smoke

    Energy Technology Data Exchange (ETDEWEB)

    Law, B.; Mason, P.A.; Moffat, A.C.; King, L.J.; Marks, V.

    1984-09-01

    Six volunteers each smoked simultaneously, in a small unventilated room (volume 27 950 liter), a cannabis cigarette containing 17.1 mg delta 9-tetrahydrocannabinol (THC). A further four subjects - passive inhalers - remained in the room during smoking and afterwards for a total of 3 h. Blood and urine samples were taken from all ten subjects and analyzed by radioimmunoassay for THC metabolites. The blood samples from the passive subjects taken up to 3 h after the start of exposure to cannabis smoke showed a complete absence of cannabinoids. In contrast, their urine samples taken up to 6 h after exposure showed significant concentrations of cannabinoid metabolites (less than or equal to 6.8 ng ml-1). These data, taken with the results of other workers, show passive inhalation of cannabis smoke to be possible. These results have important implications for forensic toxicologists who are frequently called upon to interpret cannabinoid levels in body fluids.

  17. Effects of chronic delta-9-THC treatment on cardiac beta-adrenoceptors in rats

    Energy Technology Data Exchange (ETDEWEB)

    Evans, E.B.; Seifen, E.; Kennedy, R.H.; Kafiluddi, R.; Paule, M.G.; Scallet, A.C.; Ali, S.F.; Slikker, W. Jr.

    1987-10-01

    This study was designed to determine if chronic treatment with delta-9-tetrahydrocannabinol (THC) alters cardiac beta-adrenoceptors in the rat. Following daily oral administration of 10 or 20 mg/kg THC or an equivalent volume of control solvent for 90 days, rats were sacrificed, and sarcolemmal membranes were prepared from ventricular myocardium. Beta-adrenoceptor density and binding affinity estimated with (-)(/sup 3/H)dihydroalprenolol; a beta-adrenergic antagonist, were not significantly affected by treatment with THC when compared to vehicle controls. These results suggest that the tolerance to cardiovascular effects of THC which develops during chronic exposure in the rat is not associated with alterations in cardiac beta-adrenoceptors as monitored by radiolabeled antagonist binding.

  18. Endocannabinoids and reproductive endocrinology.

    Science.gov (United States)

    Maccarrone, Mauro

    2009-04-01

    The endocannabinoids anandamide and 2-arachidonoylglycerol mimic Delta9-tetrahydrocannabinol, the chemical component responsible for the psychoactive properties of Cannabis sativa, by binding to both type 1 and type 2 cannabinoid receptors. Endocannabinoids exert several actions, both centrally and peripherally, and are synthesized or hydrolyzed by specific enzymes. In this review, the elements that constitute the endocannabinoid system (ECS) are described, with the aim of describing their interplay with other components of reproductive endocrinology, both in females and males. In particular, the interaction of the ECS with sex hormones and cytokines,1 generating an endocannabinoid/hormone/cytokine array responsible for the control of human fertility, is discussed. The data for endocannabinoids suggest that these molecules can be proposed as novel lipid hormones (lipokines) that are critically involved in reproductive events.

  19. Endocannabinoid signaling in female reproductive events: a potential therapeutic target?

    Science.gov (United States)

    Maccarrone, Mauro

    2015-01-01

    Nearly 30 years after the discovery in 1964 of the psychoactive ingredient of cannabis (Cannabis sativa), Δ(9)-tetrahydrocannabinol, its endogenous counterparts were discovered and collectively termed endocannabinoids (eCBs): N-arachidonoylethanolamine (anandamide) in 1992 and 2-arachidonoylglycerol in 1995. Since then, intense research has identified additional eCBs and an ensemble of proteins that bind, synthesize and degrade them, the so-called eCB system. Altogether, these new compounds have been recognized as key mediators of several aspects of human pathophysiology, and in particular of female fertility. Here, the main features of the eCB system are presented, in order to put in a better perspective the relevance of eCB signaling in virtually all steps of human reproduction and to highlight emerging hopes that elements of this system might indeed become novel targets to combat fertility problems.

  20. Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia.

    Science.gov (United States)

    Tsai, S J; Wang, Y C; Hong, C J

    2000-09-01

    Cannabis can induce schizophrenic-like symptoms in healthy individuals. A principal active ingredient of cannabis, delta-9-tetrahydrocannabinol, acts in the brain on a specific receptor, termed the cannabinoid receptor 1 (CNR1). The human gene for CNR1 is mapped to chromosome 6q14-15, and linkage studies have produced evidence for a schizophrenia-susceptibility locus in this region. To explore a possible role for CNR1 in the pathogenesis of schizophrenic disorders, we used an association study to genotype the CNR1 polymorphism for 127 schizophrenic patients and 146 control subjects. The results demonstrate no association between CNR1 genotypes and schizophrenic disorders (P = 0.409), with these negative findings suggesting that, for Chinese populations, the (AAT)n triplet repeat in the promoter region of the CNR1 gene is not directly involved in the pathogenesis of schizophrenic disorders.

