A coupled THC model of the FEBEX in situ test with bentonite swelling and chemical and thermal osmosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, L.; Samper, J.; Montenegro, L.

The performance assessment of a geological repository for radioactive waste requires quantifying the geochemical evolution of the bentonite engineered barrier. This barrier will be exposed to coupled thermal (T), hydrodynamic (H), mechanical (M) and chemical (C) processes. This paper presents a coupled THC model of the FEBEX (Full-scale Engineered Barrier EXperiment) in situ test which accounts for bentonite swelling and chemical and thermal osmosis. Model results attest the relevance of thermal osmosis and bentonite swelling for the geochemical evolution of the bentonite barrier while chemical osmosis is found to be almost irrelevant. The model has been tested with data collectedmore » after the dismantling of heater 1 of the in situ test. The model reproduces reasonably well the measured temperature, relative humidity, water content and inferred geochemical data. However, it fails to mimic the solute concentrations at the heater-bentonite and bentonite-granite interfaces because the model does not account for the volume change of bentonite, the CO{sub 2}(g) degassing and the transport of vapor from the bentonite into the granite. The inferred HCO{sub 3}{sup -} and pH data cannot be explained solely by solute transport, calcite dissolution and protonation/deprotonation by surface complexation, suggesting that such data may be affected also by other reactions.« less

Thermo-hydrological and chemical (THC) modeling to support Field Test Design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stauffer, Philip H.; Jordan, Amy B.; Harp, Dylan Robert

This report summarizes ongoing efforts to simulate coupled thermal-hydrological-chemical (THC) processes occurring within a hypothetical high-level waste (HLW) repository in bedded salt. The report includes work completed since the last project deliverable, “Coupled model for heat and water transport in a high level waste repository in salt”, a Level 2 milestone submitted to DOE in September 2013 (Stauffer et al., 2013). Since the last deliverable, there have been code updates to improve the integration of the salt module with the pre-existing code and development of quality assurance (QA) tests of constitutive functions and precipitation/dissolution reactions. Simulations of bench-scale experiments, bothmore » historical and currently in the planning stages have been performed. Additional simulations have also been performed on the drift-scale model that incorporate new processes, such as an evaporation function to estimate water vapor removal from the crushed salt backfill and isotopic fractionation of water isotopes. Finally, a draft of a journal paper on the importance of clay dehydration on water availability is included as Appendix I.« less

On the Freshwater Sensitivity of the Arctic-Atlantic Thermohaline Circulation

NASA Astrophysics Data System (ADS)

Lambert, E.; Eldevik, T.; Haugan, P.

2016-02-01

The North Atlantic thermohaline circulation (THC) carries heat and salt toward the Arctic. This circulation is generally believed to be inhibited by northern freshwater input as indicated by the `box-model' of Stommel (1961). The inferred freshwater-sensitivity of the THC, however, varies considerably between studies, both quantitatively and qualitatively. The northernmost branch of the Atlantic THC, which forms a double estuarine circulation in the Arctic Mediterranean, is one example where both strengthening and weakening of the circulation may occur due to increased freshwater input. We have accordingly built on Stommel's original concept to accomodate a THC similar to that in the Arctic Mediterranean. This model consists of three idealized basins, or boxes, connected by two coupled branches of circulation - the double estuary. The net transport of these two branches represents the extension of the Gulf Stream toward the Arctic. Its sensitivity to a change in freshwater forcing depends largely on the distribution of freshwater over the two northern basins. Varying this distribution opens a spectrum of qualitative behaviours ranging from Stommel's original freshwater-inhibited overturning circulation to a freshwater-facilitated estuarine circulation. Between these limiting cases, a Hopf and a cusp bifurcation divide the spectrum into three qualitative regions. In the first region, the circulation behaves similarly to Stommel's circulation, and sufficient freshwater input can induce an abrupt transition into a reversed flow; in the second, a similar transition can be found, although it does not reverse the circulation; in the third, no transition can occur and the circulation is generally facilitated by the northern freshwater input. Overall, the northern THC appears more stable than what would be inferred based on Stommel's model; it requires a larger amount and more localized freshwater input to `collapse' it, and a double estuary circulation is less prone to flow reversal.

Simultaneous quantification of Δ9-tetrahydrocannabinol, 11-hydroxy-Δ9-tetrahydrocannabinol, and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid in human plasma using two-dimensional gas chromatography, cryofocusing, and electron impact-mass spectrometry

PubMed Central

Lowe, Ross H.; Karschner, Erin L.; Schwilke, Eugene W.; Barnes, Allan J.; Huestis, Marilyn A.

2009-01-01

A two-dimensional (2D) gas chromatography/electron impact-mass spectrometry (GC/EI-MS) method for simultaneous quantification of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) in human plasma was developed and validated. The method employs 2D capillary GC and cryofocusing for enhanced resolution and sensitivity. THC, 11-OH-THC, and THCCOOH were extracted by precipitation with acetonitrile followed by solid-phase extraction. GC separation of trimethylsilyl derivatives of analytes was accomplished with two capillary columns in series coupled via a pneumatic Deans switch system. Detection and quantification were accomplished with a bench-top single quadrupole mass spectrometer operated in electron impact-selected ion monitoring mode. Limits of quantification (LOQ) were 0.125, 0.25 and 0.125 ng/mL for THC, 11-OH-THC, and THCCOOH, respectively. Accuracy ranged from 86.0 to 113.0% for all analytes. Intra- and inter-assay precision, as percent relative standard deviation, was less than 14.1% for THC, 11-OH-THC, and THCCOOH. The method was successfully applied to quantification of THC and its 11-OH-THC and THCCOOH metabolites in plasma specimens following controlled administration of THC. PMID:17640656

Medicinal cannabis: is delta9-tetrahydrocannabinol necessary for all its effects?

PubMed

Wilkinson, J D; Whalley, B J; Baker, D; Pryce, G; Constanti, A; Gibbons, S; Williamson, E M

2003-12-01

Cannabis is under clinical investigation to assess its potential for medicinal use, but the question arises as to whether there is any advantage in using cannabis extracts compared with isolated Delta9-trans-tetrahydrocannabinol (Delta9THC), the major psychoactive component. We have compared the effect of a standardized cannabis extract (SCE) with pure Delta9THC, at matched concentrations of Delta9THC, and also with a Delta9THC-free extract (Delta9THC-free SCE), using two cannabinoid-sensitive models, a mouse model of multiple sclerosis (MS), and an in-vitro rat brain slice model of epilepsy. Whilst SCE inhibited spasticity in the mouse model of MS to a comparable level, it caused a more rapid onset of muscle relaxation, and a reduction in the time to maximum effect compared with Delta9THC alone. The Delta9THC-free extract or cannabidiol (CBD) caused no inhibition of spasticity. However, in the in-vitro epilepsy model, in which sustained epileptiform seizures were induced by the muscarinic receptor agonist oxotremorine-M in immature rat piriform cortical brain slices, SCE was a more potent and again more rapidly-acting anticonvulsant than isolated Delta9THC, but in this model, the Delta9THC-free extract also exhibited anticonvulsant activity. Cannabidiol did not inhibit seizures, nor did it modulate the activity of Delta9THC in this model. Therefore, as far as some actions of cannabis were concerned (e.g. antispasticity), Delta9THC was the active constituent, which might be modified by the presence of other components. However, for other effects (e.g. anticonvulsant properties) Delta9THC, although active, might not be necessary for the observed effect. Above all, these results demonstrated that not all of the therapeutic actions of cannabis herb might be due to the Delta9THC content.

Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

PubMed

Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

2015-02-01

Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

Disposition of smoked cannabis with high {Delta}{sup 9}-tetrahydrocannabinol content: A kinetic model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hunault, Claudine C., E-mail: claudine.hunault@rivm.n; Eijkeren, Jan C.H. van; Mensinga, Tjeert T.

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: Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3 mg, 49.1 mg, and 69.4 mg THC. Blood samples were collected over a period of 0-8 h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results: Large inter-individual variability was observed in the pharmacokinetic parameters.more » The median pharmacokinetic parameters generated by the model were C{sub max} = 175 ng/mL, T{sub max} = 14 min, and AUC{sub 0-8h} = 8150 ng x min/mL for the 69.4 mg THC dose. Median model results show an almost linear dose response relation for C{sub max}/Dose = 2.8 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 136 x 10{sup -6} min/mL. However, for increasing dose level, there was a clear decreasing trend: C{sub max}/Dose = 3.4, 2.6 and 2.5 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 157, 133 and 117 x 10{sup -6} min/mL for the 29.3, 49.1 and 69.4 mg dose, respectively. Within the restriction of 8 h of observation, the apparent terminal half life of THC was 150 min. Conclusion: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8 h after smoking cannabis with a high THC content (up to 23%).« less

Disposition of smoked cannabis with high Δ(9)-tetrahydrocannabinol content: a kinetic model.

PubMed

Hunault, Claudine C; van Eijkeren, Jan C H; Mensinga, Tjeert T; de Vries, Irma; Leenders, Marianne E C; Meulenbelt, Jan

2010-08-01

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 69mg THC). Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3mg, 49.1mg, and 69.4mg THC. Blood samples were collected over a period of 0-8h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were Cmax=175ng/mL, Tmax=14min, and AUC0-8h=8150ng×min/mL for the 69.4mg THC dose. Median model results show an almost linear dose response relation for Cmax/Dose=2.8×10(-6)/mL and AUC0-8h/Dose=136×10(-6)min/mL. However, for increasing dose level, there was a clear decreasing trend: Cmax/Dose=3.4, 2.6 and 2.5×10(-6)/mL and AUC0-8h/Dose=157, 133 and 117×10(-6)min/mL for the 29.3, 49.1 and 69.4mg dose, respectively. Within the restriction of 8h of observation, the apparent terminal half life of THC was 150min. The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8h after smoking cannabis with a high THC content (up to 23%). Copyright © 2010 Elsevier Inc. All rights reserved.

Bond energies of ThO+ and ThC+: A guided ion beam and quantum chemical investigation of the reactions of thorium cation with O2 and CO

NASA Astrophysics Data System (ADS)

Cox, Richard M.; Citir, Murat; Armentrout, P. B.; Battey, Samuel R.; Peterson, Kirk A.

2016-05-01

Kinetic energy dependent reactions of Th+ with O2 and CO are studied using a guided ion beam tandem mass spectrometer. The formation of ThO+ in the reaction of Th+ with O2 is observed to be exothermic and barrierless with a reaction efficiency at low energies of k/kLGS = 1.21 ± 0.24 similar to the efficiency observed in ion cyclotron resonance experiments. Formation of ThO+ and ThC+ in the reaction of Th+ with CO is endothermic in both cases. The kinetic energy dependent cross sections for formation of these product ions were evaluated to determine 0 K bond dissociation energies (BDEs) of D0(Th+-O) = 8.57 ± 0.14 eV and D0(Th+-C) = 4.82 ± 0.29 eV. The present value of D0 (Th+-O) is within experimental uncertainty of previously reported experimental values, whereas this is the first report of D0 (Th+-C). Both BDEs are observed to be larger than those of their transition metal congeners, TiL+, ZrL+, and HfL+ (L = O and C), believed to be a result of lanthanide contraction. Additionally, the reactions were explored by quantum chemical calculations, including a full Feller-Peterson-Dixon composite approach with correlation contributions up to coupled-cluster singles and doubles with iterative triples and quadruples (CCSDTQ) for ThC, ThC+, ThO, and ThO+, as well as more approximate CCSD with perturbative (triples) [CCSD(T)] calculations where a semi-empirical model was used to estimate spin-orbit energy contributions. Finally, the ThO+ BDE is compared to other actinide (An) oxide cation BDEs and a simple model utilizing An+ promotion energies to the reactive state is used to estimate AnO+ and AnC+ BDEs. For AnO+, this model yields predictions that are typically within experimental uncertainty and performs better than density functional theory calculations presented previously.

Unheated Cannabis sativa extracts and its major compound THC-acid have potential immuno-modulating properties not mediated by CB1 and CB2 receptor coupled pathways.

PubMed

Verhoeckx, Kitty C M; Korthout, Henrie A A J; van Meeteren-Kreikamp, A P; Ehlert, Karl A; Wang, Mei; van der Greef, Jan; Rodenburg, Richard J T; Witkamp, Renger F

2006-04-01

There is a great interest in the pharmacological properties of cannabinoid like compounds that are not linked to the adverse effects of Delta(9)-tetrahydrocannabinol (THC), e.g. psychoactive properties. The present paper describes the potential immuno-modulating activity of unheated Cannabis sativa extracts and its main non-psychoactive constituent Delta(9)-tetrahydrocanabinoid acid (THCa). By heating Cannabis extracts, THCa was shown to be converted into THC. Unheated Cannabis extract and THCa were able to inhibit the tumor necrosis factor alpha (TNF-alpha) levels in culture supernatants from U937 macrophages and peripheral blood macrophages after stimulation with LPS in a dose-dependent manner. This inhibition persisted over a longer period of time, whereas after prolonged exposure time THC and heated Cannabis extract tend to induce the TNF-alpha level. Furthermore we demonstrated that THCa and THC show distinct effects on phosphatidylcholine specific phospholipase C (PC-PLC) activity. Unheated Cannabis extract and THCa inhibit the PC-PLC activity in a dose-dependent manner, while THC induced PC-PLC activity at high concentrations. These results suggest that THCa and THC exert their immuno-modulating effects via different metabolic pathways.

Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling

PubMed Central

Yang, Hongwei; Tang, Ya-ping; Sun, Hao; Song, Yunping; Chen, Chu

2013-01-01

SUMMARY Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here we show that synaptic and cognitive impairments following repeated exposure to Δ9-tetrahydrocannabinol (Δ9-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids, in the brain. COX-2 induction by Δ9-THC is mediated via CB1 receptor-coupled G-protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks down-regulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ9-THC exposures. Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. PMID:24267894

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

PubMed

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.

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

PubMed

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 Δ 9 -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.

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

PubMed

Jamontt, J M; Molleman, A; Pertwee, R G; Parsons, M E

2010-06-01

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 Delta(9)-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. 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. 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. 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.

Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors.

PubMed

Gaffal, E; Cron, M; Glodde, N; Tüting, T

2013-08-01

∆(9) -Tetrahydrocannabinol (THC), the active constituent of Cannabis sativa, exerts its biological effects in part through the G-protein-coupled CB1 and CB2 receptors, which were initially discovered in brain and spleen tissue, respectively. However, THC also has CB1/2 receptor-independent effects. Because of its immune-inhibitory potential, THC and related cannabinoids are being considered for the treatment of inflammatory skin diseases. Here we investigated the mechanism of the anti-inflammatory activity of THC and the role of CB1 and CB2 receptors. We evaluated the impact of topically applied THC on DNFB-mediated allergic contact dermatitis in wild-type and CB1/2 receptor-deficient mice. We performed immunohistochemical analyses for infiltrating immune cells and studied the influence of THC on the interaction between T cells, keratinocytes and myeloid immune cells in vitro. Topical THC application effectively decreased contact allergic ear swelling and myeloid immune cell infiltration not only in wild-type but also in CB1/2 receptor-deficient mice. We found that THC (1) inhibited the production of IFNγ by T cells, (2) decreased the production of CCL2 and of IFNγ-induced CCL8 and CXL10 by epidermal keratinocytes and (3) thereby limited the recruitment of myeloid immune cells in vitro in a CB1/2 receptor-independent manner. Topically applied THC can effectively attenuate contact allergic inflammation by decreasing keratinocyte-derived pro-inflammatory mediators that orchestrate myeloid immune cell infiltration independent of CB1/2 receptors. This has important implications for the future development of strategies to harness cannabinoids for the treatment of inflammatory skin diseases. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tensor hypercontraction. II. Least-squares renormalization

NASA Astrophysics Data System (ADS)

Parrish, Robert M.; Hohenstein, Edward G.; Martínez, Todd J.; Sherrill, C. David

2012-12-01

The least-squares tensor hypercontraction (LS-THC) representation for the electron repulsion integral (ERI) tensor is presented. Recently, we developed the generic tensor hypercontraction (THC) ansatz, which represents the fourth-order ERI tensor as a product of five second-order tensors [E. G. Hohenstein, R. M. Parrish, and T. J. Martínez, J. Chem. Phys. 137, 044103 (2012)], 10.1063/1.4732310. Our initial algorithm for the generation of the THC factors involved a two-sided invocation of overlap-metric density fitting, followed by a PARAFAC decomposition, and is denoted PARAFAC tensor hypercontraction (PF-THC). LS-THC supersedes PF-THC by producing the THC factors through a least-squares renormalization of a spatial quadrature over the otherwise singular 1/r12 operator. Remarkably, an analytical and simple formula for the LS-THC factors exists. Using this formula, the factors may be generated with O(N^5) effort if exact integrals are decomposed, or O(N^4) effort if the decomposition is applied to density-fitted integrals, using any choice of density fitting metric. The accuracy of LS-THC is explored for a range of systems using both conventional and density-fitted integrals in the context of MP2. The grid fitting error is found to be negligible even for extremely sparse spatial quadrature grids. For the case of density-fitted integrals, the additional error incurred by the grid fitting step is generally markedly smaller than the underlying Coulomb-metric density fitting error. The present results, coupled with our previously published factorizations of MP2 and MP3, provide an efficient, robust O(N^4) approach to both methods. Moreover, LS-THC is generally applicable to many other methods in quantum chemistry.

Tensor hypercontraction. II. Least-squares renormalization.

PubMed

Parrish, Robert M; Hohenstein, Edward G; Martínez, Todd J; Sherrill, C David

2012-12-14

The least-squares tensor hypercontraction (LS-THC) representation for the electron repulsion integral (ERI) tensor is presented. Recently, we developed the generic tensor hypercontraction (THC) ansatz, which represents the fourth-order ERI tensor as a product of five second-order tensors [E. G. Hohenstein, R. M. Parrish, and T. J. Martínez, J. Chem. Phys. 137, 044103 (2012)]. Our initial algorithm for the generation of the THC factors involved a two-sided invocation of overlap-metric density fitting, followed by a PARAFAC decomposition, and is denoted PARAFAC tensor hypercontraction (PF-THC). LS-THC supersedes PF-THC by producing the THC factors through a least-squares renormalization of a spatial quadrature over the otherwise singular 1∕r(12) operator. Remarkably, an analytical and simple formula for the LS-THC factors exists. Using this formula, the factors may be generated with O(N(5)) effort if exact integrals are decomposed, or O(N(4)) effort if the decomposition is applied to density-fitted integrals, using any choice of density fitting metric. The accuracy of LS-THC is explored for a range of systems using both conventional and density-fitted integrals in the context of MP2. The grid fitting error is found to be negligible even for extremely sparse spatial quadrature grids. For the case of density-fitted integrals, the additional error incurred by the grid fitting step is generally markedly smaller than the underlying Coulomb-metric density fitting error. The present results, coupled with our previously published factorizations of MP2 and MP3, provide an efficient, robust O(N(4)) approach to both methods. Moreover, LS-THC is generally applicable to many other methods in quantum chemistry.

Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling.

PubMed

Chen, Rongqing; Zhang, Jian; Fan, Ni; Teng, Zhao-Qian; Wu, Yan; Yang, Hongwei; Tang, Ya-Ping; Sun, Hao; Song, Yunping; Chen, Chu

2013-11-21

Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ(9)-THC is mediated via CB1 receptor-coupled G protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ(9)-THC exposures. Ablation of COX-2 also eliminates Δ(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2. Copyright © 2013 Elsevier Inc. All rights reserved.

Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Sullivan, Saoirse E.; Tarling, Elizabeth J.; Bennett, Andrew J.

Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251more » (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.« less

Interactions between THC and cannabidiol in mouse models of cannabinoid activity.

PubMed

Varvel, S A; Wiley, J L; Yang, R; Bridgen, D T; Long, K; Lichtman, A H; Martin, B R

2006-06-01

Interest persists in characterizing potential interactions between Delta(9)-tetrahydocannabinol (THC) and other marijuana constituents such as cannabidiol (CBD). Such interactions may have important implications for understanding the long-term health consequences of chronic marijuana use as well as for attempts to develop therapeutic uses for THC and other CB(1) agonists. We investigated whether CBD may modulate the pharmacological effects of intravenously administered THC or inhaled marijuana smoke on hypoactivity, antinociception, catalepsy, and hypothermia, the well characterized models of cannabinoid activity. Intravenously administered CBD possessed very little activity on its own and, at a dose equal to a maximally effective dose of THC (3 mg/kg), failed to alter THC's effects on any measure. However, higher doses of CBD (ED(50)=7.4 mg/kg) dose-dependently potentiated the antinociceptive effects of a low dose of THC (0.3 mg/kg). Pretreatment with 30 mg/kg CBD, but not 3 mg/kg, significantly elevated THC blood and brain levels. No interactions between THC and CBD were observed in several variations of a marijuana smoke exposure model. Either quantities of CBD were applied directly to marijuana, CBD and THC were both applied to placebo plant material, or mice were pretreated intravenously with 30 mg/kg CBD before being exposed to marijuana smoke. As the amount of CBD found in most marijuana strains in the US is considerably less than that of THC, these results suggest that CBD concentrations relevant to what is normally found in marijuana exert very little, if any, modulatory effects on CB(1)-receptor-mediated pharmacological effects of marijuana smoke.

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

PubMed

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).

Δ(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells.

PubMed

Takeda, Shuso; Ikeda, Eriko; Su, Shengzhong; Harada, Mari; Okazaki, Hiroyuki; Yoshioka, Yasushi; Nishimura, Hajime; Ishii, Hiroyuki; Kakizoe, Kazuhiro; Taniguchi, Aya; Tokuyasu, Miki; Himeno, Taichi; Watanabe, Kazuhito; Omiecinski, Curtis J; Aramaki, Hironori

2014-12-04

We recently reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor α (PPARα) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Δ(9)-THC-treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (β and γ). Δ(9)-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the Δ(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ(9)-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ(9)-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ(9)-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ(9)-THC up-regulation of FA2H in MDA-MB-231 cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders

PubMed Central

Devinsky, Orrin; Cilio, Maria Roberta; Cross, Helen; Fernandez-Ruiz, Javier; French, Jacqueline; Hill, Charlotte; Katz, Russell; Di Marzo, Vincenzo; Jutras-Aswad, Didier; Notcutt, William George; Martinez-Orgado, Jose; Robson, Philip J.; Rohrback, Brian G.; Thiele, Elizabeth; Whalley, Benjamin; Friedman, Daniel

2015-01-01

Objective To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regards to their relevance to epilepsy and other selected neuropsychiatric disorders. Methods We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology and data from studies with animal models and human subjects. Results Cannabis has been used to treat disease since ancient times. Δ9-THC is the major psychoactive ingredient and cannabidiol (CBD) is the major non-psychoactive ingredient in cannabis. Cannabis and Δ9-THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. Psychotropic effects of Δ9-THC limit tolerability. CBD is anticonvulsant in many acute animal models but there is limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of melastatin type 8 channel; the 5-HT1a receptor; the α3 and α1 glycine receptors; and the transient receptor potential of ankyrin type 1 channel. CBD has neuroprotective and anti-inflammatory effects. CBD appears to be well tolerated in humans but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ9-THC medical marijuana have claimed efficacy, but studies were not controlled. Significance CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. PMID:24854329

Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.

PubMed

Devinsky, Orrin; Cilio, Maria Roberta; Cross, Helen; Fernandez-Ruiz, Javier; French, Jacqueline; Hill, Charlotte; Katz, Russell; Di Marzo, Vincenzo; Jutras-Aswad, Didier; Notcutt, William George; Martinez-Orgado, Jose; Robson, Philip J; Rohrback, Brian G; Thiele, Elizabeth; Whalley, Benjamin; Friedman, Daniel

2014-06-01

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ(9) -Tetrahydrocannabinol (Δ(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

Cannabinoids concentration variability in cannabis olive oil galenic preparations.

PubMed

Carcieri, Chiara; Tomasello, Cristina; Simiele, Marco; De Nicolò, Amedeo; Avataneo, Valeria; Canzoneri, Luca; Cusato, Jessica; Di Perri, Giovanni; D'Avolio, Antonio

2018-01-01

Knowledge of the exact concentration of active compounds in galenic preparations is crucial to be able to ensure their quality and to properly administer the prescribed dose. Currently, the need for titration of extracts is still debated. Considering this, together with the absence of a standard preparation method, the aim of this study was to evaluate cannabinoids concentrations variability in galenic olive oil extracts, to evaluate the interlot and interlaboratory variability in the extraction yield and in the preparation composition. Two hundred and one extracts (123 (61.2%) from Bedrocan ® , 54 (26.9%) from Bediol ® , 11 (5.5%) from Bedrolite ® , and 13 (6.5%) from mixed preparations) were analysed by liquid chromatography coupled with tandem mass spectrometry, quantifying cannabinoids (THC, CBD, THCA, CBDA and CBN) concentrations. The RSD% of THC and CBD concentrations resulted higher than 50%. Specifically for Bedrocan ® , Bediol ® , Bedrolite ® (5 g/50 ml), these were THC 82%, THC 53% and CBD 91%, THC 58% and CBD 59%, respectively. The median extraction yields were greater than 75% for all preparations. Our results highlighted a wide variability in THC and CBD concentrations that justify the need for titration and opens further questions about other pharmaceutical preparations without regulatory indication for this procedure. © 2017 Royal Pharmaceutical Society.