  1. Cannabinoid patterns in seedlings of Cannabis sativa L. and their use in the determination of chemical race.

    Science.gov (United States)

    Rowan, M G; Fairbairn, J W

    1977-08-01

    We have examined the cannabinoid contents of seedlings from twelve strains of Cannabis of known chemical race. Fourteen days after emergence of the shoot those of the tetrahydrocannabinol (THC) type could be distinguished from those of the cannabidiol (CBD) type. The true leaves of the THC type contained a relatively high content of THC and also contained cannabichromene (CBC), sometimes as the major cannabinoid, whereas the CBD type had much lower amounts of THC and no CBC; CBD being the major component. A strain from China corresponded to the THC type but showed some unusual features. Seeds purchased at seven outlets in Britain were also examined. Only two batches germinated by these proved to be of a THC type and resembled the Chinese strain.

  2. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

    Science.gov (United States)

    Fernández-Ruiz, Javier; Sagredo, Onintza; Pazos, M Ruth; García, Concepción; Pertwee, Roger; Mechoulam, Raphael; Martínez-Orgado, José

    2013-01-01

    Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ9-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington's disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ9-tetrahydrocannabinol, i.e. CB1 and CB2 receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB2 receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels. PMID:22625422

  3. Simultaneous quantification of delta-9-THC, THC-acid A, CBN and CBD in seized drugs using HPLC-DAD.

    Science.gov (United States)

    Ambach, Lars; Penitschka, Franziska; Broillet, Alain; König, Stefan; Weinmann, Wolfgang; Bernhard, Werner

    2014-10-01

    An HPLC-DAD method for the quantitative analysis of Δ(9)-tetrahydrocannabinol (THC), Δ(9)-tetrahydrocannabinolic acid-A (THCA-A), cannabidiol (CBD), and cannabinol (CBN) in confiscated cannabis products has been developed, fully validated and applied to analyse seized cannabis products. For determination of the THC content of plant material, this method combines quantitation of THCA-A, which is the inactive precursor of THC, and free THC. Plant material was dried, homogenized and extracted with methanol by ultrasonication. Chromatographic separation was achieved with a Waters Alliance 2695 HPLC equipped with a Merck LiChrospher 60 RP-Select B (5μm) precolumn and a Merck LiChroCart 125-4 LiChrospher 60 RP-Select B (5μm) analytical column. Analytes were detected and quantified using a Waters 2996 photo diode array detector. This method has been accepted by the public authorities of Switzerland (Bundesamt für Gesundheit, Federal Office of Public Health), and has been used to analyse 9092 samples since 2000. Since no thermal decarboxylation of THCA-A occurs, the method is highly reproducible for different cannabis materials. Two calibration ranges are used, a lower one for THC, CBN and CBD, and a higher one for THCA-A, due to its dominant presence in fresh plant material. As provider of the Swiss proficiency test, the robustness of this method has been tested over several years, and homogeneity tests even in the low calibration range (1%) show high precision (RSD≤4.3%, except CBD) and accuracy (bias≤4.1%, except CBN). Copyright © 2014. Published by Elsevier Ireland Ltd.

  4. Medical cannabis ‒ the Canadian perspective 

    Directory of Open Access Journals (Sweden)

    Ko GD

    2016-09-01

    Full Text Available Gordon D Ko,1,2 Sara L Bober,1 Sean Mindra,3 Jason M Moreau1 1Apollo Applied Research Inc., 2Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, 3University of Ottawa Medical School, Ottawa, ON, Canada Abstract: Cannabis has been widely used as a medicinal agent in Eastern medicine with earliest evidence in ancient Chinese practice dating back to 2700 BC. Over time, the use of medical cannabis has been increasingly adopted by Western medicine and is thus a rapidly emerging field that all pain physicians need to be aware of. Several randomized controlled trials have shown a significant and dose-dependent relationship between neuropathic pain relief and tetrahydrocannabinol – the principal psychoactive component of cannabis. Despite this, barriers exist to use from both the patient perspective (cost, addiction, social stigma, lack of understanding regarding safe administration and the physician perspective (credibility, criminality, clinical evidence, patient addiction, and policy from the governing medical colleges. This review addresses these barriers and draws attention to key concerns in the Canadian medical system, providing updated treatment approaches to help clinicians work with their patients in achieving adequate pain control, reduced narcotic medication use, and enhanced quality of life. This review also includes case studies demonstrating the use of medical marijuana by patients with neuropathic low-back pain, neuropathic pain in fibromyalgia, and neuropathic pain in multiple sclerosis. While significant preclinical data have demonstrated the potential therapeutic benefits of cannabis for treating pain in osteoarthritis, rheumatoid arthritis, fibromyalgia, and cancer, further studies are needed with randomized controlled trials and larger study populations to identify the specific strains and concentrations that will work best with selected cohorts. Keywords: randomized controlled trials