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

PubMed

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.

THC-MP: High performance numerical simulation of reactive transport and multiphase flow in porous media

NASA Astrophysics Data System (ADS)

Wei, Xiaohui; Li, Weishan; Tian, Hailong; Li, Hongliang; Xu, Haixiao; Xu, Tianfu

2015-07-01

The numerical simulation of multiphase flow and reactive transport in the porous media on complex subsurface problem is a computationally intensive application. To meet the increasingly computational requirements, this paper presents a parallel computing method and architecture. Derived from TOUGHREACT that is a well-established code for simulating subsurface multi-phase flow and reactive transport problems, we developed a high performance computing THC-MP based on massive parallel computer, which extends greatly on the computational capability for the original code. The domain decomposition method was applied to the coupled numerical computing procedure in the THC-MP. We designed the distributed data structure, implemented the data initialization and exchange between the computing nodes and the core solving module using the hybrid parallel iterative and direct solver. Numerical accuracy of the THC-MP was verified through a CO2 injection-induced reactive transport problem by comparing the results obtained from the parallel computing and sequential computing (original code). Execution efficiency and code scalability were examined through field scale carbon sequestration applications on the multicore cluster. The results demonstrate successfully the enhanced performance using the THC-MP on parallel computing facilities.

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

PubMed

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.

Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability

PubMed Central

Adelli, Goutham R.; Bhagav, Prakash; Taskar, Pranjal; Hingorani, Tushar; Pettaway, Sara; Gul, Waseem; ElSohly, Mahmoud A.; Repka, Michael A.; Majumdar, Soumyajit

2017-01-01

Purpose The aim of the present study was to evaluate the utility of the relatively hydrophilic Δ9-tetrahydrocannabinol (THC) prodrugs, mono and di-valine esters (THC-Val and THC-Val-Val) and the amino acid (valine)-dicarboxylic acid (hemisuccinate) ester (THC-Val-HS), with respect to ocular penetration and intraocular pressure (IOP) lowering activity. THC, timolol, and pilocarpine eye drops were used as controls. Methods THC-Val, THC-Val-Val, and THC-Val-HS were synthesized and chemically characterized. Aqueous solubility and in vitro transcorneal permeability of THC and the prodrugs, in the presence of various surfactants and cyclodextrins, were determined. Two formulations were evaluated for therapeutic activity in the α-chymotrypsin induced rabbit glaucoma model, and the results were compared against controls comprising of THC emulsion and marketed timolol maleate and pilocarpine eye drops. Results THC-Val-HS demonstrated markedly improved solubility (96-fold) and in vitro permeability compared to THC. Selected formulations containing THC-Val-HS effectively delivered THC to the anterior segment ocular tissues in the anesthetized rabbits: 62.1 ng/100 μL of aqueous humor (AH) and 51.4 ng/50 mg of iris ciliary bodies (IC) (total THC). The duration and extent of IOP lowering induced by THC-Val-HS was 1 hour longer and 10% greater, respectively, than that obtained with THC and was comparable with the pilocarpine eye drops. Timolol ophthalmic drops, however, exhibited a longer duration of activity. Both THC and THC-Val-HS were detected in the ocular tissues following multiple dosing of THC-Val-HS in conscious animals. The concentration of THC in the iris-ciliary bodies at the 60- and 120-minute time points (53 and 57.4 ng/50 mg) were significantly greater than that of THC-Val-HS (24.2 and 11.3 ng/50 mg). Moreover, at the two time points studied, the concentration of THC was observed to increase or stay relatively constant, whereas THC-Val-HS concentration decreased by at least 50%. A similar trend was observed in the retina-choroid tissues. Conclusions A combination of prodrug derivatization and formulation development approaches significantly improved the penetration of THC into the anterior segment of the eye following topical application. Enhanced ocular penetration resulted in significantly improved IOP-lowering activity. PMID:28399267

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

PubMed

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 Elsevier Inc. All rights reserved.

Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme

PubMed Central

Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María del Rosario; Molpeceres, Jesús

2013-01-01

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) – the two major ingredients of marijuana – have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1∶1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies. PMID:23349970

Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

PubMed

Hernán Pérez de la Ossa, Dolores; Lorente, Mar; Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María Del Rosario; Molpeceres, Jesús; Velasco, Guillermo; Torres-Suárez, Ana Isabel

2013-01-01

Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

Polymeric Systems for Amorphous Δ9-Tetrahydrocannabinol Produced by a Hot-Melt Method. Part II: Effect of Oxidation Mechanisms and Chemical Interactions on Stability

PubMed Central

MUNJAL, MANISH; ELSOHLY, MAHMOUD A.; REPKA, MICHAEL A.

2010-01-01

The objectives of the present research investigations were to (i) elucidate the mechanism for the oxidative degradation of Δ9-tetrahydrocannabinol (THC) in polymer matrix systems prepared by a hot-melt fabrication procedure, and (ii) study the potential for controlling these mechanisms to reduce the degradation of THC in solid dosage formulations. Various factors considered and applied included drug-excipient compatibility, use of antioxidants, cross-linking in polymeric matrices, microenvironment pH, and moisture effect. Instability of THC in polyethylene oxide (PEO)-vitamin E succinate (VES) patches was determined to be due to chemical interaction between the drug and the vitamin as well as with the atmospheric oxygen. Of the different classes and mechanisms of antioxidants studied, quenching of oxygen by reducing agents, namely, ascorbic acid was the most effective in stabilizing THC in PEO-VES matrices. Only 5.8% of the drug degraded in the ascorbic acid-containing patch as compared to the control (31.6%) after 2 months of storage at 40°C. This coupled with the cross-linking extent and adjustment of the pH microenvironment, which seemed to have an impact on the THC degradation, might be effectively utilized towards stabilization of the drug in these polymeric matrices and other pharmaceutical dosage forms. These studies are relevant to the development of a stable transmucosal matrix system for the therapeutic delivery of amorphous THC. PMID:16886199

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease.

PubMed

Carroll, C B; Zeissler, M-L; Hanemann, C O; Zajicek, J P

2012-10-01

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is neuroprotective in models of Parkinson's disease (PD). Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms. Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ⁹-THC. Differentiated SH-SY5Y neuroblastoma cells were exposed to PD-relevant toxins: 1-methyl-4-phenylpyridinium (MPP+), lactacystin and paraquat. Changes in CB1 receptor level were determined by quantitative polymerase chain reaction and Western blotting. Cannabinoids and modulatory compounds were co-administered with toxins for 48 h and the effects on cell death, viability, apoptosis and oxidative stress assessed. We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ⁹-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ⁹-THC. However, the peroxisome proliferator-activated receptor-gamma (PPARγ) antagonist T0070907 dose-dependently blocked the neuroprotective, antioxidant and anti-apoptotic effects of Δ⁹-THC, while the PPARγ agonist pioglitazone resulted in protection from MPP+-induced neurotoxicity. Furthermore, Δ⁹-THC increased PPARγ expression in MPP+-treated SH-SY5Y cells, another indicator of PPARγ activation. We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ⁹-THC that may be mediated through PPARγ activation. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

Lattice dynamics and lattice thermal conductivity of thorium dicarbide

NASA Astrophysics Data System (ADS)

Liao, Zongmeng; Huai, Ping; Qiu, Wujie; Ke, Xuezhi; Zhang, Wenqing; Zhu, Zhiyuan

2014-11-01

The elastic and thermodynamic properties of ThC2 with a monoclinic symmetry have been studied by means of density functional theory and direct force-constant method. The calculated properties including the thermal expansion, the heat capacity and the elastic constants are in a good agreement with experiment. Our results show that the vibrational property of the C2 dimer in ThC2 is similar to that of a free standing C2 dimer. This indicates that the C2 dimer in ThC2 is not strongly bonded to Th atoms. The lattice thermal conductivity for ThC2 was calculated by means of the Debye-Callaway model. As a comparison, the conductivity of ThC was also calculated. Our results show that the ThC and ThC2 contributions of the lattice thermal conductivity to the total conductivity are 29% and 17%, respectively.

Determination of cannabinoids in hemp nut products in Taiwan by HPLC-MS/MS coupled with chemometric analysis: quality evaluation and a pilot human study.

PubMed

Chang, Chih-Wei; Tung, Chun-Wei; Tsai, Chin-Chuan; Wu, Yu-Tse; Hsu, Mei-Chich

2017-06-01

Hemp nuts are mature cannabis seeds obtained after shelling and that are commonly used in traditional Chinese medicine for treating functional constipation. In this work, we screened hemp nut products, classified them, and verified the legality of consuming them. A total of 18 products were purchased from Taiwan, China, and Canada. Validated high-performance liquid chromatography with tandem mass spectrometry methods were developed for analyzing the cannabinoid (i.e., Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol) content of the products and the concentration of urinary 11-nor-9-carboxy-THC. Chemometric techniques, namely hierarchical clustering analysis (HCA) and principal component analysis (PCA), were applied for rapidly classifying 11 concentrated powder products in Taiwan. A pilot human study comprising single and multiple administrations of a product with 1.5 µg/g of THC was conducted to examine the urinary 11-nor-9-carboxy-THC concentration. Through optimization of 3 2 full factorial design, using 60% isopropanol as the extraction solvent exhibited the highest yield of cannabinoids and was applied as the optimal condition in further analysis. The results of HCA and PCA on quality evaluation were in good agreement; however, the tested products possessed distinct CBD-to-THC ratios which ranged widely from 0.1:1 to 46.8:1. Particularly, the products with CBD-to-THC ratios higher than 1:1 were the majority in Taiwan. Our data suggested that all the tested hemp nut products met the Taiwan restriction criterion of 10 µg/g of THC. We propose a usual consumption amount of hemp nut products in Taiwan would unlikely to violate the cut-off point of 15 ng/mL of urinary 11-nor-9-carboxy-THC. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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

PubMed

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.

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

PubMed Central

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

Delta-9-tetrahydrocannabinol accumulation, metabolism and cell-type-specific adverse effects in aggregating brain cell cultures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Monnet-Tschudi, Florianne; Hazekamp, Arno; Perret, Nicolas

Despite the widespread use of Cannabis as recreational drug or as medicine, little is known about its toxicity. The accumulation, metabolism and toxicity of THC were analyzed 10 days after a single treatment, and after repeated exposures during 10 days. Mixed-cell aggregate cultures of fetal rat telencephalon were used as in vitro model, as well as aggregates enriched either in neurons or in glial cells. It was found that THC accumulated preferentially in neurons, and that glia-neuron interactions decreased THC accumulation. The quantification of 11-OH-THC and of THC-COOH showed that brain aggregates were capable of THC metabolism. No cell-type differencemore » was found for the metabolite 11-OH-THC, whereas the THC-COOH content was higher in mixed-cell cultures. No cell death was found at THC concentrations of 2 {mu}M in single treatment and of 1 {mu}M and 2 {mu}M in repeated treatments. Neurons, and particularly GABAergic neurons, were most sensitive to THC. Only the GABAergic marker was affected after the single treatment, whereas the GABAergic, cholinergic and astrocytic markers were decreased after the repeated treatments. JWH 015, a CB2 receptor agonist, showed effects similar to THC, whereas ACEA, a CB1 receptor agonist, had no effect. The expression of the cytokine IL-6 was upregulated 48 h after the single treatment with 5 {mu}M of THC or JWH 015, whereas the expression of TNF-{alpha} remained unchanged. These results suggest that the adverse effects of THC were related either to THC accumulation or to cannabinoid receptor activation and associated with IL-6 upregulation.« less

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.

PubMed

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.

Co-expression of tetanus toxin fragment C in Escherichia coli with thioredoxin and its evaluation as an effective subunit vaccine candidate.

PubMed

Yu, Yun-Zhou; Gong, Zheng-Wei; Ma, Yao; Zhang, Shu-Ming; Zhu, Heng-Qi; Wang, Wen-Bing; Du, Yun; Wang, Shuang; Yu, Wei-Yuan; Sun, Zhi-Wei

2011-08-11

The receptor-binding domain of tetanus toxin (THc), which mediates the binding of the toxin to the nerve cells, is a candidate subunit vaccine against tetanus. In this study one synthetic gene encoding the THc was constructed and highly expressed in Escherichia coli by co-expression with thioredoxin (Trx). The purified THc-vaccinated mice were completely protected against an active toxin challenge in mouse models of disease and the potency of two doses of THc was comparable to that of three doses of toxoid vaccine. And a solid-phase assay showed that the anti-THc sera inhibited the binding of THc or toxoid to the ganglioside GT1b as the anti-tetanus toxoid sera. Furthermore, mice were vaccinated once or twice at four different dosages of THc and a dose-response was observed in both the antibody titer and protective efficacy with increasing dosage of THc and number of vaccinations. The data presented in the report showed that the recombinant THc expressed in E. coli is efficacious in protecting mice against challenge with tetanus toxin suggesting that the THc protein may be developed into a human subunit vaccine candidate designed for the prevention of tetanus. Copyright © 2011 Elsevier Ltd. All rights reserved.

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

40 CFR 94.304 - Compliance requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... specified in this part, except that the applicable FEL replaces the applicable THC+NOX and PM emission... life shall be unlimited. (m) Upper limits. The FELs for THC+NOX and PM for new engines certified for...—Category 1 Upper Limits for Tier 2 Family Emission Limits Subcategory liters/cylinder Model year 1 THC+NOX...

Evaluation of Prevalent Phytocannabinoids in the Acetic Acid Model of Visceral Nociception

PubMed Central

Booker, Lamont; Naidu, Pattipati S.; Razdan, Raj K.; Mahadevan, Anu; Lichtman, Aron H.

2009-01-01

Considerable preclinical research has demonstrated the efficacy of Δ9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent of Cannabis sativa, in a wide variety of animal models of pain, but few studies have examined other phytocannabinoids. Indeed, other plant-derived cannabinoids, including cannabidiol (CBD), cannabinol (CBN), and cannabichromene (CBC) elicit antinociceptive effects in some assays. In contrast, tetrahydrocannabivarin (THCV), another component of cannabis, antagonizes the pharmacological effects of Δ9-THC. These results suggest that various constituents of this plant may interact in a complex manner to modulate pain. The primary purpose of the present study was to assess the antinociceptive effects of these other prevalent phytocannabinoids in the acetic acid stretching test, a rodent visceral pain model. Of the cannabinoid compounds tested, Δ9-THC and CBN bound to the CB1 receptor and produced antinociceptive effects. The CB1 receptor antagonist, rimonabant, but not the CB2 receptor antagonist, SR144528, blocked the antinociceptive effects of both compounds. Although THCV bound to the CB1 receptor with similar affinity as Δ9-THC, it had no effects when administered alone, but antagonized the antinociceptive effects of Δ9-THC when both drugs were given in combination. Importantly, the antinociceptive effects of Δ9-THC and CBN occurred at lower doses than those necessary to produce locomotor suppression, suggesting motor dysfunction did not account for the decreases in acetic acid-induced abdominal stretching. These data raise the intriguing possibility that other constituents of cannabis can be used to modify the pharmacological effects of Δ9-THC by either eliciting antinociceptive effects (i.e., CBN) or antagonizing (i.e., THCV) the actions of Δ9-THC. PMID:19679411

DECOVALEX-THMC Task D: Long-Term Permeability/Porosity Changes inthe EDZ and Near Field due to THM and THC Processes in Volcanic andCrystaline-Bentonite Systems, Status Report October 2005

DOE Office of Scientific and Technical Information (OSTI.GOV)

Birkholzer, J.; Rutqvist, J.; Sonnenthal, E.

The DECOVALEX project is an international cooperativeproject initiated by SKI, the Swedish Nuclear Power Inspectorate, withparticipation of about 10 international organizations. The name DECOVALEXstands for DEvelopment of COupled models and their VALidation againstExperiments. The general goal of this project is to encouragemultidisciplinary interactive and cooperative research on modelingcoupled processes in geologic formations in support of the performanceassessment for underground storage of radioactive waste. Three multi-yearproject stages of DECOVALEX have been completed in the past decade,mainly focusing on coupled thermal-hydrological-mechanicalprocesses.Currently, a fourth three-year project stage of DECOVALEX isunder way, referred to as DECOVALEX-THMC. THMC stands for Thermal,Hydrological, Mechanical, and Chemical processes.more » The new project stageaims at expanding the traditional geomechanical scope of the previousDECOVALEX project stages by incorporating geochemical processes importantfor repository performance. The U.S. Department of Energy (DOE) leadsTask D of the new DECOVALEX phase, entitled "Long-termPermeability/Porosity Changes in the EDZ and Near Field due to THC andTHM Processes for Volcanic and Crystalline-Bentonite Systems." In itsleadership role for Task D, DOE coordinates and sets the direction forthe cooperative research activities of the international research teamsengaged in Task D.« less

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.

PubMed

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.

Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.

PubMed

Walentiny, D Matthew; Vann, Robert E; Wiley, Jenny L

2015-06-01

A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Δ(9)-tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC discrimination procedure. THC (5.6 mg/kg) served as a discriminative stimulus in both genotypes, with similar THC dose-response curves between groups. Anandamide fully substituted for THC in FAAH knockout, but not wildtype, mice. Conversely, the metabolically stable anandamide analog O-1812 fully substituted in both groups, but was more potent in knockouts. The CB1 receptor antagonist rimonabant dose-dependently attenuated THC generalization in both groups and anandamide substitution in FAAH knockouts. Pharmacological inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), with JZL184 resulted in full substitution for THC in FAAH knockout mice and nearly full substitution in wildtypes. Quantification of brain endocannabinoid levels revealed expected elevations in anandamide in FAAH knockout mice compared to wildtypes and equipotent dose-dependent elevations in 2-AG following JZL184 administration. Dual inhibition of FAAH and MAGL with JZL195 resulted in roughly equipotent increases in THC-appropriate responding in both groups. While the notable similarity in THC's discriminative stimulus effects across genotype suggests that the increased baseline brain anandamide levels (as seen in FAAH knockout mice) do not alter THC's subjective effects, FAAH knockout mice are more sensitive to the THC-like effects of pharmacologically induced increases in anandamide and MAGL inhibition (e.g., JZL184). Copyright © 2015 Elsevier Ltd. All rights reserved.

Anticoagulant effects of a Cannabis extract in an obese rat model.

PubMed

Coetzee, C; Levendal, R-A; van de Venter, M; Frost, C L

2007-05-01

Blood coagulation studies were conducted to determine the possible anti-/prothrombotic effect of an organic cannabis extract and the three major cannabinoids, THC, CBD and CBN. The in vitro effect of the cannabis extract on thrombin activity produced an IC50 value of 9.89 mg/ml, compared to THC at 1.79 mg/ml. It was also found that the extract, THC and CBN showed considerable inhibition of thrombin-induced clot formation in vitro with IC50 values of 600, 87 and 83 microg/ml for the extract, THC and CBN respectively. In an in vivo model used to determine clotting times of lean and obese rats treated with a cannabis extract, 50% clotting times were found to be 1.5 and 2 fold greater than their respective control groups, supporting the results obtained in the in vitro model. The study thus shows that Cannabis sativa and the cannabinoids, THC and CBN, display anticoagulant activity and may be useful in the treatment of diseases such as type 2 diabetes in which a hypercoagulable state exists.

Blockade of THC-seeking behavior and relapse in monkeys by the cannabinoid CB(1)-receptor antagonist rimonabant.

PubMed

Justinova, Zuzana; Munzar, Patrik; Panlilio, Leigh V; Yasar, Sevil; Redhi, Godfrey H; Tanda, Gianluigi; Goldberg, Steven R

2008-11-01

Accumulating evidence suggests the endocannabinoid system modulates environmental cues' ability to induce seeking of drugs, including nicotine and alcohol. However, little attention has been directed toward extending these advances to the growing problem of cannabis use disorders. Therefore, we studied intravenous self-administration of Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, using a second-order schedule of drug seeking. Squirrel monkeys' lever responses produced only a brief cue light until the end of the session, when the final response delivered THC along with the cue. When a reinstatement procedure was used to model relapse following a period of abstinence, THC-seeking behavior was robustly reinstated by the cue or by pre-session administration of THC, other cannabinoid agonists, or morphine, but not cocaine. The cannabinoid antagonist rimonabant blocked cue-induced drug seeking, THC-induced drug seeking, and the direct reinforcing effects of THC. Thus, rimonabant and related medications might be effective as treatments for cannabinoid dependence.

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

PubMed

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.

Tetrahydrocurcumin induces mesenchymal-epithelial transition and suppresses angiogenesis by targeting HIF-1α and autophagy in human osteosarcoma

PubMed Central

Zhang, Yan; Liu, Ying; Zou, Jilong; Yan, Lixin; Du, Wei; Zhang, Yafeng; Sun, Hanliang; Lu, Peng; Geng, Shuo; Gu, Rui; Zhang, Hongyue; Bi, Zhenggang

2017-01-01

Human osteosarcoma is considered a malignant tumor with poor prognosis that readily metastasizes. Tetrahydrocurcumin (THC) has been reported to have anti-tumor activity in numerous tumors. In addition, hypoxia-inducible factor-1α (HIF-1α) has been demonstrated to be associated with tumor metastasis by regulating epithelial-mesenchymal transition (EMT). However, the role of THC in osteosarcoma remains uncertain. Therefore, this study aimed to elucidate the potential mechanisms. We found that THC significantly reduced the growth of osteosarcoma cells and suppressed migration and invasion, as tested in a nude mouse lung metastasis model. Additionally, the mesenchymal-epithelial transition (MET) process was facilitated by THC. Mechanistically, our study showed that HIF-1α had a pivotal role in the anti-metastatic effect of THC. Importantly, HIF-1α expression was downregulated by THC by inhibiting Akt/mTOR and p38 MAPK pathways. Moreover, THC exhibited a remarkable inhibitory effect on HIF-1α expression and angiogenesis under hypoxic conditions. Furthermore, THC activated autophagy and induced MET and suppressed angiogenesis in a HIF-1α-related manner. Taken together, our findings suggest that THC suppresses metastasis and invasion and this may be associated with HIF-1α and autophagy, which would potentially provide therapeutic strategies for human osteosarcoma. PMID:29207631

Decarboxylation of Δ 9-tetrahydrocannabinol: Kinetics and molecular modeling

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

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.

PubMed

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 molar ratio of main active to inactive cannabinoids, greater than 10 was found to correlate with a strong feeling of intoxication. It also matched with a significant decrease in the willingness to drive, and it matched also with a significant impairment in tracking performances. The mathematic model II proposed by Huestis et al. (1992) provided at best a rough estimate of the time of oral administration with 27% of actual values being out of range of the 95% confidence interval. The sum of THC and 11-OH-THC blood concentrations provided a better estimate of impairment than THC alone. This controlled clinical study points out the negative influence on fitness to drive after medium or high dose oral THC or dronabinol.

The yin and yang of cannabis-induced psychosis: the actions of Δ(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia.

PubMed

Arnold, J C; Boucher, A A; Karl, T

2012-01-01

The link between cannabis and psychosis has often been debated with polarized views on the topic. There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms. In the present review we will first focus on how traditional rodent models of schizophrenia have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. We will also review novel rodent models used to address genetic vulnerability to cannabis-induced schizophrenia and show that specific genes are being uncovered that modulate cannabinoid action (e.g. the schizophrenia susceptibility gene neuregulin 1). We will also review rodent studies that have addressed interactions between THC and CBD. These animal studies underscore great complexity with some studies showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC. Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors or that CBD inhibits proteins that regulate THC disposition and metabolism (e.g. the ABC transporter, P-glycoprotein).

Challenges to modeling the Sun-Earth System: A Workshop Summary

NASA Technical Reports Server (NTRS)

Spann, James F.

2006-01-01

This special issue of the Journal of' Atmospheric and Solar-Terrestrial Physics is a compilation of 23 papers presented at The 2004 Huntsville Modeling Workshop: Challenges to Modeling thc San-Earth System held in Huntsville, AB on October 18-22, 2004. The title of the workshop appropriately captures the theme of what was presented and discussed by the 120 participants. Currently, end-to-end modeling of the Sun-Earth system is a major goal of the National Space Weather and NASA living with a star (LWS) programs. While profound advances have been made in modeling isolated regions of the Sun-Earth system, minimal progress has been achieved in modeling the end-to-end system. The transfer of mass, energy and momentum through the coupled Sun-Earth system spans a wide range of scales inn time and space. The uncertainty in the underlying physics responsible for coupling contiguous regions of the Sun-Earth system is recognized as a significant barrier to progress

Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Δ(9) -tetrahydrocannabinol in Sprague-Dawley rats.

PubMed

Taffe, Michael A; Creehan, Kevin M; Vandewater, Sophia A

2015-04-01

Growing evidence shows cannabidiol (CBD) modulates some of the effects of Δ(9) -tetrahydrocannabinol (THC). CBD is a constituent of some strains of recreational cannabis but its content is highly variable. High CBD strains may have less memory-impairing effects than low-CBD strains and CBD can reverse behavioural effects of THC in monkeys. CBD/THC interactions in rodents are more complicated as CBD can attenuate or exacerbate the effects of THC. This study was undertaken to determine if CBD could reverse hypothermia or hypolocomotor effects caused by THC in rats. Male Sprague-Dawley rats were prepared with radiotelemetry devices and then given doses of THC (10-30 mg·kg(-1) , i.p.) with or without CBD. Experiments determined the effect of simultaneous or 30 min pretreatment with CBD in a 1:1 ratio with THC, as well as the effect of CBD in a 3:1 ratio. Additional experiments determined the effects of pretreatment with the cannabinoid CB1 receptor antagonist SR141716 (rimonabant). CBD did not attentuate THC-induced hypothermia or hypolocomotion but instead exaggerated these effects in some conditions. The antagonist SR141716 blocked hypolocomotor effects of THC for the first hour after injection and the hypothermia for 6 h; thus validating the pharmacological model. There is no evidence from this study that elevated CBD content in cannabis could provide protection from the physiological effects of THC, in rats. © 2014 The British Pharmacological Society.

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2013 CFR

2013-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2011 CFR

2011-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2012 CFR

2012-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2014 CFR

2014-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

40 CFR 94.306 - Certification.

Code of Federal Regulations, 2010 CFR

2010-07-01

... declarations are required for each pollutant (THC+NOX and PM). (2) Declare FELs for each engine family... model year. Manufacturers that have certified engine families with credit balances for THC+NOX and/or PM...

Effects of Δ9-THC and cannabidiol vapor inhalation in male and female rats.

PubMed

Javadi-Paydar, Mehrak; Nguyen, Jacques D; Kerr, Tony M; Grant, Yanabel; Vandewater, Sophia A; Cole, Maury; Taffe, Michael A

2018-06-16

Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection; however, most human use is via smoke inhalation and, increasingly, vapor inhalation. To compare thermoregulatory and locomotor responses to inhaled ∆ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination using an e-cigarette-based model in male and female rats METHODS: Male and female Wistar rats were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/mL) and the CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 min). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation. Plasma samples obtained following inhalation in different groups of rats were compared for THC content. THC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity, and tail-withdrawal responses to THC did not differ between estrus and diestrus. CBD inhalation alone induced modest hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex. Plasma THC varied with the concentration in the PG vehicle but did not differ across rat sex. In summary, the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. This confirms the efficacy of the e-cigarette-based method of THC delivery in female rats.

Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R.; Liberzon, Israel; Phan, K. Luan

2013-01-01

Pre-extinction administration of ∆9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely involves via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 hours after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders. PMID:24055595

Cannabinoid facilitation of fear extinction memory recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Sripada, Chandra S.; Abelson, James L.; Liberzon, Israel; Milad, Mohammed R.; Phan, K. Luan

2012-01-01

A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 hours prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 hours after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 hours after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. PMID:22796109

Single and combined effects of Δ9 -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

PubMed

King, Kirsten M; Myers, Alyssa M; Soroka-Monzo, Ariele J; Tuma, Ronald F; Tallarida, Ronald J; Walker, Ellen A; Ward, Sara Jane

2017-09-01

The non-psychoactive phytocannabinoid cannabidiol (CBD) can affect the pharmacological effects of Δ 9 -tetrahydrocannabinol (THC). We tested the possible synergy between CBD and THC in decreasing mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain. We also tested the effects of CBD on oxaliplatin- and vincristine-induced mechanical sensitivity. Paclitaxel-treated mice (8.0 mg·kg -1 i.p., days 1, 3, 5 and 7) were pretreated with CBD (0.625-20.0 mg·kg -1 i.p.), THC (0.625-20.0 mg·kg -1 i.p.) or CBD + THC (0.04 + 0.04-20.0 + 20.0 mg·kg -1 i.p.), and mechanical sensitivity was assessed on days 9, 14 and 21. Oxaliplatin-treated (6.0 mg·kg -1 i.p., day 1) or vincristine-treated mice (0.1 mg·kg -1 i.p. days 1-7) were pretreated with CBD (1.25-10.0 mg·kg -1 i.p.), THC (10.0 mg·kg -1 i.p.) or THC + CBD (0.16 mg·kg -1 THC + 0.16 mg·kg -1 CBD i.p.). Both CBD and THC alone attenuated mechanical allodynia in mice treated with paclitaxel. Very low ineffective doses of CBD and THC were synergistic when given in combination. CBD also attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity, while THC significantly attenuated vincristine- but not oxaliplatin-induced mechanical sensitivity. The low dose combination significantly attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity. CBD may be potent and effective at preventing the development of chemotherapy-induced peripheral neuropathy, and its clinical use may be enhanced by co-administration of low doses of THC. These treatment strategies would increase the therapeutic window of cannabis-based pharmacotherapies. © 2017 The British Pharmacological Society.

Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Ù9-tetrahydrocannabinol in Sprague-Dawley rats

PubMed Central

Taffe, Michael A; Creehan, Kevin M; Vandewater, Sophia A

2015-01-01

Background and Purpose Growing evidence shows cannabidiol (CBD) modulates some of the effects of Δ9-tetrahydrocannabinol (THC). CBD is a constituent of some strains of recreational cannabis but its content is highly variable. High CBD strains may have less memory-impairing effects than low-CBD strains and CBD can reverse behavioural effects of THC in monkeys. CBD/THC interactions in rodents are more complicated as CBD can attenuate or exacerbate the effects of THC. This study was undertaken to determine if CBD could reverse hypothermia or hypolocomotor effects caused by THC in rats. Experimental Approaches Male Sprague-Dawley rats were prepared with radiotelemetry devices and then given doses of THC (10–30 mg·kg−1, i.p.) with or without CBD. Experiments determined the effect of simultaneous or 30 min pretreatment with CBD in a 1:1 ratio with THC, as well as the effect of CBD in a 3:1 ratio. Additional experiments determined the effects of pretreatment with the cannabinoid CB1 receptor antagonist SR141716 (rimonabant). Key Results CBD did not attentuate THC-induced hypothermia or hypolocomotion but instead exaggerated these effects in some conditions. The antagonist SR141716 blocked hypolocomotor effects of THC for the first hour after injection and the hypothermia for 6 h; thus validating the pharmacological model. Conclusions and Implications There is no evidence from this study that elevated CBD content in cannabis could provide protection from the physiological effects of THC, in rats. PMID:25425111

A cost-effectiveness model for the use of a cannabis-derived oromucosal spray for the treatment of spasticity in multiple sclerosis.

PubMed

Gras, Adrien; Broughton, Julie

2016-12-01

Severity of spasticity in multiple sclerosis (MS) directly correlates with the level and cost of care required. This study assessed whether a tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray for treatment of moderate-severe MS spasticity is a cost-effective use of healthcare resources in Wales. A Markov model was developed to compare THC/CBD plus standard of care (SoC) treatments with SoC alone. At 30 years, total incremental cost for THC/CBD plus SoC treatment was estimated at £3,836/patient (ICER: £10,891/quality-adjusted life year [QALY]). Hospital admission costs had the greatest effect on the base case ICER. Inclusion of carer cost led to incremental cost of -£33,609/patient (ICER: -£95,423/QALY). The THC/CBD spray was found to be cost-effective for the treatment of spasticity in MS, and dominant, if home carer costs were included. Use of THC/CBD has the potential to generate cost savings by significantly improving the symptoms of moderate to severe MS spasticity.

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

PubMed

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 influence behavioral outcomes. Conclusion: These data suggest that chronic exposure to THC during adolescence leads to some of the behavioral abnormalities common in schizophrenia. Interestingly, CBD appeared to antagonize all THC-induced behavioral abnormalities. These findings support the hypothesis that adolescent THC use can impart long-term behavioral deficits; however, cotreatment with CBD prevents these deficits.

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

PubMed Central

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 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 influence behavioral outcomes. Conclusion: These data suggest that chronic exposure to THC during adolescence leads to some of the behavioral abnormalities common in schizophrenia. Interestingly, CBD appeared to antagonize all THC-induced behavioral abnormalities. These findings support the hypothesis that adolescent THC use can impart long-term behavioral deficits; however, cotreatment with CBD prevents these deficits. PMID:29098186

Intravenous administration of cannabis and lethal anaphylaxis.

PubMed

Gilbert, John D; Grabowski, Marc; Byard, Roger W

2017-04-01

Cannabis allergy appears to be increasing. A 33-year-old woman is reported who collapsed and died shortly after injecting herself with a cannabis solution prepared by pouring boiling water onto plant material. There were no significant findings at autopsy, except for a single recent venepuncture wound in the left cubital fossa. Toxicological examination of the blood revealed low levels of methylamphetamine and amphetamine with tetrahydrocannabinol (Δ 9 -THC) and 11-nor-9-carboxy-Δ 9 -THC, and no opiates. The syringe used by the decedent contained Δ 9 -THC. Serum tryptase levels were markedly elevated (>200 µg/L; N < 12 µg/L). This finding coupled with the sudden collapse after injecting an aqueous extract of cannabis indicated a likely anaphylactic or anaphylactoid reaction to the extract. Cannabis allergy may occur following handling, inhalation, swallowing or injecting Cannabis sativa plants or their products. The possibility of an allergic reaction should therefore be considered at autopsy in deaths where there has been recent contact with cannabis.

Behavioural and biochemical evidence for signs of abstinence in mice chronically treated with Δ-9-tetrahydrocannabinol

PubMed Central

Hutcheson, Daniel M; Th. Tzavara, Eleni; Smadja, Claire; Valjent, Emmanuel; Roques, Bernard P; Hanoune, Jacques; Maldonado, Rafael

1998-01-01

Tolerance and dependence induced by chronic Δ-9-tetrahydrocannabinol (THC) administration were investigated in mice. The effects on body weight, analgesia and hypothermia were measured during 6 days of treatment (10 or 20 mg kg−1 THC twice daily). A rapid tolerance to the acute effects was observed from the second THC administration.The selective CB-1 receptor antagonist SR 141716A (10 mg kg−1) was administered at the end of the treatment, and somatic and vegetative manifestations of abstinence were evaluated. SR 141716A administration precipitated several somatic signs that included wet dog shakes, frontpaw tremor, ataxia, hunched posture, tremor, ptosis, piloerection, decreased locomotor activity and mastication, which can be interpreted as being part of a withdrawal syndrome.Brains were removed immediately after the behavioural measures and assayed for adenylyl cyclase activity. An increase in basal, forskolin and calcium/calmodulin stimulated adenylyl cyclase activities was specifically observed in the cerebellum of these mice.The motivational effects of THC administration and withdrawal were evaluated by using the place conditioning paradigm. No conditioned change in preference to withdrawal associated environment was observed. In contrast, a conditioned place aversion was produced by the repeated pairing of THC (20 mg kg−1), without observing place preference at any of the doses used.This study constitutes a clear behavioural and biochemical model of physical THC withdrawal with no motivational aversive consequences. This model permits an easy quantification of THC abstinence in mice and can be useful for the elucidation of the molecular mechanisms involved in cannabinoid dependence. PMID:9884086

Circulation and oxygen cycling in the Mediterranean Sea: Sensitivity to future climate change

NASA Astrophysics Data System (ADS)

Powley, Helen R.; Krom, Michael D.; Van Cappellen, Philippe

2016-11-01

Climate change is expected to increase temperatures and decrease precipitation in the Mediterranean Sea (MS) basin, causing substantial changes in the thermohaline circulation (THC) of both the Western Mediterranean Sea (WMS) and Eastern Mediterranean Sea (EMS). The exact nature of future circulation changes remains highly uncertain, however, with forecasts varying from a weakening to a strengthening of the THC. Here we assess the sensitivity of dissolved oxygen (O2) distributions in the WMS and EMS to THC changes using a mass balance model, which represents the exchanges of O2 between surface, intermediate, and deep water reservoirs, and through the Straits of Sicily and Gibraltar. Perturbations spanning the ranges in O2 solubility, aerobic respiration kinetics, and THC changes projected for the year 2100 are imposed to the O2 model. In all scenarios tested, the entire MS remains fully oxygenated after 100 years; depending on the THC regime, average deep water O2 concentrations fall in the ranges 151-205 and 160-219 µM in the WMS and EMS, respectively. On longer timescales (>1000 years), the scenario with the largest (>74%) decline in deep water formation rate leads to deep water hypoxia in the EMS but, even then, the WMS deep water remains oxygenated. In addition, a weakening of THC may result in a negative feedback on O2 consumption as supply of labile dissolved organic carbon to deep water decreases. Thus, it appears unlikely that climate-driven changes in THC will cause severe O2 depletion of the deep water masses of the MS in the foreseeable future.

Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.

PubMed

de Salas-Quiroga, Adán; Díaz-Alonso, Javier; García-Rincón, Daniel; Remmers, Floortje; Vega, David; Gómez-Cañas, María; Lutz, Beat; Guzmán, Manuel; Galve-Roperh, Ismael

2015-11-03

The CB1 cannabinoid receptor, the main target of Δ(9)-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling.

40 CFR 86.097-9 - Emission standards for 1997 and later model year light-duty trucks.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO NOX PM Gasoline 0-3750 0... LVW (lbs) THC 1 NMHC THCE 1 NMHCE CO NOX PM Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10 Gasoline 3751-5750...—Intermediate Useful Life Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO...

Cryosphere-hydrosphere interactions: numerical modeling using the Regional Ocean Modeling System (ROMS) at different scales

NASA Astrophysics Data System (ADS)

Bergamasco, A.; Budgell, W. P.; Carniel, S.; Sclavo, M.

2005-03-01

Conveyor belt circulation controls global climate through heat and water fluxes with atmosphere and from tropical to polar regions and vice versa. This circulation, commonly referred to as thermohaline circulation (THC), seems to have millennium time scale and nowadays--a non-glacial period--appears to be as rather stable. However, concern is raised by the buildup of CO2 and other greenhouse gases in the atmosphere (IPCC, Third assessment report: Climate Change 2001. A contribution of working group I, II and III to the Third Assessment Report of the Intergovernmental Panel on Climate Change (Cambridge Univ. Press, UK) 2001, http://www.ipcc.ch) as these may affect the THC conveyor paths. Since it is widely recognized that dense-water formation sites act as primary sources in strengthening quasi-stable THC paths (Stommel H., Tellus131961224), in order to simulate properly the consequences of such scenarios a better understanding of these oceanic processes is needed. To successfully model these processes, air-sea-ice-integrated modelling approaches are often required. Here we focus on two polar regions using the Regional Ocean Modeling System (ROMS). In the first region investigated, the North Atlantic-Arctic, where open-ocean deep convection and open-sea ice formation and dispersion under the intense air-sea interactions are the major engines, we use a new version of the coupled hydrodynamic-ice ROMS model. The second area belongs to the Antarctica region inside the Southern Ocean, where brine rejections during ice formation inside shelf seas origin dense water that, flowing along the continental slope, overflow becoming eventually abyssal waters. Results show how nowadays integrated-modelling tasks have become more and more feasible and effective; numerical simulations dealing with large computational domains or challenging different climate scenarios can be run on multi-processors platforms and on systems like LINUX clusters, made of the same hardware as PCs, and codes have been accordingly modified.This relevant numerical help coming from the computer science can now allow scientists to devote larger attention in the efforts of understanding the deep mechanisms of such complex processes.

Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model

PubMed Central

Wray, Louise; Stott, Colin; Jones, Nicholas; Wright, Stephen

2017-01-01

Abstract Introduction: Cannabidiol (CBD) can convert to Δ9-tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo. Materials and Methods: Synthetic CBD (100 mg/mL) was administered orally in a sesame oil formulation twice daily to minipigs (N=3) in 15 mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 h after morning doses on Days 1 and 5. Six hours after the final dose on Day 5, the animals were euthanized, and samples of gastrointestinal (GI) tract contents were obtained. Liquid chromatography with tandem mass spectrometry analysis determined CBD, THC, and 11-hydroxy-THC (11-OH-THC) concentrations. Lower limits of quantification: plasma CBD=1 ng/mL, plasma THC and 11-OH-THC=0.5 ng/mL, GI tract CBD=2 ng/mL, and GI tract THC and 11-OH-THC=1 ng/mL. Results: THC and 11-OH-THC were undetectable in all plasma samples. Maximum plasma concentrations (Cmax) of CBD were observed between 1 and 4 h on Days 1 and 5. CBD was present in plasma 6 h after administration on Days 1 (mean 33.6 ng/mL) and 5 (mean 98.8 ng/mL). Mean Cmax CBD values, 328 ng/mL (Day 1) and 259 ng/mL (Day 5), were within range of those achieved in clinical studies. Mean CBD exposure over 6 h was similar on Days 1 (921 h·ng/mL) and 5 (881 h·ng/mL). THC and 11-OH-THC were not detected in all GI tract samples. Mean CBD concentrations reached 84,500 ng/mL in the stomach and 43,900 ng/mL in the small intestine. Conclusions: Findings of the present study show that orally dosed CBD, yielding clinically relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function. PMID:29285522

Cannabidiol Does Not Convert to Δ9-Tetrahydrocannabinol in an In Vivo Animal Model.

PubMed

Wray, Louise; Stott, Colin; Jones, Nicholas; Wright, Stephen

2017-01-01

Introduction: Cannabidiol (CBD) can convert to Δ 9 -tetrahydrocannabinol (THC) in vitro with prolonged exposure to simulated gastric fluid; however, in vitro conditions may not be representative of the in vivo gut environment. Using the minipig, we investigated whether enteral CBD converts to THC in vivo . Materials and Methods: Synthetic CBD (100 mg/mL) was administered orally in a sesame oil formulation twice daily to minipigs ( N =3) in 15 mg/kg doses for 5 consecutive days. Blood samples were taken before and 1, 2, 4, and 6 h after morning doses on Days 1 and 5. Six hours after the final dose on Day 5, the animals were euthanized, and samples of gastrointestinal (GI) tract contents were obtained. Liquid chromatography with tandem mass spectrometry analysis determined CBD, THC, and 11-hydroxy-THC (11-OH-THC) concentrations. Lower limits of quantification: plasma CBD=1 ng/mL, plasma THC and 11-OH-THC=0.5 ng/mL, GI tract CBD=2 ng/mL, and GI tract THC and 11-OH-THC=1 ng/mL. Results: THC and 11-OH-THC were undetectable in all plasma samples. Maximum plasma concentrations ( C max ) of CBD were observed between 1 and 4 h on Days 1 and 5. CBD was present in plasma 6 h after administration on Days 1 (mean 33.6 ng/mL) and 5 (mean 98.8 ng/mL). Mean C max CBD values, 328 ng/mL (Day 1) and 259 ng/mL (Day 5), were within range of those achieved in clinical studies. Mean CBD exposure over 6 h was similar on Days 1 (921 h·ng/mL) and 5 (881 h·ng/mL). THC and 11-OH-THC were not detected in all GI tract samples. Mean CBD concentrations reached 84,500 ng/mL in the stomach and 43,900 ng/mL in the small intestine. Conclusions: Findings of the present study show that orally dosed CBD, yielding clinically relevant plasma exposures, does not convert to THC in the minipig, a species predictive of human GI tract function.

40 CFR 86.709-99 - In-use emission standards for 1999 and later model year light-duty trucks.

Code of Federal Regulations, 2012 CFR

2012-07-01

...—Intermediate Useful Life 1 Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO... Fuel LVW (lbs) THC 2 NMHC 1 THCE 2 NMHCE 1 CO 1 NOX 1 PM 1 Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10... 1 Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.709-99 - In-use emission standards for 1999 and later model year light-duty trucks.

Code of Federal Regulations, 2011 CFR

2011-07-01

...—Intermediate Useful Life 1 Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO... Fuel LVW (lbs) THC 2 NMHC 1 THCE 2 NMHCE 1 CO 1 NOX 1 PM 1 Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10... 1 Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.709-99 - In-use emission standards for 1999 and later model year light-duty trucks.

Code of Federal Regulations, 2013 CFR

2013-07-01

...—Intermediate Useful Life 1 Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO... Fuel LVW (lbs) THC 2 NMHC 1 THCE 2 NMHCE 1 CO 1 NOX 1 PM 1 Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10... 1 Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.709-99 - In-use emission standards for 1999 and later model year light-duty trucks.

Code of Federal Regulations, 2010 CFR

2010-07-01

...—Intermediate Useful Life 1 Standards (g/mi) for Light Light-Duty Trucks Fuel LVW (lbs) THC NMHC THCE NMHCE CO... Fuel LVW (lbs) THC 2 NMHC 1 THCE 2 NMHCE 1 CO 1 NOX 1 PM 1 Gasoline 0-3750 0.80 0.31 4.2 0.6 0.10... 1 Standards (g/mi) for Heavy Light-Duty Trucks Fuel ALVW (lbs) THC NMHC THCE NMHCE CO NOX PM...

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

PubMed

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 and human cannabinoid studies may be related to pharmacokinetic differences associated with route of administration. Copyright © 2014 Elsevier Inc. All rights reserved.

SWCX Emission from the Helium Focusing Cone - Model to Data Comparison

NASA Technical Reports Server (NTRS)

Koutroumpa, D.; Collier, M. R.; Kuntz, K. D.; Lallement, R.; Snowden, Steven L.

2009-01-01

A model for heliospheric solar wind charge exchange (SWCX) X-ray emission is applied to a series of XMM-Newton observations of the interplanetary focusing cone of interstellar helium. The X-ray data are from three coupled observations of the South Ecliptic Pole (SEP, to observe the cone) and the Hubble Deep Field-North (HDFN. to monitor global variations of the SWCX emission due to variations in the solar wind) from the period 24 November to 15 December 2003. There is good qualitative agreement between the model predictions and thc data with the maximum SWCX flux observed at an ecliptic longitude of approx. 72deg, consistent with the central longitude of the He cone. We observe a total excess of 2.1 +/- 1.3 LU in the O VII line and 2.0 +/- 0.9 LU in the 0 VIII line. However. the SWCX emission model, which was adjusted for solar wind conditions appropriate for late 2003, predicts an excess from the He cone of only 0.5 LU and 0.2 LU, respectively, in the O VII and O VIII lines. We discuss thc model to data comparison and provide possible explanations for the discrepancies. We also qualitatively reexamine our SWCX nocicl predictions in the 1/4 keV band with data from the ROSAT All-Sky Survey towards the North and South Ecliptic Poles, when the He cone was probably first detected in soft X-rays.

Validated method for the simultaneous determination of Delta9-THC and Delta9-THC-COOH in oral fluid, urine and whole blood using solid-phase extraction and liquid chromatography-mass spectrometry with electrospray ionization.

PubMed

Teixeira, Helena; Verstraete, Alain; Proença, Paula; Corte-Real, Francisco; Monsanto, Paula; Vieira, Duarte Nuno

2007-08-06

A fully validated, sensitive and specific method for the extraction and quantification of Delta(9)-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-Delta(9)-THC (THC-COOH) and for the detection of 11-hydroxy-Delta(9)-THC (11-OH THC) in oral fluid, urine and whole blood is presented. Solid-phase extraction and liquid chromatography-mass spectrometry (LC-MS) technique were used, with electrospray ionization. Three ions were monitored for THC and THC-COOH and two for 11-OH THC. The compounds were quantified by selected ion recording of m/z 315.31, 329.18 and 343.16 for THC, 11-OH THC and THC-COOH, respectively, and m/z 318.27 and 346.26 for the deuterated internal standards, THC-d(3) and THC-COOH-d(3), respectively. The method proved to be precise for THC and THC-COOH both in terms of intra-day and inter-day analysis, with intra-day coefficients of variation (CV) less than 6.3, 6.6 and 6.5% for THC in saliva, urine and blood, respectively, and 6.8 and 7.7% for THC-COOH in urine and blood, respectively. Day-to-day CVs were less than 3.5, 4.9 and 11.3% for THC in saliva, urine and blood, respectively, and 6.2 and 6.4% for THC-COOH in urine and blood, respectively. Limits of detection (LOD) were 2 ng/mL for THC in oral fluid and 0.5 ng/mL for THC and THC-COOH and 20 ng/mL for 11-OH THC, in urine and blood. Calibration curves showed a linear relationship for THC and THC-COOH in all samples (r(2)>0.999) within the range investigated. The procedure presented here has high specificity, selectivity and sensitivity. It can be regarded as an alternative method to GC-MS for the confirmation of positive immunoassay test results, and can be used as a suitable analytical tool for the quantification of THC and THC-COOH in oral fluid, urine and/or blood samples.

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

PubMed Central

Lanfumey, Laurence; Cordomí, Arnau; Pastor, Antoni; de La Torre, Rafael; Gasperini, Paola; Navarro, Gemma; Howell, Lesley A.; Pardo, Leonardo; Lluís, Carmen; Canela, Enric I.; McCormick, Peter J.; Maldonado, Rafael; Robledo, Patricia

2015-01-01

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. PMID:26158621

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

PubMed

Viñals, Xavier; Moreno, Estefanía; Lanfumey, Laurence; Cordomí, Arnau; Pastor, Antoni; de La Torre, Rafael; Gasperini, Paola; Navarro, Gemma; Howell, Lesley A; Pardo, Leonardo; Lluís, Carmen; Canela, Enric I; McCormick, Peter J; Maldonado, Rafael; Robledo, Patricia

2015-07-01

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.