  5. Specimen Validity Testing SVT) - Effects of Oxidizing Agents on Drugs in Urine and Procedures for Detection.

    Science.gov (United States)

    Paul, B D; Dunkley, C S

    2007-07-01

    Since the inception of the drug-testing program in the U.S. Armed Forces in 1982, urine adulteration with the intent to conceal drug use has been a serious problem to forensic scientists. Initially, drug users tried almost anything that was available at the collection sites. Soon they recognized that certain chemicals could be used to destroy some drugs and interfere with the testing procedures. Some drug analytes, in particular morphine and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, a metabolite of delta-9-tetrahydrocannabinol, could not be detected in presence of some oxidizing agents. As the use of adulterants increased, specimen validity testing was introduced by the Department of Health and Human Services in 2004. While specific reagents could be used to test nitrite, chromate, and iodine, test procedures for many other oxidizing agents were not available. In an attempt to detect most oxidants, a different approach has been introduced to identify urines adulterated with oxidizing adulterants. In this approach, the oxidizing property of normal urine is compared with that of urine containing oxidizing agents. In the procedure, samples are allowed to interact with excess ferrous (Fe2+) ions and then with chromogenic compounds. In the presence of oxidants, Fe2+ ions with low reduction potential (E0 0.771 V) are immediately oxidized to ferric (Fe3+) ions, which then change the chromogenic compounds to colored chromogens. Specific spectral pattern and intensity are the keys in quantification of oxidants in urine (milliEquivalent/liter, mE/L). The method appeared to be promising in differentiating normal urine from urine adulterated with oxidizing agents. Some oxidizing adulterants in urine are unstable. If reduced, it could be reconverted to the oxidizing agents and tested by the general oxidant test. Copyright © 2007 Central Police University.

  6. The draft genome and transcriptome of Cannabis sativa.

    Science.gov (United States)

    van Bakel, Harm; Stout, Jake M; Cote, Atina G; Tallon, Carling M; Sharpe, Andrew G; Hughes, Timothy R; Page, Jonathan E

    2011-10-20

    Cannabis sativa has been cultivated throughout human history as a source of fiber, oil and food, and for its medicinal and intoxicating properties. Selective breeding has produced cannabis plants for specific uses, including high-potency marijuana strains and hemp cultivars for fiber and seed production. The molecular biology underlying cannabinoid biosynthesis and other traits of interest is largely unexplored. We sequenced genomic DNA and RNA from the marijuana strain Purple Kush using shortread approaches. We report a draft haploid genome sequence of 534 Mb and a transcriptome of 30,000 genes. Comparison of the transcriptome of Purple Kush with that of the hemp cultivar 'Finola' revealed that many genes encoding proteins involved in cannabinoid and precursor pathways are more highly expressed in Purple Kush than in 'Finola'. The exclusive occurrence of Δ9-tetrahydrocannabinolic acid synthase in the Purple Kush transcriptome, and its replacement by cannabidiolic acid synthase in 'Finola', may explain why the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) is produced in marijuana but not in hemp. Resequencing the hemp cultivars 'Finola' and 'USO-31' showed little difference in gene copy numbers of cannabinoid pathway enzymes. However, single nucleotide variant analysis uncovered a relatively high level of variation among four cannabis types, and supported a separation of marijuana and hemp. The availability of the Cannabis sativa genome enables the study of a multifunctional plant that occupies a unique role in human culture. Its availability will aid the development of therapeutic marijuana strains with tailored cannabinoid profiles and provide a basis for the breeding of hemp with improved agronomic characteristics.

  7. Therapeutic satisfaction and subjective effects of different strains of pharmaceutical-grade cannabis.

    Science.gov (United States)

    Brunt, Tibor M; van Genugten, Marianne; Höner-Snoeken, Kathrin; van de Velde, Marco J; Niesink, Raymond J M

    2014-06-01

    In The Netherlands, pharmaceutical-grade cultivated cannabis is distributed for medicinal purposes as commissioned by the Ministry of Health. Few studies have thus far described its therapeutic efficacy or subjective (adverse) effects in patients. The aims of this study are to assess the therapeutic satisfaction within a group of patients using prescribed pharmaceutical-grade cannabis and to compare the subjective effects among the available strains with special focus on their delta-9-tetrahydrocannabinol and cannabidiol content. In a cross-sectional and natural design, users of pharmaceutical-grade cannabis were investigated with questionnaires. Medical background of the patients was asked as well as experienced therapeutic effects and characteristics of cannabis use. Subjective effects were measured with psychometric scales and used to compare among the strains of cannabis used across this group of patients. One hundred two patients were included; their average age was 53 years and 76% used it for more than a year preceding this study. Chronic pain (53%; n = 54) was the most common medical indication for using cannabis followed by multiple sclerosis (23%; n = 23), and 86% (n = 88) of patients (almost) always experienced therapeutic satisfaction when using pharmaceutical cannabis. Dejection, anxiety, and appetite stimulation were found to differ among the 3 strains of cannabis. These results show that patients report therapeutic satisfaction with pharmaceutical cannabis, mainly pain alleviation. Some subjective effects were found to differ among the available strains of cannabis, which is discussed in relation to their different tetrahydrocannabinol/cannabidiol content. These results may aid in further research and critical appraisal for medicinally prescribed cannabis products.