Interface COMSOL-PHREEQC (iCP), an efficient numerical framework for the solution of coupled multiphysics and geochemistry

NASA Astrophysics Data System (ADS)

Nardi, Albert; Idiart, Andrés; Trinchero, Paolo; de Vries, Luis Manuel; Molinero, Jorge

2014-08-01

This paper presents the development, verification and application of an efficient interface, denoted as iCP, which couples two standalone simulation programs: the general purpose Finite Element framework COMSOL Multiphysics® and the geochemical simulator PHREEQC. The main goal of the interface is to maximize the synergies between the aforementioned codes, providing a numerical platform that can efficiently simulate a wide number of multiphysics problems coupled with geochemistry. iCP is written in Java and uses the IPhreeqc C++ dynamic library and the COMSOL Java-API. Given the large computational requirements of the aforementioned coupled models, special emphasis has been placed on numerical robustness and efficiency. To this end, the geochemical reactions are solved in parallel by balancing the computational load over multiple threads. First, a benchmark exercise is used to test the reliability of iCP regarding flow and reactive transport. Then, a large scale thermo-hydro-chemical (THC) problem is solved to show the code capabilities. The results of the verification exercise are successfully compared with those obtained using PHREEQC and the application case demonstrates the scalability of a large scale model, at least up to 32 threads.

BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction.

PubMed

Segal-Gavish, Hadar; Gazit, Neta; Barhum, Yael; Ben-Zur, Tali; Taler, Michal; Hornfeld, Shay Henry; Gil-Ad, Irit; Weizman, Abraham; Slutsky, Inna; Niwa, Minae; Kamiya, Atsushi; Sawa, Akira; Offen, Daniel; Barzilay, Ran

2017-07-01

Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence.

PubMed

Milman, Garry; Bergamaschi, Mateus M; Lee, Dayong; Mendu, Damodara R; Barnes, Allan J; Vandrey, Ryan; Huestis, Marilyn A

2014-04-01

Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic, daily cannabis smokers who received high-dose oral THC pharmacotherapy and later a smoked cannabis challenge. Eleven daily cannabis smokers received 0, 30, 60, or 120 mg/d THC for four 5-day medication sessions, each separated by 9 days of ad libitum cannabis smoking. On the fifth day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the first and fifth days was quantified by two-dimensional gas chromatography mass spectrometer for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5-100 for THC, 1-50 for 11-OH-THC, and 0.5-200 for THCCOOH. During placebo dosing, THC, 11-OH-THC, and THCCOOH concentrations consistently decreased, whereas all cannabinoids increased dose dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during the 60- and 120-mg/d doses, and THCCOOH increased significantly only during the 120-mg/d dose. THC, 11-OH-THC, and THCCOOH concentrations peaked within 0.25 hours after cannabis smoking, except after 120 mg/d THC when THCCOOH peaked 0.5 hours before smoking. The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 hour, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 hours after overnight oral dronabinol abstinence but cannot distinguish oral THC dosing from the smoked cannabis intake.

Plasma Cannabinoid Concentrations during Dronabinol Pharmacotherapy for Cannabis Dependence

PubMed Central

Milman, Garry; Bergamaschi, Mateus M.; Lee, Dayong; Mendu, Damodara R.; Barnes, Allan J.; Vandrey, Ryan; Huestis, Marilyn A.

2013-01-01

Background Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic daily cannabis smokers who received high-dose oral THC pharmacotherapy and later, a smoked cannabis challenge. Methods 11 daily cannabis smokers received 0, 30, 60, or 120 mg/day THC for four 5-day medication sessions, each separated by 9-days of ad-libitum cannabis smoking. On the 5th day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the 1st and 5th days was quantified by GC-GC-MS for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5–100 for THC, 1–50 11-OH-THC, and 0.5–200 THCCOOH. Results During placebo dosing, THC, 11-OH-THC and THCCOOH concentrations consistently decreased, while all cannabinoids increased dose-dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during 60 and 120 mg/day doses, and THCCOOH increased significantly only during the 120 mg/day dose. THC and 11-OH-THC, and THCCOOH concentrations peaked within 0.25 h after cannabis smoking, except after 120 mg/day THC when THCCOOH peaked 0.5 h before smoking. Conclusions The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 h, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 h after overnight oral dronabinol abstinence, but cannot distinguish oral THC dosing from smoked cannabis intake. PMID:24067260

International Collaboration Activities on Engineered Barrier Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jove-Colon, Carlos F.

The Used Fuel Disposition Campaign (UFDC) within the DOE Fuel Cycle Technologies (FCT) program has been engaging in international collaborations between repository R&D programs for high-level waste (HLW) disposal to leverage on gathered knowledge and laboratory/field data of near- and far-field processes from experiments at underground research laboratories (URL). Heater test experiments at URLs provide a unique opportunity to mimetically study the thermal effects of heat-generating nuclear waste in subsurface repository environments. Various configurations of these experiments have been carried out at various URLs according to the disposal design concepts of the hosting country repository program. The FEBEX (Full-scale Engineeredmore » Barrier Experiment in Crystalline Host Rock) project is a large-scale heater test experiment originated by the Spanish radioactive waste management agency (Empresa Nacional de Residuos Radiactivos S.A. – ENRESA) at the Grimsel Test Site (GTS) URL in Switzerland. The project was subsequently managed by CIEMAT. FEBEX-DP is a concerted effort of various international partners working on the evaluation of sensor data and characterization of samples obtained during the course of this field test and subsequent dismantling. The main purpose of these field-scale experiments is to evaluate feasibility for creation of an engineered barrier system (EBS) with a horizontal configuration according to the Spanish concept of deep geological disposal of high-level radioactive waste in crystalline rock. Another key aspect of this project is to improve the knowledge of coupled processes such as thermal-hydro-mechanical (THM) and thermal-hydro-chemical (THC) operating in the near-field environment. The focus of these is on model development and validation of predictions through model implementation in computational tools to simulate coupled THM and THC processes.« less

Idle emissions from heavy-duty diesel and natural gas vehicles at high altitude.

PubMed

McCormick, R L; Graboski, M S; Alleman, T L; Yanowitz, J

2000-11-01

Idle emissions of total hydrocarbon (THC), CO, NOx, and particulate matter (PM) were measured from 24 heavy-duty diesel-fueled (12 trucks and 12 buses) and 4 heavy-duty compressed natural gas (CNG)-fueled vehicles. The volatile organic fraction (VOF) of PM and aldehyde emissions were also measured for many of the diesel vehicles. Experiments were conducted at 1609 m above sea level using a full exhaust flow dilution tunnel method identical to that used for heavy-duty engine Federal Test Procedure (FTP) testing. Diesel trucks averaged 0.170 g/min THC, 1.183 g/min CO, 1.416 g/min NOx, and 0.030 g/min PM. Diesel buses averaged 0.137 g/min THC, 1.326 g/min CO, 2.015 g/min NOx, and 0.048 g/min PM. Results are compared to idle emission factors from the MOBILE5 and PART5 inventory models. The models significantly (45-75%) overestimate emissions of THC and CO in comparison with results measured from the fleet of vehicles examined in this study. Measured NOx emissions were significantly higher (30-100%) than model predictions. For the pre-1999 (pre-consent decree) truck engines examined in this study, idle NOx emissions increased with model year with a linear fit (r2 = 0.6). PART5 nationwide fleet average emissions are within 1 order of magnitude of emissions for the group of vehicles tested in this study. Aldehyde emissions for bus idling averaged 6 mg/min. The VOF averaged 19% of total PM for buses and 49% for trucks. CNG vehicle idle emissions averaged 1.435 g/min for THC, 1.119 g/min for CO, 0.267 g/min for NOx, and 0.003 g/min for PM. The g/min PM emissions are only a small fraction of g/min PM emissions during vehicle driving. However, idle emissions of NOx, CO, and THC are significant in comparison with driving emissions.

Prior exposure to THC increases the addictive effects of nicotine in rats.

PubMed

Panlilio, Leigh V; Zanettini, Claudio; Barnes, Chanel; Solinas, Marcelo; Goldberg, Steven R

2013-06-01

Although it is more common for drug abuse to progress from tobacco to cannabis, in many cases cannabis use develops before tobacco use. Epidemiological evidence indicates that prior cannabis use increases the likelihood of becoming dependent on tobacco. To determine whether this effect might be due to cannabis exposure per se, in addition to any genetic, social, or environmental factors that might contribute, we extended our series of studies on 'gateway drug' effects in animal models of drug abuse. Rats were exposed to THC, the main psychoactive constituent of cannabis, for 3 days (two intraperitoneal injections/day). Then, starting 1 week later, they were allowed to self-administer nicotine intravenously. THC exposure increased the likelihood of acquiring the nicotine self-administration response from 65% in vehicle-exposed rats to 94% in THC-exposed rats. When the price of nicotine was manipulated by increasing the response requirement, THC-exposed rats maintained higher levels of intake than vehicle-exposed rats, indicating that THC exposure increased the value of nicotine reward. These results contrast sharply with our earlier findings that prior THC exposure did not increase the likelihood of rats acquiring either heroin or cocaine self-administration, nor did it increase the reward value of these drugs. The findings obtained here suggest that a history of cannabis exposure might have lasting effects that increase the risk of becoming addicted to nicotine.

Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Weifeng, E-mail: liwf@mail.xjtu.edu.cn; Huang, Huimin; Niu, Xiaofeng, E-mail: niuxf@mail.xjtu.edu.cn

Excessive alcohol consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5 ml/100 g) were pre-treated with THC (10 or 20 mg/kg, ip), cimetidine (100 mg/kg, ip) or saline in different experimental sets for a period of 3 days, and animals were euthanized 4 h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increasedmore » pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20 mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO production and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression. - Highlights: • THC decreased ethanol-induced pro-inflammatory cytokine release. • THC inhibited the production of NO in serum and gastric tissue. • THC reduced NF-κB expression and MPO accumulation in ethanol-induced gastric tissue.« less

Cannabis constituents modulate δ9-tetrahydrocannabinol-induced hyperphagia in rats.

PubMed

Farrimond, Jonathan A; Hill, Andrew J; Whalley, Benjamin J; Williams, Claire M

2010-05-01

The hyperphagic effect of Delta9-tetrahydrocannabinol (Delta9THC) in humans and rodents is well known. However, no studies have investigated the importance of Delta9THC composition and any influence other non-Delta9THC cannabinoids present in Cannabis sativa may have. We therefore compared the effects of purified Delta9THC, synthetic Delta9THC (dronabinol), and Delta9THC botanical drug substance (Delta9THC-BDS), a Delta9THC-rich standardized extract comparable in composition to recreationally used cannabis. Adult male rats were orally dosed with purified Delta9THC, synthetic Delta9THC, or Delta9THC-BDS, matched for Delta9THC content (0.34-2.68 mg/kg). Prior to dosing, subjects were satiated, and food intake was recorded following Delta9THC administration. Data were then analyzed in terms of hourly intake and meal patterns. All three Delta9THC substances tested induced significant hyperphagic effects at doses >or=0.67 mg/kg. These effects included increased intake during hour one, a shorter latency to onset of feeding and a greater duration and consumption in the first meal. However, while some differences in vehicle control intakes were observed, there were significant, albeit subtle, differences in pattern of effects between the purified Delta9THC and Delta9THC-BDS. All Delta9THC compounds displayed classical Delta9THC effects on feeding, significantly increasing shortterm intake whilst decreasing latency to the first meal. We propose that the subtle adjustment to the meal patterns seen between the purified Delta9THC and Delta9THC-BDS are due to non-Delta9THC cannabinoids present in Delta9THC-BDS. These compounds and other non-cannabinoids have an emerging and diverse pharmacology and can modulate Delta9THC-induced hyperphagia, making them worth further investigation for their therapeutic potential.

Differential effects of cannabis extracts and pure plant cannabinoids on hippocampal neurones and glia.

PubMed

Ryan, Duncan; Drysdale, Alison J; Pertwee, Roger G; Platt, Bettina

2006-11-20

We have shown previously that the plant cannabinoid cannabidiol (CBD) elevates intracellular calcium levels in both cultured hippocampal neurones and glia. Here, we investigated whether the main psychotropic constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC) alone or in combination with other cannabis constituents can cause similar responses, and whether THC affects the responses induced by CBD. Our experiments were performed with 1 microM pure THC (pTHC), with 1 microM pure CBD (pCBD), with a high-THC, low CBD cannabis extract (eTHC), with a high-CBD, low THC cannabis extract (eCBD), with a mixture of eTHC and eCBD (THC:CBD=1:1) or with corresponding 'mock extracts' that contained only pTHC and pCBD mixed in the same proportion as in eTHC, eCBD or the 1:1 mixture of eTHC and eCBD. We detected significant differences in neurones both between the effects of pTHC and eTHC and between the effects of pCBD and eCBD. There were also differences between the Ca(2+) responses evoked in both neurones and glia by eTHC and mock eTHC, but not between eCBD and mock eCBD. A particularly striking observation was the much increased response size and maximal responder rates induced by the mixture of eTHC and eCBD than by the corresponding 1:1 mixture of pTHC and pCBD. Our data suggest that THC shares the ability of CBD to elevate Ca(2+) levels in neurones and glia, that THC and CBD interact synergistically and that the cannabis extracts have other constituents yet to be identified that can significantly modulate the ability of THC and CBD to raise Ca(2+) levels.

Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration?

PubMed

Lee, Dayong; Karschner, Erin L; Milman, Garry; Barnes, Allan J; Goodwin, Robert S; Huestis, Marilyn A

2013-06-01

We characterize cannabinoid disposition in oral fluid (OF) after dronabinol, synthetic oral Δ(9)-tetrahydrocannabinol (THC), and Sativex, a cannabis-extract oromucosal spray, and evaluate whether smoked cannabis relapse or Sativex compliance can be identified with OF cannabinoid monitoring. 5 and 15 mg synthetic oral THC, low (5.4 mg THC, 5.0 mg cannabidiol (CBD)) and high (16.2 mg THC, 15.0 mg CBD) dose Sativex, and placebo were administered in random order (n=14). Oral fluid specimens were collected for 10.5 h after dosing and analyzed for THC, CBD, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH). After oral THC, OF THC concentrations decreased over time from baseline, reflecting residual THC excretion from previously self-administered smoked cannabis. CBD and CBN also were rarely detected. After Sativex, THC, CBD and CBN increased greatly, peaking at 0.25-1 h. Median CBD/THC and CBN/THC ratios were 0.82-1.34 and 0.04-0.06, respectively, reflecting cannabinoids' composition in Sativex. THCCOOH/THC ratios within 4.5 h post Sativex were ≤ 1.6 pg/ng, always lower than after oral THC and placebo. THCCOOH/THC ratios increased throughout each dosing session. Lack of measurable THC, CBD and CBN in OF following oral THC, and high OF CBD/THC ratios after Sativex distinguish oral and sublingual drug delivery routes from cannabis smoking. Low THCCOOH/THC ratios suggest recent Sativex and smoked cannabis exposure. These data indicate that OF cannabinoid monitoring can document compliance with Sativex pharmacotherapy, and identify relapse to smoked cannabis during oral THC medication but not Sativex treatment, unless samples were collected shortly after smoking. Published by Elsevier Ireland Ltd.

Can oral fluid cannabinoid testing monitor medication compliance and/or cannabis smoking during oral THC and oromucosal Sativex administration?

PubMed Central

Lee, Dayong; Karschner, Erin L.; Milman, Garry; Barnes, Allan J.; Goodwin, Robert S.; Huestis, Marilyn A.

2012-01-01

OBJECTIVES We characterize cannabinoid disposition in oral fluid (OF) after Dronabinol, synthetic oral Δ9-tetrahydrocannabinol (THC), and Sativex, a cannabis-extract oromucosal spray, and evaluate whether smoked cannabis relapse or Sativex compliance can be identified with OF cannabinoid monitoring. METHODS 5 and 15 mg synthetic oral THC, low (5.4 mg THC, 5.0 mg cannabidiol (CBD)) and high (16.2 mg THC, 15.0 mg CBD) dose Sativex, and placebo were administered in random order (n=14). Oral fluid specimens were collected for 10.5h after dosing and analyzed for THC, CBD, cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH). RESULTS After oral THC, OF THC concentrations decreased over time from baseline, reflecting residual THC excretion from previously self-administered smoked cannabis. CBD and CBN also were rarely detected. After Sativex, THC, CBD and CBN increased greatly, peaking at 0.25–1h. Median CBD/THC and CBN/THC ratios were 0.82–1.34 and 0.04–0.06, respectively, reflecting cannabinoids’ composition in Sativex. THCCOOH/THC ratios within 4.5h post Sativex were ≤1.6 pg/ng, always lower than after oral THC and placebo. THCCOOH/THC ratios increased throughout each dosing session. CONCLUSIONS Lack of measurable THC, CBD and CBN in OF following oral THC, and high OF CBD/THC ratios after Sativex distinguish oral and sublingual drug delivery routes from cannabis smoking. Low THCCOOH/THC ratios suggest recent Sativex and smoked cannabis exposure. These data indicate that OF cannabinoid monitoring can document compliance with Sativex pharmacotherapy, and identify relapse to smoked cannabis during oral THC medication but not Sativex treatment, unless samples were collected shortly after smoking. PMID:23146820

Cannabidiol-Δ9-tetrahydrocannabinol interactions on acute pain and locomotor activity.

PubMed

Britch, Stevie C; Wiley, Jenny L; Yu, Zhihao; Clowers, Brian H; Craft, Rebecca M

2017-06-01

Previous studies suggest that cannabidiol (CBD) may potentiate or antagonize Δ 9 -tetrahydrocannabinol's (THC) effects. The current study examined sex differences in CBD modulation of THC-induced antinociception, hypolocomotion, and metabolism. In Experiment 1, CBD (0, 10 or 30mg/kg) was administered 15min before THC (0, 1.8, 3.2, 5.6 or 10mg/kg), and rats were tested for antinociception and locomotion 15-360min post-THC injection. In Experiments 2 and 3, CBD (30mg/kg) was administered 13h or 15min before THC (1.8mg/kg); rats were tested for antinociception and locomotion 30-480min post-THC injection (Experiment 2), or serum samples were taken 30-360min post-THC injection to examine CBD modulation of THC metabolism (Experiment 3). In Experiment 1, CBD alone produced no antinociceptive effects, while enhancing THC-induced paw pressure but not tail withdrawal antinociception 4-6h post-THC injection. CBD alone increased locomotor activity at 6h post-injection, but enhanced THC-induced hypolocomotion 4-6h post-THC injection, at lower THC doses. There were no sex differences in CBD-THC interactions. In Experiments 2 and 3, CBD did not significantly enhance THC's effects when CBD was administered 13h or 15min before THC; however, CBD inhibited THC metabolism, and this effect was greater in females than males. These results suggest that CBD may enhance THC's antinociceptive and hypolocomotive effects, primarily prolonging THC's duration of action; however, these effects were small and inconsistent across experiments. CBD inhibition of THC metabolism as well other mechanisms likely contribute to CBD-THC interactions on behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure of the rabbit.

PubMed

ElSohly, M A; Harland, E C; Benigni, D A; Waller, C W

1984-06-01

Thirty-two different cannabinoids were tested for their ability to reduce intraocular pressure (IOP) in the rabbit. These included many of delta 9- and delta 8-THC derivatives and metabolites along with other natural and synthetic cannabinoids. In addition, some non-cannabinoid constituents of Cannabis were screened using the same model. All compounds were administered intravenously, while only a few were tested topically in mineral oil. Water soluble derivatives of delta 9- and delta 8-THC were prepared and tested topically in aqueous solution. The data revealed that certain derivatives of delta 9-and delta 8-THC were more active in lowering IOP than the parent cannabinoids. In addition, compounds other than delta 9- and delta 8-THC and their derivatives were shown to have activity.

Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC.

PubMed

Hunault, Claudine C; Mensinga, Tjeert T; de Vries, Irma; Kelholt-Dijkman, Hermien H; Hoek, Jani; Kruidenier, Maaike; Leenders, Marianne E C; Meulenbelt, Jan

2008-12-01

Delta9-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). The pharmacokinetics of THC after smoking cannabis cigarettes containing more than approximately 35 mg THC (3.55% THC cigarettes) is unknown. To be able to perform suitable exposure risk analysis, it is important to know if there is a linear relation at higher doses. The present study aimed to characterise the pharmacokinetics of THC, the active metabolite 11-OH-THC and the inactive metabolite THC-COOH after smoking a combination of tobacco and cannabis containing high THC doses. This double-blind, placebo-controlled, four-way, cross-over study included 24 male non-daily cannabis users (two to nine joints per month). Participants were randomly assigned to smoke cannabis cigarettes containing 29.3, 49.1 and 69.4 mg THC and a placebo. Serial serum samples collected over a period of 0-8 h were analysed by liquid chromatography electrospray tandem mass spectrometry. Effects on heart rate, blood pressure and 'high' feeling were also measured. Mean maximal concentrations (Cmax) were 135.1, 202.9 and 231.0 microg/L for THC and 9.2, 16.4 and 15.8 microg/L for 11-OH-THC after smoking a 29.3-, 49.1- and 69.4-mg THC cigarette, respectively. A large inter-individual variability in Cmax was observed. Heart rate and 'high' feeling significantly increased with increasing THC dose. This study demonstrates that the known linear association between THC dose and THC serum concentration also applies for high THC doses.

Numerical Simulation of Tuff Dissolution and Precipitation Experiments: Validation of Thermal-Hydrologic-Chemical (THC) Coupled-Process Modeling

NASA Astrophysics Data System (ADS)

Dobson, P. F.; Kneafsey, T. J.

2001-12-01

As part of an ongoing effort to evaluate THC effects on flow in fractured media, we performed a laboratory experiment and numerical simulations to investigate mineral dissolution and precipitation. To replicate mineral dissolution by condensate in fractured tuff, deionized water equilibrated with carbon dioxide was flowed for 1,500 hours through crushed Yucca Mountain tuff at 94° C. The reacted water was collected and sampled for major dissolved species, total alkalinity, electrical conductivity, and pH. The resulting steady-state fluid composition had a total dissolved solids content of about 140 mg/L; silica was the dominant dissolved constituent. A portion of the steady-state reacted water was flowed at 10.8 mL/hr into a 31.7-cm tall, 16.2-cm wide vertically oriented planar fracture with a hydraulic aperture of 31 microns in a block of welded Topopah Spring tuff that was maintained at 80° C at the top and 130° C at the bottom. The fracture began to seal within five days. A 1-D plug-flow model using the TOUGHREACT code developed at Berkeley Lab was used to simulate mineral dissolution, and a 2-D model was developed to simulate the flow of mineralized water through a planar fracture, where boiling conditions led to mineral precipitation. Predicted concentrations of the major dissolved constituents for the tuff dissolution were within a factor of 2 of the measured average steady-state compositions. The fracture-plugging simulations result in the precipitation of amorphous silica at the base of the boiling front, leading to a hundred-fold decrease in fracture permeability in less than 6 days, consistent with the laboratory experiment. These results help validate the use of the TOUGHREACT code for THC modeling of the Yucca Mountain system. The experiment and simulations indicate that boiling and concomitant precipitation of amorphous silica could cause significant reductions in fracture porosity and permeability on a local scale. The TOUGHREACT code will be used to evaluate larger-scale silica sealing observed in a portion of the Yellowstone geothermal system, a natural analog for the precipitation-experiment processes.

Cannabidiol-Δ9-tetrahydrocannabinol interactions on acute pain and locomotor activity

PubMed Central

Britch, Stevie C.; Wiley, Jenny L.; Yu, Zhihao; Clowers, Brian H.; Craft, Rebecca M.

2017-01-01

Background Previous studies suggest that cannabidiol (CBD) may potentiate or antagonize Δ9-tetrahydrocannabinol’s (THC) effects. The current study examined sex differences in CBD-THC interactions on antinociception, locomotion, and THC metabolism. Methods In Experiment 1, CBD (0, 10 or 30 mg/kg) was administered 15 min before THC (0, 1.8, 3.2, 5.6 or10 mg/kg), and rats were tested for antinociception and locomotion 15–360 min post-THC injection. In Experiments 2 and 3, CBD (30 mg/kg) was administered 13 hr or 15 min before THC (1.8 mg/kg); rats were tested for antinociception and locomotion 30–480 min post-THC injection (Experiment 2), or serum samples were taken 30–360 min post-THC injection to examine CBD modulation of THC metabolism (Experiment 3). Results In Experiment 1, CBD alone produced no antinociceptive effects, while enhancing THC-induced paw pressure but not tail withdrawal antinociception 4–6 hr post-THC injection. CBD alone increased locomotor activity at 6 hr post-injection, but enhanced THC-induced hypolocomotion 4–6 hr post-THC injection, at lower THC doses. There were no sex differences in CBD-THC interactions. In Experiments 2 and 3, CBD did not significantly enhance THC’s effects when CBD was administered 13 hr or 15 min before THC; however, CBD inhibited THC metabolism, and this effect was greater in females than males. Conclusions These results suggest that CBD may enhance THC’s antinociceptive and hypolocomotive effects, primarily prolonging THC’s duration of action; however, these effects were small and inconsistent across experiments. CBD inhibition of THC metabolism as well other mechanisms likely contribute to CBD-THC interactions on behavior. PMID:28445853

Cognitive function and mood in MDMA/THC users, THC users and non-drug using controls.