  8. Analysis of cannabinoids in laser-microdissected trichomes of medicinal Cannabis sativa using LCMS and cryogenic NMR.

    Science.gov (United States)

    Happyana, Nizar; Agnolet, Sara; Muntendam, Remco; Van Dam, Annie; Schneider, Bernd; Kayser, Oliver

    2013-03-01

    Trichomes, especially the capitate-stalked glandular hairs, are well known as the main sites of cannabinoid and essential oil production of Cannabis sativa. In this study the distribution and density of various types of Cannabis sativa L. trichomes, have been investigated by scanning electron microscopy (SEM). Furthermore, glandular trichomes were isolated over the flowering period (8 weeks) by laser microdissection (LMD) and the cannabinoid profile analyzed by LCMS. Cannabinoids were detected in extracts of 25-143 collected cells of capitate-sessile and capitate stalked trichomes and separately in the gland (head) and the stem of the latter. Δ(9)-Tetrahydrocannabinolic acid [THCA (1)], cannabidiolic acid [CBDA (2)], and cannabigerolic acid [CBGA (3)] were identified as most-abundant compounds in all analyzed samples while their decarboxylated derivatives, Δ(9)-tetrahydrocannabinol [THC (4)], cannabidiol [CBD (5)], and cannabigerol [CBG (6)], co-detected in all samples, were present at significantly lower levels. Cannabichromene [CBC (8)] along with cannabinol (CBN (9)) were identified as minor compounds only in the samples of intact capitate-stalked trichomes and their heads harvested from 8-week old plants. Cryogenic nuclear magnetic resonance spectroscopy (NMR) was used to confirm the occurrence of major cannabinoids, THCA (1) and CBDA (2), in capitate-stalked and capitate-sessile trichomes. Cryogenic NMR enabled the additional identification of cannabichromenic acid [CBCA (7)] in the dissected trichomes, which was not possible by LCMS as standard was not available. The hereby documented detection of metabolites in the stems of capitate-stalked trichomes indicates a complex biosynthesis and localization over the trichome cells forming the glandular secretion unit. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Rapid identification of drug-type strains in Cannabis sativa using loop-mediated isothermal amplification assay.

    Science.gov (United States)

    Kitamura, Masashi; Aragane, Masako; Nakamura, Kou; Watanabe, Kazuhito; Sasaki, Yohei

    2017-01-01

    In Cannabis sativa L., tetrahydrocannabinol (THC) is the primary psychoactive compound and exists as the carboxylated form, tetrahydrocannabinolic acid (THCA). C. sativa is divided into two strains based on THCA content-THCA-rich (drug-type) strains and THCA-poor (fiber-type) strains. Both strains are prohibited by law in many countries including Japan, whereas the drug-type strains are regulated in Canada and some European countries. As the two strains cannot be discriminated by morphological analysis, a simple method for identifying the drug-type strains is required for quality control in legal cultivation and forensic investigation. We have developed a novel loop-mediated isothermal amplification (LAMP) assay for identifying the drug-type strains of C. sativa. We designed two selective LAMP primer sets for on-site or laboratory use, which target the drug-type THCA synthase gene. The LAMP assay was accomplished within approximately 40 min. The assay showed high specificity for the drug-type strains and its sensitivity was the same as or higher than that of conventional polymerase chain reaction. We also showed the effectiveness of melting curve analysis that was conducted after the LAMP assay. The melting temperature values of the drug-type strains corresponded to those of the cloned drug-type THCA synthase gene, and were clearly different from those of the cloned fiber-type THCA synthase gene. Moreover, the LAMP assay with simple sample preparation could be accomplished within 1 h from sample treatment to identification without the need for special devices or techniques. Our rapid, sensitive, specific, and simple assay is expected to be applicable to laboratory and on-site detection.

  10. Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells.

    Science.gov (United States)

    Yamaori, Satoshi; Kinugasa, Yuka; Jiang, Rongrong; Takeda, Shuso; Yamamoto, Ikuo; Watanabe, Kazuhito

    2015-09-01

    We herein investigated the inducibility of cytochrome P450 1A1 (CYP1A1) by Δ(9)-tetrahydrocannabinol, cannabidiol (CBD), and cannabinol, three major phytocannabinoids, using human hepatoma HepG2 cells. The expression of CYP1A1 and the aryl hydrocarbon receptor (AhR) was measured by a quantitative real-time polymerase chain reaction and/or Western blotting. Δ(9)-Tetrahydrocannabinol and CBD concentration-dependently induced the expression of CYP1A1 mRNA, whereas cannabinol showed little or no induction. Among the phytocannabinoids tested, CBD was the most potent inducer of CYP1A1 expression. The induction of CYP1A1 expression by CBD was significantly attenuated by the knockdown of AhR expression with AhR small interfering RNAs. The role of protein tyrosine kinases (PTKs) in the CBD-mediated induction of CYP1A1 was then examined using herbimycin A, a PTK inhibitor. The upregulation of CYP1A1 by CBD was significantly suppressed by herbimycin A as was the induction by omeprazole but not 3-methylcholanthrene. The inducibility of CYP1A1 by CBD-related compounds was examined to clarify the structural requirements for CBD-mediated CYP1A1 induction. Olivetol, which corresponds to the pentylresorcinol moiety of CBD, significantly induced the expression of CYP1A1, whereas d-limonene, CBD-2'-monomethyl ether, and CBD-2',6'-dimethyl ether did not. These results showed that CBD may have induced human CYP1A1 expression through the activation of PTK-dependent AhR signaling, in which two phenolic hydroxyl groups in the pentylresorcinol moiety of CBD may play structurally important roles. Copyright © 2015. Published by Elsevier Inc.

  11. Safety and efficacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of high-grade glioma.

    Science.gov (United States)

    Duntsch, Christopher; Divi, Murali Krishna; Jones, Terreia; Zhou, Qihong; Krishnamurthy, Mathangi; Boehm, Peter; Wood, George; Sills, Allen; Moore, Bob M

    2006-04-01

    To test in vitro and in vivo the safety and efficacy of a novel chemotherapeutic agent, KM-233, for the treatment of glioma. In vitro cell cytotoxicity assays were used to measure and compare the cytotoxic effects of KM-233, Delta(8)-tetrahydrocannabinol (THC), and bis-chloroethyl-nitrosurea (BCNU) against human U87 glioma cells. An organotypic brain slice culture model was used for safety and toxicity studies. A human glioma-SCID mouse side-pocket tumor model was used to test in vivo the safety and efficacy of KM-233 with intratumoral and intra-peritoneal administration. KM-233 is a classical cannabinoid with good blood brain barrier penetration that possesses a selective affinity for the CB2 receptors relative to THC. KM-233 was as efficacious in its cytotoxicity against human U87 glioma as Delta(8)-tetrahydrocannabinol, and superior to the commonly used anti-glioma chemotherapeutic agent, BCNU. The cytotoxic effects of KM-233 against human glioma cells in vitro occur as early as two hours after administration, and dosing of KM-233 can be cycled without compromising cytotoxic efficacy and while improving safety. Cyclical dosing of KM-233 to treat U87 glioma in a SCID mouse xenograft side pocket model was effective at reducing the tumor burden with both systemic and intratumoral administration. These studies provide both in vitro and in vivo evidence that KM-233 shows promising efficacy against human glioma cell lines in both in vitro and in vivo studies, minimal toxicity to healthy cultured brain tissue, and should be considered for definitive preclinical development in animal models of glioma.

  12. Quality Control of Traditional Cannabis Tinctures: Pattern, Markers, and Stability.

    Science.gov (United States)

    Peschel, Wieland

    2016-04-18

    Traditional tinctures of Cannabis sativa L. became obsolete before elucidation of the main cannabinoids and routine quality testing for medicines. In view of increasing medicinal use of cannabinoids and associated safety concerns, tinctures from a Δ9-tetrahydrocannabinol (THC)-type chemovar were studied. High-performance liquid chromatography with diode-array detection (HPLC/DAD) was used to determine THC, Δ9-tetrahydrocannabinolic acid A (THCA), cannabinol (CBN), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannflavin A/B, and total phenolics. Derived group and ratio markers describe absolute and relative profiles when varying plant part (flos, folium), extraction solvent (EtOH percentage), storage conditions ('shelf' or 'fridge' up to 15 months), and pasteurization (2 h 70 °C, 20 min 80 °C). Tinctures from female flowering tops contained ten-fold more cannabinoids than tinctures from leaves; tinctures (80%-90% EtOH) contained ten-fold more cannabinoids than tinctures (40% EtOH). The analysis of CBGA + CBG, the main co-cannabinoids aside from THCA + THC, appears more relevant than CBDA + CBD. The decarboxylation of THCA to THC-the main change during storage of freshly prepared tinctures-is after 15 months in the 'fridge' comparable to 3 months on the 'shelf'. Minimally increased CBN totals did not correlate to diminished totals of THCA and THC (up to 15% after 3 months 'shelf', 45% after 15 months 'fridge'). Instead, total cannabinoids or acidic/neutral cannabinoid ratios are better stability markers. Moderate changes after pasteurization and partial losses below 10% for total cannabinoids after 9 months 'fridge' indicate possibilities for a reasonable shelf life. Yet storage and use of non-stabilized tinctures remain critical without authorized specification and stability data because a consistent cannabinoid content is not guaranteed.