PubMed

Lamers, C T J; Bechara, A; Rizzo, M; Ramaekers, J G

2006-03-01

Repeated ecstasy (MDMA) use is reported to impair cognition and cause increased feelings of depression and anxiety. Yet, many relevant studies have failed to control for use of drugs other than MDMA, especially marijuana (THC). To address these confounding effects we compared behavioural performance of 11 MDMA/THC users, 15 THC users and 15 non-drug users matched for age and intellect. We tested the hypothesis that reported feelings of depression and anxiety and cognitive impairment (memory, executive function and decision making) are more severe in MDMA/THC users than in THC users. MDMA/THC users reported more intense feelings of depression and anxiety than THC users and non-drug users. Memory function was impaired in both groups of drug users. MDMA/THC users showed slower psychomotor speed and less mental flexibility than non-drug users. THC users exhibited less mental flexibility and performed worse on the decision making task compared to non-drug users but these functions were similar to those in MDMA/THC users. It was concluded that MDMA use is associated with increased feelings of depression and anxiety compared to THC users and non-drug users. THC users were impaired in some cognitive abilities to the same degree as MDMA/THC users, suggesting that some cognitive impairment attributed to MDMA is more likely due to concurrent THC use.

Δ9-tetrahydrocannabinol (Δ9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice.

PubMed

Rodríguez, Guadalupe; Neugebauer, Nichole M; Yao, Katherine Lan; Meltzer, Herbert Y; Csernansky, John G; Dong, Hongxin

2017-08-01

The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Δ9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia. Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10mg/kg). In turn, Δ9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Δ9-THC later in life displayed behavioral changes in the locomotor activity paradigm (p<0.001) that was consistent with a schizophrenia-related phenotype, as well as potentiated changes in the NOR (p<0.01) and MWM (p<0.05) paradigms as compared to mice that received PCP alone. Decreased cortical receptor expression of NMDA receptor 1 subunit (NR1) was observed in mice that received PCP and PCP+Δ9-THC, while mice that received Δ9-THC and PCP+Δ9-THC displayed decreases in CB1 receptor expression. These findings suggest that administration of Δ9-THC during the early adulthood can potentiate the development of schizophrenia-related behavioral phenotypes induced by neonatal exposure to PCP in mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Rapid analysis of Δ-9-tetrahydrocannabinol in hair using direct analysis in real time ambient ionization orbitrap mass spectrometry.

PubMed

Duvivier, Wilco F; van Beek, Teris A; Pennings, Ed J M; Nielen, Michel W F

2014-04-15

Forensic hair analysis methods are laborious, time-consuming and provide only a rough retrospective estimate of the time of drug intake. Recently, hair imaging methods using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) were reported, but these methods require the application of MALDI matrix and are performed under vacuum. Direct analysis of entire locks of hair without any sample pretreatment and with improved spatial resolution would thus address a need. Hair samples were attached to stainless steel mesh screens and scanned in the X-direction using direct analysis in real time (DART) ambient ionization orbitrap MS. The DART gas temperature and the accuracy of the probed hair zone were optimized using Δ-9-tetrahydrocannabinol (THC) as a model compound. Since external contamination is a major issue in forensic hair analysis, sub-samples were measured before and after dichloromethane decontamination. The relative intensity of the THC signal in spiked blank hair versus that of quinine as the internal standard showed good reproducibility (26% RSD) and linearity of the method (R(2)  = 0.991). With the DART hair scan THC could be detected in hair samples from different chronic cannabis users. The presence of THC was confirmed by quantitative liquid chromatography/tandem mass spectrometry. Zones with different THC content could be clearly distinguished, indicating that the method might be used for retrospective timeline assessments. Detection of THC in decontaminated drug user hair showed that the DART hair scan not only probes THC on the surface of hair, but penetrates deeply enough to measure incorporated THC. A new approach in forensic hair analysis has been developed by probing complete locks of hair using DART-MS. Longitudinal scanning enables detection of incorporated compounds and can be used as pre-screening for THC without sample preparation. The method could also be adjusted for the analysis of other drugs of abuse. Copyright © 2014 John Wiley & Sons, Ltd.

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

PubMed Central

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

Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC.

PubMed

Hložek, Tomáš; Uttl, Libor; Kadeřábek, Lukáš; Balíková, Marie; Lhotková, Eva; Horsley, Rachel R; Nováková, Pavlína; Šíchová, Klára; Štefková, Kristýna; Tylš, Filip; Kuchař, Martin; Páleníček, Tomáš

2017-12-01

Metabolic and behavioural effects of, and interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route. Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated. In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels. Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility. In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not. In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour. Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, if confirmed in humans and given the increasing medical use of CBD-only products, might have important legal and forensic ramifications. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract.

PubMed

Nadulski, Thomas; Pragst, Fritz; Weinberg, Gordon; Roser, Patrik; Schnelle, Martin; Fronk, Eva-Maria; Stadelmann, Andreas Michael

2005-12-01

Cannabidiol (CBD) is known to modify the effects of Delta-tetrahydrocannabinol (THC) by decreasing anxiety and antagonizing other THC-effects. As a reason, pharmacodynamic as well as pharmacokinetic mechanisms were suggested. In context of the use of cannabis-based medicine extracts for therapeutic purposes, a study was performed in a double-blind and placebo-controlled cross-over design in which each of 24 volunteers (12 male and 12 female, age 18-45 years) obtained soft-gelatin capsules with 10 mg THC (THC-set), cannabis extract containing 10 mg THC +5.4 mg CBD (CAN-set) or placebo in weekly intervals. Blood samples were taken 30 minutes before and 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours and 24 hours after the intake. The concentrations of THC, of its metabolites 11-OH-THC, THC-COOH and of CBD in the plasma samples were determined by automatic solid phase extraction, derivatization with N,O-bis(trimethylsilyl)triflouroacetamide and gas chromatography-mass spectrometry. The concentration versus time curves (maximum concentrations Cmax, corresponding time tmax and areas under the curves AUC) were evaluated by statistical methods with respect to equivalence or differences between the CAN-set and the THC-set. Furthermore, the intra-individual ratios of Cmax and AUC for 11-OH-THC/THC, THC-COOH/THC and THC-COOH/11-OH-THC were compared between the THC-set and the CAN-set. Despite the large variation of the data, evidence emerged from the total of the results that CBD partially inhibits the CYP 2C catalyzed hydroxylation of THC to 11-OH-THC. The probability for this inhibition is particularly high for oral intake because THC and CBD attain relatively high concentrations in the liver and because of the high first-pass metabolism of THC. However, the effect of CBD is small in comparison to the variability caused by other factors. Therefore, a pharmacokinetic reason for the differences determined between pure THC and cannabis extract is improbable at the doses chosen in this study. Significantly higher AUC and Cmax and shorter tmax were found for females as compared with males.

Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.

PubMed

Ibarra-Lecue, Inés; Mollinedo-Gajate, Irene; Meana, J Javier; Callado, Luis F; Diez-Alarcia, Rebeca; Urigüen, Leyre

2018-04-27

Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ 9 -tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease.

PubMed

Laprairie, Robert B; Bagher, Amina M; Kelly, Melanie E M; Denovan-Wright, Eileen M

2016-03-01

Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB1) decrease in the basal ganglia. Decreasing CB1 levels are strongly correlated with chorea and cognitive deficit. CB1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh(Q7/Q7)) or mutant huntingtin protein (STHdh(Q111/Q111)). Signaling bias was assessed using the Black and Leff operational model. Relative activity [ΔlogR (τ/KA)] and system bias (ΔΔlogR) were calculated relative to the reference compound WIN55,212-2 for Gαi/o, Gαs, Gαq, Gβγ, and β-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, Δ(9)-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC+CBD (1:1), and compared between wild-type and HD cells. The Emax of Gαi/o-dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Gαi/o/Gβγ bias and normalized CB1 protein levels and improved cell viability, whereas CP55,940 and THC displayed β-arrestin1 bias and reduced CB1 protein levels and cell viability in HD cells. CBD was not a CB1 agonist but inhibited THC-dependent signaling (THC+CBD). Therefore, enhancing Gαi/o-biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are β-arrestin-biased--such as THC found at high levels in modern varieties of marijuana--may be detrimental to CB1 signaling, particularly in HD where CB1 levels are already reduced. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

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

PubMed

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, P<0.001) and more (β=13.7, P<0.001) THC than imported cannabis resin. Linear regression models were used to study the trends in THC of the different cannabis products over time. A marginal, but significant (P<0.001), overall decline of THC per year of 0.22% was found in all cannabis products. However, no significant difference was found between the five products in the THC linear trajectories across time. Of all the cannabis products, only imported cannabis resin contained a relatively high CBD/THC ratio (median 0.42). The average tetrahydrocannabinol (THC) content of the most popular herbal cannabis products in the Netherlands has decreased slightly since 2005. The popular Nederwiet type still has a relatively high THC to cannabidiol ratio. © 2015 Society for the Study of Addiction.

Gonadal hormone modulation of Δ9-tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats

PubMed Central

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

2016-01-01

The gonadal hormones testosterone (T) in adult males and estradiol (E2) in adult females have been reported to modulate behavioral effects of Δ9-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/100 g body weight), or E2 (1-mm Silastic capsule/rat). Three weeks later, saline or the cytochrome P450 inhibitor proadifen (25 mg/kg; to block THC metabolism and boost THC's effects) was injected i.p.; one h later, vehicle or THC (3 mg/kg females, 5 mg/kg males) was injected i.p., and rats were tested for antinociceptive and motoric effects 15-240 min 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. PMID:27670094

Subjective and physiological effects of oromucosal sprays containing cannabinoids (nabiximols): potentials and limitations for psychosis research.

PubMed

Schoedel, Kerri A; Harrison, Sarah Jane

2012-01-01

Cannabis use is associated with a spectrum of effects including euphoria, relaxation, anxiety, perceptual alterations, paranoia, and impairments in attention and memory. Cannabis is made up of approximately 80 different cannabinoid compounds, which have synergistic or antagonistic effects on the principle active ingredient in cannabis, delta-9-tetrahydrocannabinol (THC). The net overall effect of cannabis is thought to be related to the ratio of its composite constituents; in particular, the ratio of THC to cannabidiol (CBD). Since cannabinoids induce subjective and cognitive changes that share qualitative similarities with schizophrenia, cannabinoids have been used to model psychosis. Some limitations of cannabinoid models of psychosis include the relatively high variability in experiences between different individuals, the potential for inducing unwanted effects, such as toxic psychosis in study subjects, and the lack of data showing that effective anti-psychotic treatments can reverse the behavioural and cognitive/motor effects of cannabinoids. Nabiximols (Sativex®) is an oromucosal spray containing THC and CBD in an approximate 1:1 ratio. While not extensively studied, most studies confirm that nabiximols, despite the different route of administration and presence of CBD, have similar or slightly reduced subjective/cognitive effects compared to similar doses of oral THC. While the presence of CBD may have utility in some models, it is likely that the concentrations are not high enough to meaningfully affect those aspects important for psychosis research. This review suggests that while it may present an alternative to the use of oral THC, oromucosal nabiximols may not present substantial advantages for use in psychosis research.

Modeling brine-rock interactions in an enhanced geothermal systemdeep fractured reservoir at Soultz-Sous-Forets (France): a joint approachusing two geochemical codes: frachem and toughreact

DOE Office of Scientific and Technical Information (OSTI.GOV)

Andre, Laurent; Spycher, Nicolas; Xu, Tianfu

The modeling of coupled thermal, hydrological, and chemical (THC) processes in geothermal systems is complicated by reservoir conditions such as high temperatures, elevated pressures and sometimes the high salinity of the formation fluid. Coupled THC models have been developed and applied to the study of enhanced geothermal systems (EGS) to forecast the long-term evolution of reservoir properties and to determine how fluid circulation within a fractured reservoir can modify its rock properties. In this study, two simulators, FRACHEM and TOUGHREACT, specifically developed to investigate EGS, were applied to model the same geothermal reservoir and to forecast reservoir evolution using theirmore » respective thermodynamic and kinetic input data. First, we report the specifics of each of these two codes regarding the calculation of activity coefficients, equilibrium constants and mineral reaction rates. Comparisons of simulation results are then made for a Soultz-type geothermal fluid (ionic strength {approx}1.8 molal), with a recent (unreleased) version of TOUGHREACT using either an extended Debye-Hueckel or Pitzer model for calculating activity coefficients, and FRACHEM using the Pitzer model as well. Despite somewhat different calculation approaches and methodologies, we observe a reasonably good agreement for most of the investigated factors. Differences in the calculation schemes typically produce less difference in model outputs than differences in input thermodynamic and kinetic data, with model results being particularly sensitive to differences in ion-interaction parameters for activity coefficient models. Differences in input thermodynamic equilibrium constants, activity coefficients, and kinetics data yield differences in calculated pH and in predicted mineral precipitation behavior and reservoir-porosity evolution. When numerically cooling a Soultz-type geothermal fluid from 200 C (initially equilibrated with calcite at pH 4.9) to 20 C and suppressing mineral precipitation, pH values calculated with FRACHEM and TOUGHREACT/Debye-Hueckel decrease by up to half a pH unit, whereas pH values calculated with TOUGHREACT/Pitzer increase by a similar amount. As a result of these differences, calcite solubilities computed using the Pitzer formalism (the more accurate approach) are up to about 1.5 orders of magnitude lower. Because of differences in Pitzer ion-interaction parameters, the calcite solubility computed with TOUGHREACT/Pitzer is also typically about 0.5 orders of magnitude lower than that computed with FRACHEM, with the latter expected to be most accurate. In a second part of this investigation, both models were applied to model the evolution of a Soultz-type geothermal reservoir under high pressure and temperature conditions. By specifying initial conditions reflecting a reservoir fluid saturated with respect to calcite (a reasonable assumption based on field data), we found that THC reservoir simulations with the three models yield similar results, including similar trends and amounts of reservoir porosity decrease over time, thus pointing to the importance of model conceptualization. This study also highlights the critical effect of input thermodynamic data on the results of reactive transport simulations, most particularly for systems involving brines.« less

Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops.

PubMed

Pijlman, F T A; Rigter, S M; Hoek, J; Goldschmidt, H M J; Niesink, R J M

2005-06-01

The total concentration of THC has been monitored in cannabis preparations sold in Dutch coffee shops since 1999. This annual monitoring was issued by the Ministry of Health after reports of increased potency. The level of the main psychoactive compound, Delta9-tetrahydrocannabinol (THC), is measured in marijuana and hashish. A comparison is made between imported and Dutch preparations, and between seasons. Samples of cannabis preparations from randomly selected coffee shops were analyzed using gas chromatography (GC-FID) for THC, CBD and CBN. In 2004, the average THC level of Dutch home-grown marijuana (Nederwiet) (20.4% THC) was significantly higher than that of imported marijuana (7.0% THC). Hashish derived from Dutch marijuana (Nederhasj) contained 39.3% THC in 2004, compared with 18.2% THC in imported hashish. The average THC percentage of Dutch marijuana, Dutch hashish and imported hashish was significantly higher than in previous years. It nearly doubled over 5 years. During this period, the THC percentage in imported marijuana remained unchanged. A higher price had to be paid for cannabis with higher levels of THC. Whether the increase in THC levels causes increased health risks for users can only be concluded when more data are available on adjusted patterns of use, abuse liability, bioavailability and levels of THC in the brain.

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

PubMed

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 <20% of the analyte limit of quantitation PAR. The intra-assay accuracy ranged from 83.5% to 118% of target and the intra-run imprecision ranged from 2.0% to 19.1%. The inter-assay accuracy ranged from 90.3% to 104% of target and the inter-run imprecision ranged from 6.5% to 12.0%. Stability was established for 25 hours at room temperature, 207 days at -20°C, after three freeze-thaw cycles and for 26 days for rederivatized processed samples. After smoking marijuana predictable concentrations of 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.

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

PubMed Central

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

2017-01-01

Abstract 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 <20% of the analyte limit of quantitation PAR. The intra-assay accuracy ranged from 83.5% to 118% of target and the intra-run imprecision ranged from 2.0% to 19.1%. The inter-assay accuracy ranged from 90.3% to 104% of target and the inter-run imprecision ranged from 6.5% to 12.0%. Stability was established for 25 hours at room temperature, 207 days at −20°C, after three freeze-thaw cycles and for 26 days for rederivatized processed samples. After smoking marijuana predictable concentrations of 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. PMID:28069869

Reintoxication: the release of fat-stored delta(9)-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure.

PubMed

Gunasekaran, N; Long, L E; Dawson, B L; Hansen, G H; Richardson, D P; Li, K M; Arnold, J C; McGregor, I S

2009-11-01

Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in adipose tissue where it is stored for long periods of time. Here we investigated whether conditions that promote lipolysis can liberate THC from adipocytes to yield increased blood levels of THC. In vitro studies involved freshly isolated rat adipocytes that were incubated with THC before exposure to the lipolytic agent adrenocorticotrophic hormone (ACTH). A complementary in vivo approach examined the effects of both food deprivation and ACTH on blood levels of THC in rats that had been repeatedly injected with THC (10 mg.kg(-1)) for 10 consecutive days. Lipolysis promoted by ACTH or food deprivation was indexed by measurement of glycerol levels. ACTH increased THC levels in the medium of THC-pretreated adipocytes in vitro. ACTH also enhanced THC release from adipocytes in vitro when taken from rats repeatedly pretreated with THC in vivo. Finally, in vivo ACTH exposure and 24 h food deprivation both enhanced the levels of THC and its metabolite, (-)-11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH) in the blood of rats that had been pre-exposed to repeated THC injections. The present study shows that lipolysis enhances the release of THC from fat stores back into blood. This suggests the likelihood of 'reintoxication' whereby food deprivation or stress may raise blood THC levels in animals chronically exposed to the drug. Further research will need to confirm whether this can lead to functional effects, such as impaired cognitive function or 'flashbacks'.

40 CFR 86.708-98 - In-use emission standards for 1998 and later model year light-duty vehicles.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM Gasoline 0.41 0.25 3.4 0.4 0.08... H98-2—Full Useful Life 1 Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.708-98 - In-use emission standards for 1998 and later model year light-duty vehicles.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM Gasoline 0.41 0.25 3.4 0.4 0.08... H98-2—Full Useful Life 1 Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.708-98 - In-use emission standards for 1998 and later model year light-duty vehicles.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM Gasoline 0.41 0.25 3.4 0.4 0.08... H98-2—Full Useful Life 1 Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM...

40 CFR 86.708-98 - In-use emission standards for 1998 and later model year light-duty vehicles.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM Gasoline 0.41 0.25 3.4 0.4 0.08... H98-2—Full Useful Life 1 Standards (g/mi) for Light-Duty Vehicles Fuel THC NMHC THCE NMHCE CO NOX PM...

THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

PubMed

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

2016-02-01

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.

THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the sub-chronic PCP model of schizophrenia

PubMed Central

Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

2017-01-01

Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the CSF levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared to THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. PMID:26510449

Thermohaline circulation at three key sections in the North Atlantic over 1985-2002

NASA Astrophysics Data System (ADS)

Marsh, Robert; de Cuevas, Beverly A.; Coward, Andrew C.; Bryden, Harry L.; Álvarez, Marta

2005-05-01

Efforts are presently underway to monitor the Thermohaline Circulation (THC) in the North Atlantic. A measuring strategy has been designed to monitor both the Meridional Overturning Circulation (MOC) in the subtropics and dense outflows at higher latitudes. To provide a historical context for these new observations, we diagnose an eddy-permitting ocean model simulation of the period 1985-2002. We present time series of the THC, MOC and heat transport, at key hydrographic sections in the subtropics, the northeast Atlantic and the Labrador Sea. The simulated THC compares well with observations. We find considerable variability in the THC on each section, most strikingly in the Labrador Sea during the early 1990's, consistent with observed changes. Overturning in the northeast Atlantic declines by ~20% over the 1990's, coincident with an increase in the subtropics. We speculate that MOC weakening may soon be detected in the subtropics, if the decline continues in mid-latitudes.

Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS in plasma after oral application of small doses of THC and cannabis extract.

PubMed

Nadulski, Thomas; Sporkert, Frank; Schnelle, Martin; Stadelmann, Andreas M; Roser, Patrik; Schefter, Tom; Pragst, Fritz

2005-01-01

Besides the psychoactive Delta(9)-tetrahydrocannabinol (THC), hashish and marijuana as well as cannabis-based medicine extracts contain varying amounts of cannabidiol (CBD) and of the degradation product cannabinol (CBN). The additional determination of these compounds is interesting from forensic and medical points of view because it can be used for further proof of cannabis exposure and because CBD is known to modify the effects of THC. Therefore, a method for the simultaneous quantitative determination of THC, its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), CBD and CBN from plasma was developed. The method was based on automatic solid-phase extraction with C(18) ec columns, derivatization with N,O-bistrimethylsilyltrifluoroacetamide (BSTFA), and gas chromatography-electron impact ionization-mass spectrometry (GC-EI-MS) with deuterated standards. The limits of detection were between 0.15 and 0.29 ng/mL for THC, 11-OH-THC, THC-COOH, and CBD and 1.1 ng/mL for CBN. The method was applied in a prospective pharmacokinetic study after single oral administration of 10 mg THC alone or together with 5.4 mg CBD in cannabis extract. The maximum plasma concentrations after cannabis extract administration ranged between 1.2 and 10.3 ng/mL (mean 4.05 ng/mL) for THC, 1.8 and 12.3 ng/mL (mean 4.9 ng/mL) for 11-OH-THC, 19 and 71 ng/mL (mean 35 ng/mL) for THC-COOH, and 0.2 and 2.6 ng/mL (mean 0.95 ng/mg) for CBD. The peak concentrations (mean values) of THC, 11-OH-THC, THC-COOH, and CBD were observed at 56, 82, 115, and 60 min, respectively, after intake. CBN was not detected. Caused by the strong first-pass metabolism, the concentrations of the metabolites were increased during the first hours after drug administration when compared to literature data for smoking. Therefore, the concentration ratio 11-OH-THC/THC was discussed as a criterion for distinguishing oral from inhalative cannabis consumption.

Chronic Administration of Δ9-Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

PubMed Central

Chandra, Lawrance C.; Kumar, Vinay; Torben, Workineh; Stouwe, Curtis Vande; Winsauer, Peter; Amedee, Angela; Molina, Patricia E.

2014-01-01

ABSTRACT Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of Δ9-tetrahydrocannabinol (Δ9-THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including Δ9-THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of Δ9-THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving Δ9-THC (n = 3) and SIV-infected macaques administered either vehicle (VEH/SIV; n = 4) or THC (THC/SIV; n = 4). Chronic Δ9-THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ∼28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4+ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal inflammation. Whether similar miRNA modulation occurs in other tissues requires further investigation. IMPORTANCE Gastrointestinal (GI) tract disease/inflammation is a hallmark of HIV/SIV infection. Previously, we showed that chronic treatment of SIV-infected macaques with Δ9-tetrahydrocannabinol (Δ9-THC) increased survival and decreased viral replication and infection-induced gastrointestinal inflammation. Here, we show that chronic THC administration to SIV-infected macaques induced an anti-inflammatory microRNA expression profile in the intestine at 60 days p.i. These included several miRNAs bioinformatically predicted to directly target CXCL12, a chemokine known to regulate lymphocyte and macrophage trafficking into the intestine. Specifically, miR-99b was significantly upregulated in THC-treated SIV-infected macaques and confirmed to directly target NADPH oxidase 4 (NOX4), a reactive oxygen species generator known to damage intestinal epithelial cells. Elevated miR-99b expression was associated with a significantly decreased number of NOX4+ epithelial cells in the intestines of THC-treated SIV-infected macaques. Overall, our results show that selective upregulation of anti-inflammatory miRNA expression contributes to THC-mediated suppression of gastrointestinal inflammation and maintenance of intestinal homeostasis. PMID:25378491

Subjective and physiological effects after controlled Sativex and oral THC administration.

PubMed

Karschner, E L; Darwin, W D; McMahon, R P; Liu, F; Wright, S; Goodwin, R S; Huestis, M A

2011-03-01

Sativex is a cannabis-plant extract delivering nearly 1:1 Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and "good drug effects" with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses.