  13. Up in Smoke: Uncovering a Lack of Evidence for Proton Pump Inhibitors as a Source of Tetrahydrocannibol Immunoassay False Positives.

    Science.gov (United States)

    Powers, Jennifer L; Rasmussen, Natalie N; Hurst, Dow; Strathmann, Frederick G

    2017-11-08

    It is recommended that positives in immunoassay drug screens be followed up with more specific confirmatory testing. The drug package insert for pantoprazole mentions reports of false-positive urine screening tests for tetrahydrocannabinol in patients receiving proton pump inhibitors, but no method details or data are given, referenced, or found in literature searches. Thus, we investigated this using our laboratory's assay. A spiked sample and samples from 32 patients taking a proton pump inhibitor were analyzed using the EMIT II Plus Cannabinoid assay with a 20 ng/mL cutoff. Additionally, we examined urine samples from 50 patients with false-positive or low-positive screens for evidence of a proton pump inhibitor. To determine whether O-desmethyl pantoprazole sulfate, the major metabolite, shares any structural or electrostatic similarity to suggest a basis for cross-reactivity in the immunoassay, we used computational techniques for analyses. Molecular electrostatic potential energy (MEP) maps were calculated for the global minimum conformers, and the maximum common substructure Tanimoto similarity was calculated for the modeled compounds. Neither the spiked sample nor the patient samples were found to screen positive. None of the false-positive or low-positive screens were found to contain a proton pump inhibitor. Computational studies showed very little similarity in shape or electrostatics between the two molecules. We find no supporting evidence of pantoprazole as the cause of false positives in the EMIT II Plus Cannabinoid assay and caution the use of proton pump inhibitors as an explanation for tetrahydrocannabinol immunoassay false positives.

  14. An observational postmarketing safety registry of patients in the UK, Germany, and Switzerland, who have been prescribed Sativex® (THC:CBD, nabiximols oromucosal spray

    Directory of Open Access Journals (Sweden)

    Etges T

    2016-11-01

    Full Text Available Tilden Etges, Kari Karolia, Thomas Grint, Adam Taylor, Heather Lauder, Brian Daka, Stephen Wright GW Pharmaceuticals, Cambridge, UK Abstract: The global exposure of Sativex® (Δ9-tetrahydrocannabinol [THC]:cannabidiol [CBD], nabiximols is estimated to be above 45,000 patient-years since it was given marketing approval for treating treatment-resistant spasticity in multiple sclerosis (MS. An observational registry to collect safety data from patients receiving THC:CBD was set up following its approval in the UK, Germany, and Switzerland, with the aim of determining its long-term safety in clinical practice. Twice a year, the Registry was opened to prescribing physicians to voluntarily report data on patients’ use of THC:CBD, clinically significant adverse events (AEs, and special interest events. The Registry contains data from 941 patients with 2,213.98 patient-years of exposure. Within this cohort, 60% were reported as continuing treatment, while 83% were reported as benefiting from the treatment. Thirty-two percent of patients stopped treatment, with approximately one third citing lack of effectiveness and one quarter citing AEs. Psychiatric AEs of clinical significance were reported in 6% of the patients, 6% reported falls requiring medical attention, and suicidality was reported in 2%. Driving ability was reported to have worsened in 2% of patients, but improved in 7%. AEs were more common during the first month of treatment. The most common treatment-related AEs included dizziness (2.3% and fatigue (1.7%. There were no signals to indicate abuse, diversion, or dependence. The long-term risk profile from the Registry is consistent with the known (labeled safety profile of THC:CBD, and therefore supports it being a well-tolerated and beneficial medication for the treatment of MS spasticity. No evidence of new long-term safety concerns has emerged. Keywords: cannabidiol, tetrahydrocannabinol, non-interventional, multiple sclerosis

  15. Illicit psychotropic substance contents in the air of Italy

    Science.gov (United States)