Subjective and Physiological Effects After Controlled Sativex and Oral THC Administration

PubMed Central

Karschner, EL; Darwin, WD; McMahon, RP; Liu, F; Wright, S; Goodwin, RS; Huestis, MA

2013-01-01

Sativex is a cannabis-plant extract delivering nearly 1:1 Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) by oromucosal spray. It has been suggested that CBD attenuates THC-induced tachycardia, anxiety, and euphoria. In this study, pharmacodynamic effects were compared over 10.5 h in nine cannabis smokers randomly assigned to receive placebo, 5 and 15 mg oral synthetic THC, and low (5.4 mg THC, 5.0 mg CBD) and high (16.2 mg THC, 15.0 mg CBD) doses of Sativex. At therapeutic doses, no substantial CBD-induced modulation of THC's effects was evident. Oral THC and Sativex produced similar, clinically insignificant increases in heart rate, anxiety, and “good drug effects” with no serious adverse events. Oral and oromucosal THC have slower absorption, lower rate of THC delivery to the brain, and fewer associated adverse events as compared with smoked cannabis. These results indicate that Sativex has a pharmacodynamic safety profile comparable to that of oral THC at low, therapeutic doses. PMID:21289620

Thermohaline circulation and its box models simulation

NASA Astrophysics Data System (ADS)

Bazyura, Kateryna; Polonsky, Alexander; Sannikov, Viktor

2014-05-01

Ocean Thermochaline circulation (THC) is the part of large-scale World Ocean circulation and one of the main climate system components. It is generated by global meridional density gradients, which are controlled by surface heat and freshwater fluxes. THC regulates climate variability on different timescales (from decades to thousands years) [Stocker (2000), Clark (2002)]. Study of paleoclimatic evidences of abrupt and dramatic changes in ocean-atmosphere system in the past (such as, Dansgaard-Oeschger and Heinrich events or Younger Dryas, see e.g., [Rahmstorf (2002), Alley & Clark(1999)]) shows that these events are connected with THC regimes. At different times during last 120,000 years, three THC modes have prevailed in the Atlantic. They can be labeled as stadial, interstadial and Heinrich modes or as cold, warm and off mode. THC collapse (or thermohaline catastrophe) can be one of the consequences of global warming (including modern anthropogenic climate changes occurring at the moment). The ideas underlying different box-model studies, possibility of thermochaline catastrophe in present and past are discussed in this presentation. Response of generalized four box model of North Atlantic thermohaline circulation [developing the model of Griffies & Tzippermann (1995)] on periodic, stochastic and linear forcing is studied in details. To estimate climatic parameters of the box model we used monthly salinity and temperature data of ECMWF operational Ocean Reanalysis System 3 (ORA-S3) and data from atmospheric NCEP/NCAR reanalysis on precipitation, and heat fluxes for 1959-2011. Mean values, amplitude of seasonal cycle, amplitudes and periods of typical interdecadal oscillations, white noise level, linear trend coefficients and their significance level were estimated for every hydrophysical parameter. In response to intense freshwater or heat forcing, THC regime can change resulting in thermohaline catastrophe. We analyze relevant thresholds of external forcing in cases of using linear and nonlinear seawater state equation. In the frame of four-box model it is shown that: 1) The occurrence of the thermohaline catastrophe, which is likely happened at Younger Dryas period or developed as Heinrich events in the past, is improbable in modern climate epoch. 2) Choice of nonlinear seawater equitation of state leads to stabilization of warm mode of THC, which corresponds to modern climate state. 3) Typical white noise in heat and freshwater fluxes leads to generation of multidecadal oscillations of volume transport. Time-scale of these oscillations coincides with Atlantic Multidecadal oscillation periodicity. So, it is shown that that recent climate is characterized by quasi-periodical stable multidecadal THC warm regime. Stocker, T. F., 2000: Past and future reorganisations in the climate system. Quat. Sci.Rev, Vol. 19, P.301-319. Clark U., 2002: The role of the thermohaline circulation in abrupt climate change. Nature. Vol. 415, P.863-869. Rahmstorf S., 2002: Ocean circulation and climate during the past 120000 years. Nature. Vol. 419, P.207-214. Alley, R. B. & Clark, P. U., 1999: The deglaciation of the Northern Hemisphere: a global perspective. Annu.Rev. Earth Planet. Sci. Vol. 27, P.149-182. Griffies S.M., Tziperman E., 1995: A linear thermohaline oscillator driven by stochastic atmospheric forcing. Journal of Climate. Vol. 8. P. 2440-2453.

[Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

PubMed

Goullé, Jean-Perre; Guerbet, Michel

2014-03-01

Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself.

Reintoxication: the release of fat-stored Δ9-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure

PubMed Central

Gunasekaran, N; Long, LE; Dawson, BL; Hansen, GH; Richardson, DP; Li, KM; Arnold, JC; McGregor, IS

2009-01-01

Background and purpose: Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in adipose tissue where it is stored for long periods of time. Here we investigated whether conditions that promote lipolysis can liberate THC from adipocytes to yield increased blood levels of THC. Experimental approach: In vitro studies involved freshly isolated rat adipocytes that were incubated with THC before exposure to the lipolytic agent adrenocorticotrophic hormone (ACTH). A complementary in vivo approach examined the effects of both food deprivation and ACTH on blood levels of THC in rats that had been repeatedly injected with THC (10 mg·kg−1) for 10 consecutive days. Lipolysis promoted by ACTH or food deprivation was indexed by measurement of glycerol levels. Key results: ACTH increased THC levels in the medium of THC-pretreated adipocytes in vitro. ACTH also enhanced THC release from adipocytes in vitro when taken from rats repeatedly pretreated with THC in vivo. Finally, in vivo ACTH exposure and 24 h food deprivation both enhanced the levels of THC and its metabolite, (-)-11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) in the blood of rats that had been pre-exposed to repeated THC injections. Conclusions and implications: The present study shows that lipolysis enhances the release of THC from fat stores back into blood. This suggests the likelihood of ‘reintoxication’ whereby food deprivation or stress may raise blood THC levels in animals chronically exposed to the drug. Further research will need to confirm whether this can lead to functional effects, such as impaired cognitive function or ‘flashbacks’. PMID:19681888

A novel single-step GC-MS/MS method for cannabinoids and 11-OH-THC metabolite analysis in hair.

PubMed

Angeli, Ilaria; Casati, Sara; Ravelli, Alessandro; Minoli, Mauro; Orioli, Marica

2018-06-05

THC, CBD, CBN, THC-COOH and 11-OH-THC are the most popular markers of cannabis consumption and abuse. The use of this drug is a serious social problem worldwide. In this study, a method based on gas chromatography-tandem mass spectrometry (GC-MS/MS) operated in electron ionization (EI) with simple and rapid liquid-liquid extraction (LLE) and derivatization was developed and validated for the simultaneous determination of THC, CBD, CBN and 11-OH-THC in hair samples. The detection of all compounds was based on multiple reaction monitoring (MRM) transitions. The most important advantage of this method is the single-step, quick, easy and effective sample extraction procedure for THC, CBD, CBN and 11-OH-THC. The method showed a good linearity with a correlation coefficient (r 2 ) between 0.997 and 0.999 for all substances. The variation coefficient (%CV) was <5% for THC, 11-OH-THC and CBD and <13% for CBN. The limit of detection (LOD) was 0.03 pg/mg for 11-OH-THC and it ranged from 0.3 to 1.4 pg/mg for THC, CBD and CBN. The limit of quantification was 0.1 pg/mg for 11-OH-THC and it ranged from 0.9 to 4.7 pg/mg for THC, CBD and CBN. Analytical recovery was higher than 88% for 11-OH-THC and it ranged between 68 and 97% for THC, CBD and CBN. Intra- and inter-assay precision and accuracy were always lower than 9-14% and 5-9%, respectively. In parallel, we have quantified the THC-COOH level, following the methods previously set-up by us. The whole procedure was successfully applied to more than 200 different hair samples from cannabis consumers, disclosing the presence of 11-OH-THC in a range between 0.2 pg/mg and 27 pg/mg, and the presence of THC-COOH in a range between 0.05 pg/mg and 42.05 pg/mg. These data provided a good start towards the use of 11-THC-OH as alternative hair biomarker of cannabis consumption. Copyright © 2018 Elsevier B.V. All rights reserved.

A Two-Year Study of Δ 9 Tetrahydrocannabinol Concentrations in Drivers; Part 2: Physiological Signs on Drug Recognition Expert (DRE) and non-DRE Examinations,.

PubMed

Declues, Kari; Perez, Shelli; Figueroa, Ariana

2018-03-01

Whole blood samples were examined for ∆ 9 -Tetrahydrocannabinol (THC) over 2 years in drivers suspected of driving under the influence. Part one of the study examined the link between [THC] and performance on field sobriety tests. This portion examined objective signs, eye examinations and physiological indicators; and their relationship to the presence of THC. Several objective signs were excellent indicators of the presence of THC: red eyes (94%), droopy eyelids (85.6%), affected speech (87.6%), tongue coating (96.2%), and odor of marijuana (82.4%). About 63.6% of THC positive subjects had dialted pupils (room light). THC positive subjects had either rebound dilation or hippus in 88.8% of cases. Pulse and blood pressure (BP) were evaluated to determine any correlation with [THC]. An increased pulse rate correlated well to the presence of THC (88.5%), but not [THC]. BP did not correlate to [THC] and was also a poor indicator of THC in the blood (50% high). © 2017 American Academy of Forensic Sciences.

An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine.

PubMed

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 (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy. This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.

40 CFR 86.143-96 - Calculations; evaporative emissions.

Code of Federal Regulations, 2014 CFR

2014-07-01

....1005(f): ER28AP14.005 Where: m THCE = the sum of the mass of THCE in the SHED. m THC = the mass of THC and all oxygenated hydrocarbons in the SHED, as measured by the FID. Calculate THC mass based on ρ THC. ρ THC = the effective C1-equivalent density of THC as specified in 40 CFR 1066.1005(f). m OHCi = the...

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

PubMed

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.

Cloud point extraction of Δ9-tetrahydrocannabinol from cannabis resin.

PubMed

Ameur, S; Haddou, B; Derriche, Z; Canselier, J P; Gourdon, C

2013-04-01

A cloud point extraction coupled with high performance liquid chromatography (HPLC/UV) method was developed for the determination of Δ(9)-tetrahydrocannabinol (THC) in micellar phase. The nonionic surfactant "Dowfax 20B102" was used to extract and pre-concentrate THC from cannabis resin, prior to its determination with a HPLC-UV system (diode array detector) with isocratic elution. The parameters and variables affecting the extraction were investigated. Under optimum conditions (1 wt.% Dowfax 20B102, 1 wt.% Na2SO4, T = 318 K, t = 30 min), this method yielded a quite satisfactory recovery rate (~81 %). The limit of detection was 0.04 μg mL(-1), and the relative standard deviation was less than 2 %. Compared with conventional solid-liquid extraction, this new method avoids the use of volatile organic solvents, therefore is environmentally safer.

Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

PubMed

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 results indicate that Δ9-THC reduces METH-induced brain damage via inhibition of nNOS expression and astrocyte activation through CB1-dependent and independent mechanisms, respectively.

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

PubMed Central

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

2012-01-01

Introduction 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. Δ9-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. Methods 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. Results 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). Discussion 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. PMID:21764230

Combined effects of THC and caffeine on working memory in rats

PubMed Central

Panlilio, Leigh V; Ferré, Sergi; Yasar, Sevil; Thorndike, Eric B; Schindler, Charles W; Goldberg, Steven R

2012-01-01

BACKGROUND AND PURPOSE Cannabis and caffeine are two of the most widely used psychoactive substances. Δ9-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Here, we evaluate the effects of these drugs using a rodent model of working memory. EXPERIMENTAL APPROACH Rats were given THC (0, 1 and 3 mg·kg−1, i.p.) along with caffeine (0, 1, 3 and 10 mg·kg−1, i.p.), the selective adenosine A1-receptor antagonist CPT (0, 3 and 10 mg·kg−1) or the selective adenosine A2A-receptor antagonist SCH58261 (0 and 5 mg·kg−1) and were tested with a delayed non-matching-to-position procedure in which behaviour during the delay was automatically recorded as a model of memory rehearsal. KEY RESULTS THC alone produced memory deficits at 3 mg·kg−1. The initial exposure to caffeine (10 mg·kg−1) disrupted the established pattern of rehearsal-like behaviour, but tolerance developed rapidly to this effect. CPT and SCH58261 alone had no significant effects on rehearsal or memory. When a subthreshold dose of THC (1 mg·kg−1) was combined with caffeine (10 mg·kg−1) or CPT (10 mg·kg−1), memory performance was significantly impaired, even though performance of the rehearsal-like pattern was not significantly altered. CONCLUSION AND IMPLICATIONS Caffeine did not counteract memory deficits induced by THC but actually exacerbated them. These results are consistent with recent findings that adenosine A1 receptors modulate cannabinoid signalling in the hippocampus. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21699509

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

PubMed

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.

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

PubMed

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).

In Vitro Stability of Free and Glucuronidated Cannabinoids in Blood and Plasma Following Controlled Smoked Cannabis

PubMed Central

Karschner, Erin L.; Desrosiers, Nathalie A.; Gorelick, David A.; Huestis, Marilyn A.

2013-01-01

BACKGROUND Blood and plasma cannabinoid stability is important for test interpretation and is best studied in authentic rather than fortified samples. METHODS Low and high blood and plasma pools were created for each of 10 participants after they smoked a cannabis cigarette. The stabilities of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide, and THCCOOH-glucuronide were determined after 1 week at room temperature; 1, 2, 4, 12, and 26 (±2) weeks at 4 °C; and 1, 2, 4, 12, 26 (±2), and 52 (±4) weeks at −20 °C. Stability was assessed by Friedman test. RESULTS Numbers of THC-glucuronide and CBD-positive blood samples were insufficient to assess stability. In blood, 11-OH-THC and CBN were stable for 1 week at room temperature, whereas THC and THCCOOH-glucuronide decreased and THCCOOH increased. In blood, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, and CBN were stable for 12, 4, 4, 12, and 26 weeks, respectively, at 4 °C and 12, 12, 26, 26, and 52 weeks at −20 °C. In plasma, THC-glucuronide, THC, CBN, and CBD were stable for 1 week at room temperature, whereas THCCOOH-glucuronide and 11-OH-THC decreased and THCCOOH increased. In plasma, THC-glucuronide, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, CBN, and CBD were stable for 26, 26, 2, 2, 26, 12, and 26 weeks, respectively, at 4 °C and 52, 52, 26, 26, 52, 52, and 52 weeks, respectively, at −20 °C. CONCLUSIONS Blood and plasma samples should be stored at −20 °C for no more than 3 and 6 months, respectively, to assure accurate cannabinoid quantitative results. PMID:23519966

Sex-Dependent Psychoneuroendocrine Effects of THC and MDMA in an Animal Model of Adolescent Drug Consumption

PubMed Central

Llorente-Berzal, Alvaro; Puighermanal, Emma; Burokas, Aurelijus; Ozaita, Andrés; Maldonado, Rafael; Marco, Eva M.; Viveros, Maria-Paz

2013-01-01

Ecstasy is a drug that is usually consumed by young people at the weekends and frequently, in combination with cannabis. In the present study we have investigated the long-term effects of administering increasing doses of delta-9-tetrahydrocannabinol [THC; 2.5, 5, 10 mg/kg; i.p.] from postnatal day (pnd) 28 to 45, alone and/or in conjunction with 3,4-methylenedioxymethamphetamine [MDMA; two daily doses of 10 mg/kg every 5 days; s.c.] from pnd 30 to 45, in both male and female Wistar rats. When tested one day after the end of the pharmacological treatment (pnd 46), MDMA administration induced a reduction in directed exploration in the holeboard test and an increase in open-arm exploration in an elevated plus maze. In the long-term, cognitive functions in the novel object test were seen to be disrupted by THC administration to female but not male rats. In the prepulse inhibition test, MDMA-treated animals showed a decrease in prepulse inhibition at the most intense prepulse studied (80 dB), whereas in combination with THC it induced a similar decrease at 75 dB. THC decreased hippocampal Arc expression in both sexes, while in the frontal cortex this reduction was only evident in females. MDMA induced a reduction in ERK1/2 immunoreactivity in the frontal cortex of male but not female animals, and THC decreased prepro-orexin mRNA levels in the hypothalamus of males, although this effect was prevented when the animals also received MDMA. The results presented indicate that adolescent exposure to THC and/or MDMA induces long-term, sex-dependent psychophysiological alterations and they reveal functional interactions between the two drugs. PMID:24223797

Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury.

PubMed

Hochhauser, Edith; Lahat, Eylon; Sultan, Maya; Pappo, Orit; Waldman, Maayan; Sarne, Yosef; Shainberg, Asher; Gutman, Mordechai; Safran, Michal; Ben Ari, Ziv

2015-01-01

Ischemia/reperfusion (I/R) injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC), a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg) in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. C57Bl Mice were studied in in vivo model of hepatic segmental (70%) ischemia for 60min followed by reperfusion for 6 hours. THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway), the acute proinflammatory response (TNF-α, IL-1α, IL-10 and c-FOS hepatic mRNA levels, and ERK signaling pathway activation). This was followed by cell death (the cleavage of the pro-apoptotic caspase 3, DNA fragmentation and TUNEL) after 6 hours of reperfusion. Significantly less hepatic injury was detected in the THC treated I/R mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice. A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury. THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma. © 2015 S. Karger AG, Basel.

40 CFR 1065.303 - Summary of required calibration and verifications

Code of Federal Regulations, 2010 CFR

2010-07-01

.... THC FID optimization, and THC FID verification Optimize and determine CH4 response for THC FID analyzers: Upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers.... For THC FID analyzers: Upon initial installation, after major maintenance, and after FID optimization...

40 CFR 1065.660 - THC and NMHC determination.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 32 2010-07-01 2010-07-01 false THC and NMHC determination. 1065.660... CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC and NMHC determination. (a) THC determination and THC/CH 4 initial contamination corrections. (1) If we require you to...

40 CFR 1065.303 - Summary of required calibration and verifications

Code of Federal Regulations, 2011 CFR

2011-07-01

.... THC FID optimization, and THC FID verification Optimize and determine CH4 response for THC FID analyzers: Upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers.... For THC FID analyzers: Upon initial installation, after major maintenance, and after FID optimization...

The Coast Artillery Journal. Volume 71, Number 2, 1929

DTIC Science & Technology

1929-08-01

Although airplancs had bcen used in the minor Balkan -Wars in thc pcriod just pre- ceding thc ,Yorld \\\\’ar and had becn tcntatiycly fired on by...wedges or pins. Incidcntally all loose pieces arc fastencd to thc caniagc with chains. 1\\. targct moying at thc spced of an airplanc has a widc...rangc of possiblc mancU\\’cr <lUt’jng thc timc of flight of thc projectilc .. \

Rectal bioavailability of delta-9-tetrahydrocannabinol from the hemisuccinate ester in monkeys.

PubMed

ElSohly, M A; Stanford, D F; Harland, E C; Hikal, A H; Walker, L A; Little, T L; Rider, J N; Jones, A B

1991-10-01

Oral administration of delta-9-tetrahydrocannabinal (delta 9-THC) was shown to result in low and erratic bioavailability, while the drug showed no bioavailability from various suppository formulations. delta 9-THC-Hemisuccinate was formulated as a prodrug for delta 9-THC in suppositories using Witepsol H15 base. The bioavailability of delta 9-THC from this formulation was evaluated in monkeys. The plasma levels of delta 9-THC and its metabolite 11-nor-delta 9-THC-9-COOH were determined using GC/MS analysis. The calculated bioavailability of delta 9-THC from this formulation was found to be 13.5%. Non-compartmental analysis of the plasma concentration data using statistical moments showed the mean residence time (MRT) for delta 9-THC in the body to be 3 h following iv administration of delta 9-THC or its hemisuccinate ester (3.4 and 2.7 h, respectively), as compared with 5.8 h following rectal administration of the delta 9-THC hemisuccinate. The observed rectal bioavailability of delta 9-THC from suppositories containing the hemisuccinate ester as a prodrug is of significant importance in developing an alternative approach to oral administration of the drug.

Separate and combined effects of gabapentin and Δ9-THC in humans discriminating Δ9-THC

PubMed Central

Lile, Joshua A.; Wesley, Michael J.; Kelly, Thomas H.; Hays, Lon R.

2015-01-01

The aim of the present study was to examine a potential mechanism of action of gabapentin to manage cannabis-use disorders by determining the interoceptive effects of gabapentin in cannabis users discriminating Δ9-THC using a pharmacologically selective drug-discrimination procedure. Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received gabapentin (600 and 1200 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ9-THC served as a discriminative stimulus, produced positive subjective effects, elevated heart rate and impaired psychomotor performance. Both doses of gabapentin substituted for the Δ9-THC discriminative stimulus and engendered subjective and performance-impairing effects that overlapped with those of Δ9-THC when administered alone. When administered concurrently, gabapentin shifted the discriminative-stimulus effects of Δ9-THC leftward/upward, and combinations of Δ9-THC and gabapentin generally produced larger effects on cannabinoid-sensitive outcomes relative to Δ9-THC alone. These results suggest that one mechanism by which gabapentin might facilitate cannabis abstinence is by producing effects that overlap with those of cannabinoids. PMID:26313650

Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers.

PubMed

Marsot, A; Audebert, C; Attolini, L; Lacarelle, B; Micallef, J; Blin, O

Cannabis is the most widely used illegal drug in the world. Delta-9-tetrahydrocannabinol (THC) is the main source of the pharmacological effect. Some studies have been carried out and showed significant variability in the described models as the values of the estimated pharmacokinetic parameters. The objective of this study was to develop a population pharmacokinetic model for THC in occasional cannabis smokers. Twelve male volunteers (age: 20-28years, body weight: 62.5-91.0kg), tobacco (3-8 cigarette per day) and cannabis occasional smokers were recruited from the local community. After ad libitum smoking cannabis cigarette according a standardized procedure, 16 blood samples up to 72h were collected. Population pharmacokinetic analysis was performed using a non-linear mixed effects model, with NONMEM software. Demographic and biological data were investigated as covariates. A three-compartment model with first-order elimination fitted the data. The model was parameterized in terms of micro constants and central volume of distribution (V 1 ). Normal ALT concentration (6.0 to 45.0IU/l) demonstrated a statistically significant correlation with k 10 . The mean values (%Relative Standard Error (RSE)) for k 10 , k 12 , k 21 , k 23 , k 32 and V 1 were 0.408h -1 (48.8%), 4.070h -1 (21.4%), 0.022h -1 (27.0%), 1.070h -1 (14.3%), 1.060h -1 (16.7%) and 19.10L (39.7%), respectively. We have developed a population pharmacokinetic model able to describe the quantitative relationship between administration of inhaled doses of THC and the observed plasma concentrations after smoking cannabis. In addition, a linear relationship between ALT concentration and value of k 10 has been described and request further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

[Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].

PubMed

Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

2014-03-01

To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.

Delta-9-Tetrahydrocannabinol-Induced Dopamine Release as a Function of Psychosis Risk: 18F-Fallypride Positron Emission Tomography Study

PubMed Central

Kuepper, Rebecca; Ceccarini, Jenny; Lataster, Johan; van Os, Jim; van Kroonenburgh, Marinus; van Gerven, Joop M. A.; Marcelis, Machteld; Van Laere, Koen; Henquet, Cécile

2013-01-01

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 Δ9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ9-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 Δ9-THC administration, reflecting dopamine release. While Δ9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ9-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 Δ9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis. PMID:23936196

Tetrahydrocannabinols in clinical and forensic toxicology.

PubMed

Kochanowski, Maciej; Kała, Maria

2005-01-01

Cannabinoids are the natural constituents of marihuana (cannabis). The main of them are delta9-tetrahydrocannabinol (9THC)--psychoactive agent, cannabinol (CBN) and cannabidiol (CBD). Cannabis is administered either by smoking or orally. 9THC potency and duration of action as well as its and two of its major metabolites concentrations in organism highly depend on the route of administration. A single active dose of 9THC is estimated on 520 mg. 9THC is rapidly metabolised. It is hydroxylated to an active metabolite, I1 -hydroxy-delta9-tetrahydro-cannabinol (11-OH-THC), then oxidised to an inactive 11-nor-9-carboxy-delta9-tetrahydrocannabinol (THCCOOH), which is conjugated with glucuronic acid and predominantly excreted in the urine. The maximum psychological effect persists for 4-6 h after administration despite of very low 9THC blood concentrations. 9THC plasma concentration declined to values of 2-3 ng/ml during 3-4 h after smoking. Such a low concentration of the active compound in human organism create a demand for use of sensitive analytical methods for detection and determination of 9THC and its metabolites. The most effective techniques for 9THC and related compounds determination in biological material are chromatographic ones (gas and liquid) with mass spectrometric detection and different ionization modes. 9THC and its two metabolites (11-OH-THC and THCCOOH) are present in blood and hair, 9THC in saliva, and THCCOOH in urine. 9THC and related compounds are determined in autopsy material, although deaths by overdose of cannabis are exceptionally rare. Fatalities happen most often after intravenous injection of hashish oil. 9THC and its metabolites determination in different biological materials gives the basis for a wide interpretation of analytical results for clinical and forensic toxicology purposes.

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

PubMed Central

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

2014-01-01

Background Recent changes in the legality of cannabis have prompted evaluation of whether blood levels of Δ9-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. Methods 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.) and another received chronic THC (1 mg/kg/12 h s.c.) for several years. Results 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). Conclusion 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. PMID:24703610

Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway.

PubMed

Todd, Stephanie M; Zhou, Cilla; Clarke, David J; Chohan, Tariq W; Bahceci, Dilara; Arnold, Jonathon C

2017-02-01

The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

40 CFR 1065.660 - THC, NMHC, and CH4 determination.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 33 2014-07-01 2014-07-01 false THC, NMHC, and CH4 determination. 1065... POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC, NMHC, and CH4 determination. (a) THC determination and initial THC/CH 4 contamination corrections. (1) If we...

40 CFR 1065.660 - THC, NMHC, and CH4 determination.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 34 2012-07-01 2012-07-01 false THC, NMHC, and CH4 determination. 1065... POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC, NMHC, and CH4 determination. (a) THC determination and initial THC/CH 4 contamination corrections. (1) If we...

40 CFR 1065.660 - THC, NMHC, and CH4 determination.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 34 2013-07-01 2013-07-01 false THC, NMHC, and CH4 determination. 1065... POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC, NMHC, and CH4 determination. (a) THC determination and initial THC/CH 4 contamination corrections. (1) If we...

40 CFR 1065.660 - THC, NMHC, and CH4 determination.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 33 2011-07-01 2011-07-01 false THC, NMHC, and CH4 determination. 1065... POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Calculations and Data Requirements § 1065.660 THC, NMHC, and CH4 determination. (a) THC determination and THC/CH 4 initial contamination corrections. (1) If we...

Analysis of the Variable Pressure Growth Chamber using the CASE/A simulation package

NASA Technical Reports Server (NTRS)

Mcfadden, Carl D.; Edeen, Marybeth A.

1992-01-01

A computer simulation of the Variable Pressure Growth Chamber (VPGC), located at the NASA Johnson Space Center, has been developed using the Computer Aided Systems Engineering and Analysis (CASE/A) package. The model has been used to perform several analyses of the VPGC. The analyses consisted of a study of the effects of a human metabolic load on the VPGC and a study of two new configurations for the temperature and humidity control (THC) subsystem in the VPGC. The objective of the human load analysis was to study the effects of a human metabolic load on the air revitalization and THC subsystems. This included the effects on the quantity of carbon dioxide injected and oxygen removed from the chamber and the effects of the additional sensible and latent heat loads. The objective of the configuration analysis was to compare the two new THC configurations against the current THC configuration to determine which had the best performance.

Total hydrocarbon content (THC) testing in liquid oxygen (LOX) systems

NASA Astrophysics Data System (ADS)

Meneghelli, B. J.; Obregon, R. E.; Ross, H. R.; Hebert, B. J.; Sass, J. P.; Dirschka, G. E.

2015-12-01

The measured Total Hydrocarbon Content (THC) levels in liquid oxygen (LOX) systems at Stennis Space Center (SSC) have shown wide variations. Examples of these variations include the following: 1) differences between vendor-supplied THC values and those obtained using standard SSC analysis procedures; and 2) increasing THC values over time at an active SSC test stand in both storage and run vessels. A detailed analysis of LOX sampling techniques, analytical instrumentation, and sampling procedures will be presented. Additional data obtained on LOX system operations and LOX delivery trailer THC values during the past 12-24 months will also be discussed. Field test results showing THC levels and the distribution of the THC's in the test stand run tank, modified for THC analysis via dip tubes, will be presented.

Total Hydrocarbon Content (THC) Testing in Liquid Oxygen (LOX)

NASA Technical Reports Server (NTRS)

Meneghelli, B. J.; Obregon, R. E.; Ross, H. R.; Hebert, B. J.; Sass, J. P.; Dirschka, G. E.

2016-01-01

The measured Total Hydrocarbon Content (THC) levels in liquid oxygen (LOX) systems at Stennis Space Center (SSC) have shown wide variations. Examples of these variations include the following: 1) differences between vendor-supplied THC values and those obtained using standard SSC analysis procedures; and 2) increasing THC values over time at an active SSC test stand in both storage and run vessels. A detailed analysis of LOX sampling techniques, analytical instrumentation, and sampling procedures will be presented. Additional data obtained on LOX system operations and LOX delivery trailer THC values during the past 12-24 months will also be discussed. Field test results showing THC levels and the distribution of the THC's in the test stand run tank, modified for THC analysis via dip tubes, will be presented.

Comparison of Cannabinoid Concentrations in Plasma, Oral Fluid and Urine in Occasional Cannabis Smokers After Smoking Cannabis Cigarette.

PubMed

Marsot, Amélie; Audebert, Christine; Attolini, Laurence; Lacarelle, Bruno; Micallef, Joelle; Blin, Olivier

A randomized cross-over, double blind placebo controlled study of smoked cannabis was carried out on occasional cannabis smokers. The objective of this research was to describe the pharmacokinetic parameters of THC and its metabolites in plasma, oral fluid and urine, from samples obtained simultaneously to provide estimations of THC and metabolites concentrations after smoking a cannabis cigarette. Blood, oral fluid and urine samples were collected until up to 72 h after smoking the cannabis cigarette (4% of delta-9-tetrathydrocannabinol (THC)). THC, 11-OH-THC and THC-COOH were analyzed by gas-chromatography-mass spectrometry. Pharmacokinetic parameters were estimated from these data. Eighteen male healthy adults participated in the study. In total, 560 plasma, 288 oral fluid and 448 urine samples were quantified for cannabinoids. Plasma, oral fluid and urine pharmacokinetic parameters were calculated. A wide range of median THC Cmax (1.6-160.0 µg/L and 55.4-123120.0 µg/L in plasma and oral fluid, respectively), 11-OH-THC Cmax (0-11.1 µg/L in plasma) and THC-COOH Cmax (1.0-56.3 µg/L in plasma) was observed. When expressed as a percentage of the total available THC dose, and corrected for molar equivalents, mean percentage of total THC dose excreted was 1.9 +/-2.5 % with range of 0.2-7.5%. This high inter-individual variability was also observed on other calculated pharmacokinetic parameters. Prediction of plasma THC concentration from THC oral fluid concentration or from THC-COOH urinary concentrations is not feasible due to the large variations observed. The results from this study support the assumption that a positive oral fluid THC result or a positive urine fluid result are indicative of a recent cannabis exposure. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

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

PubMed Central

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

THC and CBD in blood samples and seizures in Norway: Does CBD affect THC-induced impairment in apprehended subjects?

PubMed

Havig, Stine Marie; Høiseth, Gudrun; Strand, Maren Cecilie; Karinen, Ritva Anneli; Brochmann, Gerd-Wenche; Strand, Dag Helge; Bachs, Liliana; Vindenes, Vigdis

2017-07-01

Several publications have suggested increasing cannabis potency over the last decade, which, together with lower amounts of cannabidiol (CBD), could contribute to an increase in adverse effects after cannabis smoking. Naturalistic studies on tetrahydrocannabinol (THC) and CBD in blood samples are, however, missing. This study aimed to investigate the relationship between THC- and CBD concentrations in blood samples among cannabis users, and to compare cannabinoid concentrations with the outcome of a clinical test of impairment (CTI) and between traffic accidents and non-accident driving under the influence of drugs (DUID)-cases. Assessment of THC- and CBD contents in cannabis seizures was also included. THC- and CBD concentrations in blood samples from subjects apprehended in Norway from April 2013-April 2015 were included (n=6134). A CTI result was compared with analytical findings in cases where only THC and/or CBD were detected (n=705). THC- and CBD content was measured in 41 cannabis seizures. Among THC-positive blood samples, 76% also tested positive for CBD. There was a strong correlation between THC- and CBD concentrations in blood samples (Pearson's r=0.714, p<0.0005). Subjects judged as impaired by a CTI had significantly higher THC- (p<0.001) and CBD (p=0.008) concentrations compared with not impaired subjects, but after multivariate analyses, impairment could only be related to THC concentration (p=0.004). Analyzing seizures revealed THC/CBD ratios of 2:1 for hashish and 200:1 for marijuana. More than ¾ of the blood samples testing positive for THC, among subjects apprehended in Norway, also tested positive for CBD, suggesting frequent consumption of high CBD cannabis products. The simultaneous presence of CBD in blood does, however, not appear to affect THC-induced impairment on a CTI. Seizure sample analysis did not reveal high potency cannabis products, and while CBD content appeared high in hashish, it was almost absent in marijuana. Copyright © 2017. Published by Elsevier B.V.

Delta-9-Tetrahydrocannabinol/Cannabidiol Oromucosal Spray (Sativex®): A Review in Multiple Sclerosis-Related Spasticity.

PubMed

Keating, Gillian M

2017-04-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (THC/CBD, Sativex ® , nabiximols) is available in numerous countries worldwide for the treatment of multiple sclerosis (MS)-related moderate to severe spasticity in patients who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. Twelve weeks' therapy with THC/CBD improved MS-related spasticity in patients with an inadequate response to other anti-spasticity agents who had undergone a successful initial trial of THC/CBD therapy, according to the results of a pivotal phase 3 trial. Improvements in spasticity were maintained in the longer term with THC/CBD with no evidence of dose tolerance, and results of real-world studies confirm the effectiveness of THC/CBD in everyday clinical practice. Improvements in health-related quality of life and activities of daily living were also seen with THC/CBD. THC/CBD is generally well tolerated; adverse effects such as dizziness may occur whilst the THC/CBD dosage is being optimized. THC/CBD has low abuse potential and a low risk of psychoactive effects. In conclusion, THC/CBD oromucosal spray is a useful option for the treatment of MS-related spasticity not completely relieved with current anti-spasticity medication.

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2014 CFR

2014-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C = THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC = THC concentration (uncorrected...

Dronabinol has preferential antileukemic activity in acute lymphoblastic and myeloid leukemia with lymphoid differentiation patterns.

PubMed

Kampa-Schittenhelm, Kerstin Maria; Salitzky, Olaf; Akmut, Figen; Illing, Barbara; Kanz, Lothar; Salih, Helmut Rainer; Schittenhelm, Marcus Matthias

2016-01-16

It has been previously demonstrated in several cancer models, that Dronabinol (THC) may have anti-tumor activity--however, controversial data exists for acute leukemia. We have anecdotal evidence that THC may have contributed to disease control in a patient with acute undifferentiated leukemia. To test this hypothesis, we evaluated the antileukemic efficacy of THC in several leukemia cell lines and native leukemia blasts cultured ex vivo. Expression analysis for the CB1/2 receptors was performed by Western immunoblotting and flow cytometry. CB-receptor antagonists as well as a CRISPR double nickase knockdown approach were used to evaluate for receptor specificity of the observed proapoptotic effects. Meaningful antiproliferative as well as proapoptotic effects were demonstrated in a subset of cases--with a preference of leukemia cells from the lymphatic lineage or acute myeloid leukemia cells expressing lymphatic markers. Induction of apoptosis was mediated via CB1 as well as CB2, and expression of CB receptors was a prerequisite for therapy response in our models. Importantly, we demonstrate that antileukemic concentrations are achievable in vivo. Our study provides rigorous data to support clinical evaluation of THC as a low-toxic therapy option in a well defined subset of acute leukemia patients.

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

NASA Astrophysics Data System (ADS)

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.

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2012 CFR

2012-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C=THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC=THC concentration (uncorrected), ppmvd CO2...

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2013 CFR

2013-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C=THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC=THC concentration (uncorrected), ppmvd CO2...

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2011 CFR

2011-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C=THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC=THC concentration (uncorrected), ppmvd CO2...

40 CFR 63.9800 - How do I conduct performance tests and establish operating limits?

Code of Federal Regulations, 2010 CFR

2010-07-01

... determine compliance with the total hydrocarbon (THC) emission concentration limit listed in Table 1 to this... using Equation 1 of this section: ER16AP03.000 Where: C THC-C=THC concentration, corrected to 18 percent oxygen, parts per million by volume, dry basis (ppmvd) C THC=THC concentration (uncorrected), ppmvd CO2...

Radioimmunoanalysis of delta-9-THC in blood by means of an /sup 125/I tracer. [Delta-9-Tetrahydrocannabinol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Owens, S.M.; McBay, A.J.; Reisner, H.M.

A radioimmunoassay for delta-9-THC in plasma, whole blood, or hemolyzed blood specimens has been presented. Samples and standards were diluted with methanol and centrifuged. An aliquot of the supernatant fluid was incubated with RIA buffer, /sup 125/I-labeled delta-8-THC and rabbit anti-THC serum. Solid phase goat anti-rabbit immunoglobulins were added to separate bound from free THC. After centrifugation the supernatant fluid was aspirated and the radioactivity of the precipitate was counted in a gamma counter. The concentration of THC was calculated from a standard curve using the logit-log transformation of the average counts of duplicate tubes. The assay had several advantages.more » Methanol dilution gave better results than direct analysis. The /sup 125/I-labeled THC had high specific activity and could be counted in a gamma counter. The immunological separation of antibody-bound THC from free THC was better than separation techniques using ammonium sulfate and activated charcoal. THC was determined in 0.1 ml of sample with a sensitivity of 1.5 ng/ml in plasma and 3.0 ng/ml in hemolyzed blood.« less

Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration.

PubMed

Karschner, Erin L; Darwin, W David; Goodwin, Robert S; Wright, Stephen; Huestis, Marilyn A

2011-01-01

Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.

Enzymatic Degradation of Aromatic and Aliphatic Polyesters by P. pastoris Expressed Cutinase 1 from Thermobifida cellulosilytica

PubMed Central

Gamerith, Caroline; Vastano, Marco; Ghorbanpour, Sahar M.; Zitzenbacher, Sabine; Ribitsch, Doris; Zumstein, Michael T.; Sander, Michael; Herrero Acero, Enrique; Pellis, Alessandro; Guebitz, Georg M.

2017-01-01

To study hydrolysis of aromatic and aliphatic polyesters cutinase 1 from Thermobifida cellulosilytica (Thc_Cut1) was expressed in P. pastoris. No significant differences between the expression of native Thc_Cut1 and of two glycosylation site knock out mutants (Thc_Cut1_koAsn and Thc_Cut1_koST) concerning the total extracellular protein concentration and volumetric activity were observed. Hydrolysis of poly(ethylene terephthalate) (PET) was shown for all three enzymes based on quantification of released products by HPLC and similar concentrations of released terephthalic acid (TPA) and mono(2-hydroxyethyl) terephthalate (MHET) were detected for all enzymes. Both tested aliphatic polyesters poly(butylene succinate) (PBS) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) were hydrolyzed by Thc_Cut1 and Thc_Cut1_koST, although PBS was hydrolyzed to significantly higher extent than PHBV. These findings were also confirmed via quartz crystal microbalance (QCM) analysis; for PHBV only a small mass change was observed while the mass of PBS thin films decreased by 93% upon enzymatic hydrolysis with Thc_Cut1. Although both enzymes led to similar concentrations of released products upon hydrolysis of PET and PHBV, Thc_Cut1_koST was found to be significantly more active on PBS than the native Thc_Cut1. Hydrolysis of PBS films by Thc_Cut1 and Thc_Cut1_koST was followed by weight loss and scanning electron microscopy (SEM). Within 96 h of hydrolysis up to 92 and 41% of weight loss were detected with Thc_Cut1_koST and Thc_Cut1, respectively. Furthermore, SEM characterization of PBS films clearly showed that enzyme tretment resulted in morphological changes of the film surface. PMID:28596765

Fasting and exercise increase plasma cannabinoid levels in THC pre-treated rats: an examination of behavioural consequences.

PubMed

Wong, Alexander; Keats, Kirily; Rooney, Kieron; Hicks, Callum; Allsop, David J; Arnold, Jonathon C; McGregor, Iain S

2014-10-01

Δ(9)-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in fat tissue where it can remain for prolonged periods. Under conditions of increased fat utilisation, blood cannabinoid concentrations can increase. However, it is unclear whether this has behavioural consequences. Here, we examined whether rats pre-treated with multiple or single doses of THC followed by a washout would show elevated plasma cannabinoids and altered behaviour following fasting or exercise manipulations designed to increase fat utilisation. Behavioural impairment was measured as an inhibition of spontaneous locomotor activity or a failure to successfully complete a treadmill exercise session. Fat utilisation was indexed by plasma free fatty acid (FFA) levels with plasma concentrations of THC and its terminal metabolite (-)-11-nor-9-carboxy-∆(9)-tetrahydrocannabinol (THC-COOH) also measured. Rats given daily THC (10 mg/kg) for 5 days followed by a 4-day washout showed elevated plasma THC-COOH when fasted for 24 h relative to non-fasted controls. Fasted rats showed lower locomotor activity than controls suggesting a behavioural effect of fat-released THC. However, rats fasted for 20 h after a single 5-mg/kg THC injection did not show locomotor suppression, despite modestly elevated plasma THC-COOH. Rats pre-treated with THC (5 mg/kg) and exercised 20 h later also showed elevated plasma THC-COOH but did not differ from controls in their likelihood of completing 30 min of treadmill exercise. These results confirm that fasting and exercise can increase plasma cannabinoid levels. Behavioural consequences are more clearly observed with pre-treatment regimes involving repeated rather than single THC dosing.

Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers.

PubMed

Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schroeder, Jennifer R; Schwope, David M; Kelly, Deanna L; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

2013-01-01

Δ9-tetrahydrocannabinol (THC) promotes sleep in animals; clinical use of THC is associated with somnolence. Human laboratory studies of oral THC have not shown consistent effects on sleep. We prospectively evaluated self-reported sleep parameters during controlled oral THC administration to research volunteers. Thirteen male chronic daily cannabis smokers (mean ± SD age 24.6± 3.7 years, self-reported smoking frequency of 5.5 ± 5.9 (range 1-24) joint-equivalents daily at study entry) were administered oral THC doses (20 mg) around-the-clock for 7 days (40-120 mg daily) starting the afternoon after admission. The St. Mary's Hospital Sleep Questionnaire was completed every morning. Plasma THC and 11-OH-THC (active metabolite) concentrations were measured in venous blood samples collected every evening. Changes in sleep characteristics over time and associations between sleep characteristics and plasma cannabinoid concentrations were evaluated with repeated measures mixed linear regression. Higher evening THC and 11-OH-THC concentrations were significantly associated with shorter sleep latency, less difficulty falling asleep, and more daytime sleep the following day. In contrast, the duration of calculated and self-reported nighttime sleep decreased slightly (3.54 and 5.34 minutes per night, respectively) but significantly during the study. These findings suggest that tolerance to the somnolent effects of THC may have occurred, but results should be considered preliminary due to design limitations. Somnolence from oral THC may dissipate with chronic, high-dose use. This has implications for patients who may take chronic oral THC for medicinal purposes, including cannabis dependence treatment. (Am J Addict 2013;22:510-514). Copyright © American Academy of Addiction Psychiatry.

Identification of Recent Cannabis Use: Whole-Blood and Plasma Free and Glucuronidated Cannabinoid Pharmacokinetics following Controlled Smoked Cannabis Administration

PubMed Central

Schwope, David M.; Karschner, Erin L.; Gorelick, David A.; Huestis, Marilyn A.

2013-01-01

BACKGROUND Δ9-Tetrahydrocannabinol (THC) is the most frequently observed illicit drug in investigations of accidents and driving under the influence of drugs. THC-glucuronide has been suggested as a marker of recent cannabis use, but there are no blood data following controlled THC administration to test this hypothesis. Furthermore, there are no studies directly examining whole-blood cannabinoid pharmacokinetics, although this matrix is often the only available specimen. METHODS Participants (9 men, 1 woman) resided on a closed research unit and smoked one 6.8% THC cannabis cigarette ad libitum. We quantified THC, 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide and THCCOOH-glucuronide directly in whole blood and plasma by liquid chromatography/ tandem mass spectrometry within 24 h of collection to obviate stability issues. RESULTS Median whole blood (plasma) observed maximum concentrations (Cmax) were 50 (76), 6.4 (10), 41 (67), 1.3 (2.0), 2.4 (3.6), 89 (190), and 0.7 (1.4) μg/L 0.25 h after starting smoking for THC, 11-OH-THC, THCCOOH, CBD, CBN, and THCCOOH-glucuronide, respectively, and 0.5 h for THC-glucuronide. At observed Cmax, whole-blood (plasma) detection rates were 60% (80%), 80% (90%), and 50% (80%) for CBD, CBN, and THC-glucuronide, respectively. CBD and CBN were not detectable after 1 h in either matrix (LOQ 1.0 μg/L). CONCLUSIONS Human whole-blood cannabinoid data following cannabis smoking will assist whole blood and plasma cannabinoid interpretation, while furthering identification of recent cannabis intake. PMID:21836075

Neural correlates of interactions between cannabidiol and Δ(9) -tetrahydrocannabinol in mice: implications for medical cannabis.

PubMed

Todd, S M; Arnold, J C

2016-01-01

It has been proposed that medicinal strains of cannabis and therapeutic preparations would be safer with a more balanced concentration ratio of Δ(9) -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. 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). 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. 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. © 2015 The British Pharmacological Society.

Modeling Coupled Processes in Clay Formations for Radioactive Waste Disposal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Hui-Hai; Rutqvist, Jonny; Zheng, Liange

As a result of the termination of the Yucca Mountain Project, the United States Department of Energy (DOE) has started to explore various alternative avenues for the disposition of used nuclear fuel and nuclear waste. The overall scope of the investigation includes temporary storage, transportation issues, permanent disposal, various nuclear fuel types, processing alternatives, and resulting waste streams. Although geologic disposal is not the only alternative, it is still the leading candidate for permanent disposal. The realm of geologic disposal also offers a range of geologic environments that may be considered, among those clay shale formations. Figure 1-1 presents themore » distribution of clay/shale formations within the USA. Clay rock/shale has been considered as potential host rock for geological disposal of high-level nuclear waste throughout the world, because of its low permeability, low diffusion coefficient, high retention capacity for radionuclides, and capability to self-seal fractures induced by tunnel excavation. For example, Callovo-Oxfordian argillites at the Bure site, France (Fouche et al., 2004), Toarcian argillites at the Tournemire site, France (Patriarche et al., 2004), Opalinus clay at the Mont Terri site, Switzerland (Meier et al., 2000), and Boom clay at Mol site, Belgium (Barnichon et al., 2005) have all been under intensive scientific investigations (at both field and laboratory scales) for understanding a variety of rock properties and their relations with flow and transport processes associated with geological disposal of nuclear waste. Clay/shale formations may be generally classified as indurated and plastic clays (Tsang et al., 2005). The latter (including Boom clay) is a softer material without high cohesion; its deformation is dominantly plastic. For both clay rocks, coupled thermal, hydrological, mechanical and chemical (THMC) processes are expected to have a significant impact on the long-term safety of a clay repository. For example, the excavation-damaged zone (EDZ) near repository tunnels can modify local permeability (resulting from induced fractures), potentially leading to less confinement capability (Tsang et al., 2005). Because of clay's swelling and shrinkage behavior (depending on whether the clay is in imbibition or drainage processes), fracture properties in the EDZ are quite dynamic and evolve over time as hydromechanical conditions change. To understand and model the coupled processes and their impact on repository performance is critical for the defensible performance assessment of a clay repository. Within the Natural Barrier System (NBS) group of the Used Fuel Disposition (UFD) Campaign at DOE's Office of Nuclear Energy, LBNL's research activities have focused on understanding and modeling such coupled processes. LBNL provided a report in this April on literature survey of studies on coupled processes in clay repositories and identification of technical issues and knowledge gaps (Tsang et al., 2010). This report will document other LBNL research activities within the natural system work package, including the development of constitutive relationships for elastic deformation of clay rock (Section 2), a THM modeling study (Section 3) and a THC modeling study (Section 4). The purpose of the THM and THC modeling studies is to demonstrate the current modeling capabilities in dealing with coupled processes in a potential clay repository. In Section 5, we discuss potential future R&D work based on the identified knowledge gaps. The linkage between these activities and related FEPs is presented in Section 6.« less

Cannabinoids and metabolites in expectorated oral fluid after 8 days of controlled around-the-clock oral THC administration.

PubMed

Milman, Garry; Barnes, Allan J; Schwope, David M; Schwilke, Eugene W; Goodwin, Robert S; Kelly, Deana L; Gorelick, David A; Huestis, Marilyn A

2011-08-01

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 Δ(9)-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, 11-hydroxy-THC, cannabidiol, and cannabinol, and negative chemical ionization for 11-nor-9-carboxy-THC (THCCOOH). Linear ranges for THC, 11-hydroxy-THC, and cannabidiol were 0.25-50 ng/mL; cannabinol 1-50 ng/mL; and THCCOOH 5-500 pg/mL. THCCOOH was the most prevalent analyte in 344 specimens (96.9%), with concentrations up to 1,390.3 pg/mL. 11-hydroxy-THC, cannabidiol, and cannabinol were detected in 1, 1, and 3 specimens, respectively. THC was detected in only 13.8% of specimens. The highest THC concentrations were obtained at admission (median 1.4 ng/mL, range 0.3-113.6) from previously self-administered smoked cannabis. A total of 2.5 and 3.7% of specimens were THC-positive at the recommended Substance Abuse and Mental Health Services Administration (2 ng/mL) and Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) (1 ng/mL) confirmation cutoffs, respectively. THC is currently the only analyte for monitoring cannabis exposure in OF; however, these data indicate chronic therapeutic oral THC administration and illicit oral THC use are unlikely to be identified with current guidelines. Measurement of THCCOOH may improve the detection and interpretation of OF cannabinoid tests and minimize the possibility of OF contamination from passive inhalation of cannabis smoke.

Cannabinoids and metabolites in expectorated oral fluid after 8 days of controlled around-the-clock oral THC administration

PubMed Central

Milman, Garry; Barnes, Allan J.; Schwope, David M.; Schwilke, Eugene W.; Goodwin, Robert S.; Kelly, Deana L.; Gorelick, David A.