    Cecinato, Angelo; Balducci, Catia; Budetta, Valentina; Pasini, Antonello

    2010-06-01

    Two in-field campaigns were performed in 2009 to elucidate the contents of illicit psychotropic substances in airborne particulates of Italian cities. Twenty-eight localities of eight Italian regions were investigated in winter, and further eleven sites in June (14 regions in total), thanks to contribution of Regional Environmental Agencies. Cocaine was found almost everywhere, although some sites were rural or suburban. The maximum was recorded in Milan in winter (˜0.39 ng m -3), and "high" values (up to ˜0.16 ng m -3) in other Northern cities and in Rome. Besides cocaine, three cannabinoids will be monitored, namely Δ 9-tetrahydrocannabinol, cannabidiol and cannabinol. The three compounds often affected the air at lower extents than cocaine, and sometimes resulted absent. Cannabinol accounted for up to 90% of the total. The concentrations of illicit compounds were up to six times lower in June than in winter. This decrease was probably induced by the lowering of boundary layer height typical of winter, and by the oxidizing capacity of atmosphere, which is stronger in the warm season. Compared to n-alkanes, polynuclear aromatic compounds, nicotine, caffeine and airborne particulate, cocaine seemed to follow a peculiar behaviour; in fact, meaningful (≥0.80) Pearson (linear) regression coefficients were calculated from the corresponding concentrations only at local scale (e.g. Rome), and within just one season. Improvements of the method are needed to monitor illicit drug metabolites (e.g. benzoylecgonine, ecgonine methyl ester, 9-carboxy-11-nor-Δ 9-tetrahydrocannabinol), heroin and semi-volatile amphetamines.

  16. Decarboxylation Study of Acidic Cannabinoids: A Novel Approach Using Ultra-High-Performance Supercritical Fluid Chromatography/Photodiode Array-Mass Spectrometry.

    Science.gov (United States)

    Wang, Mei; Wang, Yan-Hong; Avula, Bharathi; Radwan, Mohamed M; Wanas, Amira S; van Antwerp, John; Parcher, Jon F; ElSohly, Mahmoud A; Khan, Ikhlas A

    2016-01-01

    Introduction: Decarboxylation is an important step for efficient production of the major active components in cannabis, for example, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), cannabidiol (CBD), and cannabigerol (CBG). These cannabinoids do not occur in significant concentrations in cannabis but can be formed by decarboxylation of their corresponding acids, the predominant cannabinoids in the plant. Study of the kinetics of decarboxylation is of importance for phytocannabinoid isolation and dosage formulation for medical use. Efficient analytical methods are essential for simultaneous detection of both neutral and acidic cannabinoids. Methods:C. sativa extracts were used for the studies. Decarboxylation conditions were examined at 80°C, 95°C, 110°C, 130°C, and 145°C for different times up to 60 min in a vacuum oven. An ultra-high performance supercritical fluid chromatography/photodiode array-mass spectrometry (UHPSFC/PDA-MS) method was used for the analysis of acidic and neutral cannabinoids before and after decarboxylation. Results: Decarboxylation at different temperatures displayed an exponential relationship between concentration and time indicating a first-order or pseudo-first-order reaction. The rate constants for Δ(9)-tetrahydrocannabinolic acid-A (THCA-A) were twice those of the cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA). Decarboxylation of THCA-A was forthright with no side reactions or by-products. Decarboxylation of CBDA and CBGA was not as straightforward due to the unexplained loss of reactants or products. Conclusion: The reported UHPSFC/PDA-MS method provided consistent and sensitive analysis of phytocannabinoids and their decarboxylation products and degradants. The rate of change of acidic cannabinoid concentrations over time allowed for determination of rate constants. Variations of rate constants with temperature yielded values for reaction energy.

  17. Triphasic blood pressure responses to cannabinoids: do we understand the mechanism?

    Science.gov (United States)

    Malinowska, Barbara; Baranowska-Kuczko, Marta; Schlicker, Eberhard

    2012-01-01

    The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ9-tetrahydrocannabinol and the chemically related substances CP55940 and HU210), endogenously formed (e.g. anandamide) and synthetic compounds (e.g. WIN55212-2). Beyond their psychotropic effects, cannabinoids have complex effects on blood pressure, including biphasic changes of Δ9-tetrahydrocannabinol and WIN55212-2 and an even triphasic effect of anandamide. The differing pattern of blood pressure changes displayed by the three types of compounds is not really surprising since, although they share an agonistic effect at cannabinoid CB1 and CB2 receptors, some compounds have additional effects. In particular, anandamide is known for its pleiotropic effects, and there is overwhelming evidence that anandamide influences blood pressure via (i) CB1 receptors, (ii) TRPV1 receptors, (iii) endothelial cannabinoid receptors and (iv) degradation products. This review is dedicated to the description of the effects of externally added cannabinoids on cardiovascular parameters in vivo. First, the cardiovascular effects of cannabinoids in anaesthetized animals will be highlighted since most data have been generated in experiments of that type. The text will follow the three phases of anandamide on blood pressure, and we will check to which extent cardiovascular changes elicited by other cannabinoids show overlap with those effects or differ. The second part will be dedicated to the cardiovascular effects of the cannabinoids in conscious animals. In the third part, cardiovascular effects in humans will be discussed, and similarities and differences with respect to the data from animals will be examined. PMID:22022923

  18. Postmortem Fluid and Tissue Concentrations of THC, 11-OH-THC and THC-COOH.

    Science.gov (United States)

    Saenz, Sunday R; Lewis, Russell J; Angier, Mike K; Wagner, Jarrad R

    2017-07-01

    Marijuana is the most commonly abused illicit drug worldwide. Marijuana is used for its euphoric and relaxing properties. However, marijuana use has been shown to result in impaired memory, cognitive skills and psychomotor function. The Federal Aviation Administration's Civil Aerospace Medical Institute conducts toxicological analysis on aviation fatalities. Due to severe trauma associated with aviation accidents, blood is not always available; therefore, the laboratory must rely on specimens other than blood for toxicological analysis in ~30-40% of cases. However, the postmortem distribution of cannabinoids has not been well characterized. The purpose of this research is to evaluate the distribution of Δ9-tetrahydrocannabinol (THC), and its metabolites, 11-hydroxy-tetrahydrocannabinol (11-OH-THC) and THC-COOH, in postmortem fluid and tissue specimens from 11 fatal aviation accident cases (2014-2015) previously found positive for cannabinoids. Specimens evaluated, when available, included: blood, urine, vitreous humor, liver, lung, kidney, spleen, muscle, brain, heart and bile. We developed and validated (following SWGTOX guidelines) a sensitive and robust method using solid-phase extraction and liquid chromatography-tandem mass spectrometry to identify and quantify THC, 11-OH-THC and THC-COOH in postmortem fluids and tissues. The method readily identified and quantified these cannabinoids in postmortem fluids and tissues below 1 ng/mL. Qualitative cannabinoid results within each case were comparable between blood and non-blood specimens. However, there was no consistent distribution of the cannabinoids between blood and any other fluids or tissues. Therefore, while quantitative interpretation of non-blood postmortem fluid and tissues samples is not prudent, a majority of the non-blood specimens tested could be suitable alternative/supplemental choices for qualitative cannabinoid detection. Published by Oxford University Press 2017. This work is written by (a) US

  19. Sensitive determination of THC and main metabolites in human plasma by means of microextraction in packed sorbent and gas chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Rosado, T; Fernandes, L; Barroso, M; Gallardo, E

    2017-02-01

    Cannabis is one of the most available and consumed illicit drug in the world and its identification and quantification in biological specimens can be a challenge given its low concentrations in body fluids. The present work describes a fast and fully validated procedure for the simultaneous detection and quantification of ▵9-tetrahydrocannabinol (▵9_THC) and its two main metabolites 11-hydroxy ▵9_tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-▵9- tetrahydrocannbinol (THC-COOH) in plasma samples using microextraction by packed sorbent (MEPS) and gas chromatography-tandem mass spectrometry (GC-MS/MS). A small plasma volume (0.25mL) pre-diluted (1:20), was extracted with MEPS M1 sorbent as follows: conditioning (4 cycles of 250μL methanol and 4 cycles of 250μL 0.1% formic acid in water); sample load (26 cycles of 250μL); wash (100μL of 3% acetic acid in water followed by 100μL 5% methanol in water); and elution (6 cycles of 100μL of 10% ammonium hydroxide in methanol). The procedure allowed the quantification of all analytes in the range of 0.1-30ng/mL. Recoveries ranged from 53 to 78% (THC), 57 to 66% (11-OH-THC) and 62 to 65% (THC-COOH), allowing the limits of detection and quantification to be set at 0.1ng/mL for all compounds. Intra-day precision and accuracy revealed coefficients of variation (CVs) lower than 10% at the studied concentrations, with a mean relative error within±9%, while inter-day precision and accuracy showed CVs lower than 15% for all analytes at the tested concentrations, with an inaccuracy within±8%. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Determination of the relative percentage distribution of THCA and Δ(9)-THC in herbal cannabis seized in Austria - Impact of different storage temperatures on stability.

    Science.gov (United States)

    Taschwer, Magdalena; Schmid, Martin G

    2015-09-01

    Cannabis is globally by far the most widespread illicit drug of abuse. Especially since its legalization in some of the US, controversies about the legal status of cannabis for recreational and medical use have come up. Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), which is the major active ingredient in cannabis products, is mainly responsible for the psychoactive effects. Its inactive biosynthetic precursor tetrahydrocannabinolic acid (THCA) is present in different quantities in fresh and undried cannabis plants. Under influence of drying, temperature and UV exposure it decomposes to Δ(9)-THC. In this study, a quantification of Δ(9)-THC and THCA was carried out to check the stability of cannabis samples. The determination of the degradation of THCA to Δ(9)-THC in 29 cannabis products seized in Austria was monitored by HPLC-UV. Mobile phase consisted of a 25mM triethylammoniumphosphate buffer (pH 3.0) and acetonitrile (36:64). A common LiChrospher(®) 100 RP-18 column was utilized as stationary phase. To check the influence of low as well as high temperature on the degradation process of the cannabinoid THCA to Δ(9)-THC, samples were stored in a freezer or in a drying cabinet for a specified time period. It was shown successfully that high storage temperatures led to a more rapid and complete decomposition of THCA to Δ(9)-THC while at low temperatures only slight or no changes of the percentage distribution were determined. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.