2013-01-01

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, 11-hydroxy-THC, cannabidiol, and cannabinol, and negative chemical ionization for 11-nor-9-carboxy-THC (THCCOOH). Linear ranges for THC, 11-hydroxy-THC, and cannabidiol were 0.25–50 ng/mL; cannabinol 1–50 ng/mL; and THCCOOH 5–500 pg/mL. THCCOOH was the most prevalent analyte in 344 specimens (96.9%), with concentrations up to 1,390.3 pg/mL. 11-hydroxy-THC, cannabidiol, and cannabinol were detected in 1, 1, and 3 specimens, respectively. THC was detected in only 13.8% of specimens. The highest THC concentrations were obtained at admission (median 1.4 ng/mL, range 0.3–113.6) from previously self-administered smoked cannabis. A total of 2.5 and 3.7% of specimens were THC-positive at the recommended Substance Abuse and Mental Health Services Administration (2 ng/mL) and Driving Under the Influence of Drugs, Alcohol and Medicines (DRUID) (1 ng/mL) confirmation cutoffs, respectively. THC is currently the only analyte for monitoring cannabis exposure in OF; however, these data indicate chronic therapeutic oral THC administration and illicit oral THC use are unlikely to be identified with current guidelines. Measurement of THCCOOH may improve the detection and interpretation of OF cannabinoid tests and minimize the possibility of OF contamination from passive inhalation of cannabis smoke. PMID:21637933

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

PubMed Central

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

Disposition of Cannabichromene, Cannabidiol, and Δ9-Tetrahydrocannabinol and its Metabolites in Mouse Brain following Marijuana Inhalation Determined by High-Performance Liquid Chromatography–Tandem Mass Spectrometry

PubMed Central

Poklis, Justin L.; Thompson, Candace C.; Long, Kelly A.; Lichtman, Aron H.; Poklis, Alphonse

2011-01-01

A liquid chromatography–tandem mass spectrometry (LC–MS–MS) method was developed for the analysis of marijuana cannabinoids in mouse brain tissue using an Applied Biosystems 3200 Q trap with a turbo V source for TurbolonSpray attached to a Shimadzu SCL HPLC system. The method included cannabichromene (CBC), cannabidiol (CBD), D9-tetrahydrocannabinol (THC), 11-hydroxytetrahydrocannabinol (11-OH-THC), and 11-nor-D9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). These compounds were isolated by liquid-liquid extraction using cold acetonitrile. The following transition ions were monitored by multiple reaction monitoring (MRM): m/z 315>193, 315>259 for THC/CBD/CBC; m/z 331>193, 331>105 for 11-OH-THC; m/z 345>299, 345>193 for THC-COOH;c m/z 318>196 for THC-d3; m/z 334>196 for 11-OH-THC-d3, and m/z 348>302 for THCCOOH-d3. Linearity for THC, 1-OH-THC, and THC-COOH was 1-200 ng/g; for CBC and CBD, it was 0.5–20 ng/g. Within-run and between-run precisions for all the analytes yielded coefficients of variation of < 20%. Four C57BL6 mice were sacrificed 20 min after nose-only exposure to the smoke of 200 mg of marijuana containing 0.44 mg CBC, 0.93 mg CBD, and 8.81 mg THC. The mean brain concentrations were 3.9 ± 1.5 ng/g CBC, 21 ± 3.9 ng/g CBD, 364 ± 74 ng/g THC, and 28 ± 5.9 ng/g 11-OH-THC. THCCOOH was not detected. The relative mean brain cannabinoid concentrations correlated to the amounts of the cannabinoids in the inhaled marijuana. PMID:21258613

Δ9-Tetrahydrocannabinol Prevents Methamphetamine-Induced Neurotoxicity

PubMed Central

Castelli, M. Paola; 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 results indicate that Δ9-THC reduces METH-induced brain damage via inhibition of nNOS expression and astrocyte activation through CB1-dependent and independent mechanisms, respectively. PMID:24844285

Opioid antagonism of cannabinoid effects: differences between marijuana smokers and nonmarijuana smokers.

PubMed

Haney, Margaret

2007-06-01

In non-human animals, opioid antagonists block the reinforcing and discriminative-stimulus effects of Delta(9)-tetrahydrocannabinol (THC), while in human marijuana smokers, naltrexone (50 mg) enhances the reinforcing and subjective effects of THC. The objective of this study was to test a lower, more opioid-selective dose of naltrexone (12 mg) in combination with THC. The influence of marijuana-use history and sex was also investigated. Naltrexone (0, 12 mg) was administered 30 min before oral THC (0-40 mg) or methadone (0-10 mg) capsules, and subjective effects, task performance, pupillary diameter, and cardiovascular parameters were assessed in marijuana smoking (Study 1; n=22) and in nonmarijuana smoking (Study 2; n=21) men and women. The results show that in marijuana smokers, low-dose naltrexone blunted the intoxicating effects of a low THC dose (20 mg), while increasing ratings of anxiety at a higher THC dose (40 mg). In nonmarijuana smokers, low-dose naltrexone shifted THC's effects in the opposite direction, enhancing the intoxicating effects of a low THC dose (2.5 mg) and decreasing anxiety ratings following a high dose of THC (10 mg). There were no sex differences in these interactions, although among nonmarijuana smokers, men were more sensitive to the effects of THC alone than women. To conclude, a low, opioid-selective dose of naltrexone blunted THC intoxication in marijuana smokers, while in nonmarijuana smokers, naltrexone enhanced THC intoxication. These data demonstrate that the interaction between opioid antagonists and cannabinoid agonists varies as a function of marijuana use history.

The inheritance of chemical phenotype in Cannabis sativa L.

PubMed Central

de Meijer, Etienne P M; Bagatta, Manuela; Carboni, Andrea; Crucitti, Paola; Moliterni, V M Cristiana; Ranalli, Paolo; Mandolino, Giuseppe

2003-01-01

Four crosses were made between inbred Cannabis sativa plants with pure cannabidiol (CBD) and pure Delta-9-tetrahydrocannabinol (THC) chemotypes. All the plants belonging to the F(1)'s were analyzed by gas chromatography for cannabinoid composition and constantly found to have a mixed CBD-THC chemotype. Ten individual F(1) plants were self-fertilized, and 10 inbred F(2) offspring were collected and analyzed. In all cases, a segregation of the three chemotypes (pure CBD, mixed CBD-THC, and pure THC) fitting a 1:2:1 proportion was observed. The CBD/THC ratio was found to be significantly progeny specific and transmitted from each F(1) to the F(2)'s derived from it. A model involving one locus, B, with two alleles, B(D) and B(T), is proposed, with the two alleles being codominant. The mixed chemotypes are interpreted as due to the genotype B(D)/B(T) at the B locus, while the pure-chemotype plants are due to homozygosity at the B locus (either B(D)/B(D) or B(T)/B(T)). It is suggested that such codominance is due to the codification by the two alleles for different isoforms of the same synthase, having different specificity for the conversion of the common precursor cannabigerol into CBD or THC, respectively. The F(2) segregating groups were used in a bulk segregant analysis of the pooled DNAs for screening RAPD primers; three chemotype-associated markers are described, one of which has been transformed in a sequence-characterized amplified region (SCAR) marker and shows tight linkage to the chemotype and codominance. PMID:12586720

Acute administration of THC impairs spatial but not associative memory function in zebrafish.

PubMed

Ruhl, Tim; Prinz, Nicole; Oellers, Nadine; Seidel, Nathan Ian; Jonas, Annika; Albayram, Onder; Bilkei-Gorzo, Andras; von der Emde, Gerhard

2014-10-01

The present study examined the effect of acute administration of endocannabinoid receptor CB1 ligand ∆-9-tetrahydrocannabinol (THC) on intracellular signalling in the brain and retrieval from two different memory systems in the zebrafish (Danio rerio). First, fish were treated with THC and changes in the phosphorylation level of mitogen-activated protein (MAP) kinases Akt and Erk in the brain were determined 1 h after drug treatment. Next, animals of a second group learned in a two-alternative choice paradigm to discriminate between two colours, whereas a third group solved a spatial cognition task in an open-field maze by use of an ego-allocentric strategy. After memory acquisition and consolidation, animals were pharmacologically treated using the treatment regime as in the first group and then tested again for memory retrieval. We found an enhanced Erk but not Akt phosphorylation suggesting that THC treatment specifically activated Erk signalling in the zebrafish telencephalon. While CB1 agonist THC did not affect behavioural performance of animals in the colour discrimination paradigm, spatial memory was significantly impaired. The effect of THC on spatial learning is probably specific, since neither motor activity nor anxiety-related behaviour was influenced by the drug treatment. That indicates a striking influence of the endocannabinoid system (ECS) on spatial cognition in zebrafish. The results are very coincident with reports on mammals, demonstrating that the ECS is functional highly conserved during vertebrate evolution. We further conclude that the zebrafish provides a promising model organism for ongoing research on the ECS.

Exposure to marijuana smoke impairs memory retrieval in mice.

PubMed

Niyuhire, Floride; Varvel, Stephen A; Martin, Billy R; Lichtman, Aron H

2007-09-01

Marijuana (Cannabis sativa) and its primary psychoactive component, delta-9-tetrahydrocannabinol (Delta(9)-THC), have long been known to disrupt cognition in humans. Although Delta(9)-THC and other cannabinoids disrupt performance in a wide range of animal models of learning and memory, few studies have investigated the effects of smoked marijuana in these paradigms. Moreover, in preclinical studies, cannabinoids are generally administered before acquisition, and because retention is generally evaluated soon afterward, it is difficult to distinguish between processes related to acquisition and retrieval. In the present study, we investigated the specific effects of marijuana smoke and injected Delta(9)-THC on acquisition versus memory retrieval in a mouse repeated acquisition Morris water-maze task. To distinguish between these processes, subjects were administered Delta(9)-THC or they were exposed to marijuana smoke either 30 min before acquisition or 30 min before the retention test. Inhalation of marijuana smoke or injected Delta(9)-THC impaired the ability of the mice to learn the location of the hidden platform and to recall the platform location once learning had already taken place. In contrast, neither drug impaired performance in a cued task in which the platform was made visible. Finally, the cannabinoid-1 (CB(1)) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (rimonabant) blocked the memory disruptive effects of both Delta(9)-THC and marijuana. These data represent the first evidence demonstrating that marijuana impairs memory retrieval through a CB(1) receptor mechanism of action and independently of its effects on sensorimotor performance, motivation, and initial acquisition.

Effect of hydrolysis on identifying prenatal cannabis exposure

PubMed Central

Gray, Teresa R.; Barnes, Allan J.

2011-01-01

Identification of prenatal cannabis exposure is important due to potential cognitive and behavioral consequences. A two-dimensional gas chromatography–mass spectrometry method for cannabinol, Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 8β,11-dihydroxy-THC, and 11-nor-9-carboxy-THC (THCCOOH) quantification in human meconium was developed and validated. Alkaline, enzymatic, and enzyme–alkaline tandem hydrolysis conditions were optimized with THC- and THCCOOH-glucuronide reference standards. Limits of quantification ranged from 10 to 15 ng/g, and calibration curves were linear to 500 ng/g. Bias and intra-day and inter-day imprecision were <12.3%. Hydrolysis efficiencies were analyte-dependent; THC-glucuronide was effectively cleaved by enzyme, but not base. Conversely, THCCOOH-glucuronide was most sensitive to alkaline hydrolysis. Enzyme–alkaline tandem hydrolysis maximized efficiency for both glucuronides. Identification of cannabinoid-positive meconium specimens nearly doubled following alkaline and enzyme–alkaline hydrolysis. Although no 11-OH-THC glucuronide standard is available, enzymatic hydrolysis improved 11-OH-THC detection in authentic specimens. Maximal identification of cannabis-exposed neonates and the widest range of cannabis biomarkers are achieved with enzyme–alkaline tandem hydrolysis. PMID:20517601

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.

PubMed

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

2017-11-15

The lipophilic phytocannabinoids cannabidiol (CBD) and Δ 9 -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 compounds that currently cannot be administered orally. Copyright © 2017. Published by Elsevier B.V.

Combined effects of THC and caffeine on working memory in rats.

PubMed

Panlilio, Leigh V; Ferré, Sergi; Yasar, Sevil; Thorndike, Eric B; Schindler, Charles W; Goldberg, Steven R

2012-04-01

Cannabis and caffeine are two of the most widely used psychoactive substances. Δ(9) -Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, induces deficits in short-term memory. Caffeine, a non-selective adenosine receptor antagonist, attenuates some memory deficits, but there have been few studies addressing the effects of caffeine and THC in combination. Here, we evaluate the effects of these drugs using a rodent model of working memory. Rats were given THC (0, 1 and 3 mg·kg(-1) , i.p.) along with caffeine (0, 1, 3 and 10 mg·kg(-1) , i.p.), the selective adenosine A(1) -receptor antagonist CPT (0, 3 and 10 mg·kg(-1) ) or the selective adenosine A(2A) -receptor antagonist SCH58261 (0 and 5 mg·kg(-1) ) and were tested with a delayed non-matching-to-position procedure in which behaviour during the delay was automatically recorded as a model of memory rehearsal. THC alone produced memory deficits at 3 mg·kg(-1) . The initial exposure to caffeine (10 mg·kg(-1) ) disrupted the established pattern of rehearsal-like behaviour, but tolerance developed rapidly to this effect. CPT and SCH58261 alone had no significant effects on rehearsal or memory. When a subthreshold dose of THC (1 mg·kg(-1) ) was combined with caffeine (10 mg·kg(-1) ) or CPT (10 mg·kg(-1) ), memory performance was significantly impaired, even though performance of the rehearsal-like pattern was not significantly altered. Caffeine did not counteract memory deficits induced by THC but actually exacerbated them. These results are consistent with recent findings that adenosine A(1) receptors modulate cannabinoid signalling in the hippocampus. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. Published 2011. This article is a U.S. Government work and is in the public domain in the USA.

Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease.

PubMed

Sagredo, Onintza; Pazos, M Ruth; Satta, Valentina; Ramos, José A; Pertwee, Roger G; Fernández-Ruiz, Javier

2011-09-01

We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington's disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies. Copyright © 2011 Wiley-Liss, Inc.

Metabolic patterns of JWH-210, RCS-4, and THC in pig urine elucidated using LC-HR-MS/MS: Do they reflect patterns in humans?

PubMed

Schaefer, Nadine; Helfer, Andreas G; Kettner, Mattias; Laschke, Matthias W; Schlote, Julia; Ewald, Andreas H; Meyer, Markus R; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

2017-04-01

The knowledge of pharmacokinetic (PK) properties of synthetic cannabinoids (SCs) is important for interpretation of analytical results found for example in intoxicated individuals. In the absence of human data from controlled studies, animal models elucidating SC PK have to be established. Pigs providing large biofluid sample volumes were tested for prediction of human PK data. In this context, the metabolic fate of two model SCs, namely 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4), was elucidated in addition to Δ 9 -tetrahydrocannabinol (THC). After intravenous administration of the compounds, hourly collected pig urine was analyzed by liquid chromatography-high resolution mass spectrometry. The following pathways were observed: for JWH-210, hydroxylation at the ethyl side chain or pentyl chain and combinations of them followed by glucuronidation; for RCS-4, hydroxylation at the methoxyphenyl moiety or pentyl chain followed by glucuronidation as well as O-demethylation followed by glucuronidation or sulfation; for THC, THC glucuronidation, 11-hydroxylation, followed by carboxylation and glucuronidation. For both SCs, parent compounds could not be detected in urine in contrast to THC. These results were consistent with those obtained from human hepatocyte and/or human case studies. Urinary markers for the consumption of JWH-210 were the glucuronide of the N-hydroxypentyl metabolite (detectable for 3-4 h) and of RCS-4 the glucuronides of the N-hydroxypentyl, hydroxy-methoxyphenyl (detectable for at least 6 h), and the O-demethyl-hydroxy metabolites (detectable for 4 h). Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ⁹-THC in humans discriminating Δ⁹-THC.

PubMed

Lile, Joshua A; Kelly, Thomas H; Hays, Lon R

2014-10-01

Our previous research suggested the involvement of γ-aminobutyric acid (GABA), in particular the GABAB receptor subtype, in the interoceptive effects of Δ(9)-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)-THC using pharmacologically selective drug-discrimination procedures. Ten cannabis users learned to discriminate 30 mg oral Δ(9)-THC from placebo and then received diazepam (5 and 10mg), Δ(9)-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Δ(9)-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug) and elevated heart rate. Diazepam alone impaired performance on psychomotor performance tasks and increased ratings on a limited number of self-report questionnaire items (e.g., Any Effect, Sedated), but did not substitute for the Δ(9)-THC discriminative stimulus or alter the Δ(9)-THC discrimination dose-response function. Similarly, diazepam had limited impact on the other behavioral effects of Δ(9)-THC. These results suggest that the GABAA receptor subtype has minimal involvement in the interoceptive effects of Δ(9)-THC, and by extension cannabis, in humans. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells*

PubMed Central

Kozela, Ewa; Pietr, Maciej; Juknat, Ana; Rimmerman, Neta; Levy, Rivka; Vogel, Zvi

2010-01-01

Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. However, the mechanisms of these effects are not completely understood. Using the BV-2 mouse microglial cell line and lipopolysaccharide (LPS) to induce an inflammatory response, we studied the signaling pathways engaged in the anti-inflammatory effects of cannabinoids as well as their influence on the expression of several genes known to be involved in inflammation. We found that the two major cannabinoids present in marijuana, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), decrease the production and release of proinflammatory cytokines, including interleukin-1β, interleukin-6, and interferon (IFN)β, from LPS-activated microglial cells. The cannabinoid anti-inflammatory action does not seem to involve the CB1 and CB2 cannabinoid receptors or the abn-CBD-sensitive receptors. In addition, we found that THC and CBD act through different, although partially overlapping, mechanisms. CBD, but not THC, reduces the activity of the NF-κB pathway, a primary pathway regulating the expression of proinflammatory genes. Moreover, CBD, but not THC, up-regulates the activation of the STAT3 transcription factor, an element of homeostatic mechanism(s) inducing anti-inflammatory events. Following CBD treatment, but less so with THC, we observed a decreased level of mRNA for the Socs3 gene, a main negative regulator of STATs and particularly of STAT3. However, both CBD and THC decreased the activation of the LPS-induced STAT1 transcription factor, a key player in IFNβ-dependent proinflammatory processes. In summary, our observations show that CBD and THC vary in their effects on the anti-inflammatory pathways, including the NF-κB and IFNβ-dependent pathways. PMID:19910459

Strain and sex differences in puberty onset and the effects of THC administration on weight gain and brain volumes.

PubMed

Keeley, R J; Trow, J; McDonald, R J

2015-10-01

The use of recreational marijuana is widespread and frequently begins and persists through adolescence. Some research has shown negative consequences of adolescent marijuana use, but this is not seen across studies, and certain factors, like genetic background and sex, may influence the results. It is critical to identify which characteristics predispose an individual to be susceptible to the negative consequences of chronic exposure to marijuana in adolescence on brain health and behavior. To this end, using males and females of two strains of rats, Long-Evans hooded (LER) and Wistar (WR) rats, we explored whether these anatomically and behaviorally dimorphic strains demonstrated differences in puberty onset and strain-specific effects of adolescent exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. Daily 5 mg/kg treatment began on the day of puberty onset and continued for 14 days. Of particular interest were metrics of growth and volumetric estimates of brain areas involved in cognition that contain high densities of cannabinoid receptors, including the hippocampus and its subregions, the amygdala, and the frontal cortex. Brain volumetrics were analyzed immediately following the treatment period. LER and WR females started puberty at different ages, but no strain differences were observed in brain volumes. THC decreased weight gain throughout the treatment period for all groups. Only the hippocampus and some of its subregions were affected by THC, and increased volumes with THC administration was observed exclusively in females, regardless of strain. Long-term treatment of THC did not affect all individuals equally, and females displayed evidence of increased sensitivity to the effects of THC, and by extension, marijuana. Identifying differences in adolescent physiology of WR and LER rats could help determine the cause for strain and sex differences in brain and behavior of adults and help to refine the use of animal models in marijuana research. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

PubMed Central

Wakley, Alexa A.; Wiley, Jenny L.; Craft, Rebecca M.

2014-01-01

Background Sex differences in cannabinoid effects have been reported in rodents, with adult females typically being more sensitive than adult males. The present study compared the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) in adult, gonadally intact female vs. male rats. Methods Cumulative dose-effect curves were obtained for THC (1.0–18 mg/kg i.p.) on warm water tail withdrawal and paw pressure tests. Vehicle or the sex-specific ED80 dose for THC was administered twice daily for 9 days; THC dose-effect curves were then re-determined. Results On the pre-chronic test day, THC was significantly more potent in females than males in producing antinociception on the tail withdrawal and paw pressure tests. After 9 days of twice-daily THC treatment (5.4 mg/kg/injection in females, 7.6 mg/kg/injection in males), THC potency on both tests decreased more in females than males. On the tail withdrawal test, chronic THC produced 4.2- vs. 2.8-fold increases in ED50 values in females vs. males, respectively. On the paw pressure test, chronic THC produced 4.4- vs. 2.9-fold increases in ED50 values in females vs. males, respectively. Chronic THC treatment did not significantly disrupt estrous cycling in females. Conclusions These results demonstrate that – even when sex differences in acute THC potency are controlled for – females develop more antinociceptive tolerance to THC than males. Given the importance of drug tolerance in the development of drug dependence, these results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure. PMID:25131716

Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects.

PubMed

Eichler, Martin; Spinedi, Luca; Unfer-Grauwiler, Sandra; Bodmer, Michael; Surber, Christian; Luedi, Markus; Drewe, Juergen

2012-05-01

The most important psychoactive constituent of CANNABIS SATIVA L. is Δ (9)-tetrahydrocannabinol (THC). Cannabidiol (CBD), another important constituent, is able to modulate the distinct unwanted psychotropic effect of THC. In natural plant extracts of C. SATIVA, large amounts of THC and CBD appear in the form of THCA-A (THC-acid-A) and CBDA (cannabidiolic acid), which can be transformed to THC and CBD by heating. Previous reports of medicinal use of cannabis or cannabis preparations with higher CBD/THC ratios and use in its natural, unheated form have demonstrated that pharmacological effects were often accompanied with a lower rate of adverse effects. Therefore, in the present study, the pharmacokinetics and metabolic profiles of two different C. SATIVA extracts (heated and unheated) with a CBD/THC ratio > 1 were compared to synthetic THC (dronabinol) in a double-blind, randomized, single center, three-period cross-over study involving 9 healthy male volunteers. The pharmacokinetics of the cannabinoids was highly variable. The metabolic pattern was significantly different after administration of the different forms: the heated extract showed a lower median THC plasma AUC (24 h) than the unheated extract of 2.84 vs. 6.59 pmol h/mL, respectively. The later was slightly higher than that of dronabinol (4.58 pmol h/mL). On the other hand, the median sum of the metabolites (THC, 11-OH-THC, THC-COOH, CBN) plasma AUC (24 h) was higher for the heated than for the unheated extract. The median CBD plasma AUC (24 h) was almost 2-fold higher for the unheated than for the heated extract. These results indicate that use of unheated extracts may lead to a beneficial change in metabolic pattern and possibly better tolerability. © Georg Thieme Verlag KG Stuttgart · New York.

Cognitive and subjective dose-response effects of acute oral Delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users.

PubMed

Curran, H Valerie; Brignell, Catherine; Fletcher, Sally; Middleton, Paul; Henry, John

2002-10-01

Although some aspects of memory functions are known to be acutely impaired by delta(9)-tetrahydrocannabinol (delta(9)-THC; the main active constituent of marijuana), effects on other aspects of memory are not known and the time course of functional impairments is unclear. The present study aimed to detail the acute and residual cognitive effects of delta(9)-THC in infrequent cannabis users. A balanced, double-blind cross-over design was used to compare the effects of 7.5 mg and 15 mg delta(9)-THC with matched placebo in 15 male volunteers. Participants were assessed pre and 1, 2, 4, 6, 8, 24 and 48 h post-drug. Delta(9)-THC 15 mg impaired performance on two explicit memory tasks at the time of peak plasma concentration (2 h post-drug). At the same time point, performance on an implicit memory task was preserved intact. The higher dose of delta(9)-THC resulted in no learning whatsoever occurring over a three-trial selective reminding task at 2 h. Working memory was generally unaffected by delta(9)-THC. In several tasks, delta(9)-THC increased both speed and error rates, reflecting "riskier" speed-accuracy trade-offs. Subjective effects were also most marked at 2 h but often persisted longer, with participants rating themselves as "stoned" for 8 h. Participants experienced a strong drug effect, liked this effect and, until 4 h, wanted more oral delta(9)-THC. No effects of delta(9)-THC were found 24 or 48 h following ingestion indicating that the residual effects of oral delta(9)-THC are minimal. These data demonstrate that oral delta(9)-THC impairs episodic memory and learning in a dose-dependent manner whilst sparing perceptual priming and working memory.

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

PubMed Central

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

Separate and combined effects of the GABAB agonist baclofen and Δ9-THC in humans discriminating Δ9-THC

PubMed Central

Lile, Joshua A.; Kelly, Thomas H.; Hays, Lon R.

2012-01-01

Background Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ9-THC. The aim of the present study was to determine the potential involvement of the GABAB receptor subtype by assessing the separate and combined effects of the GABAB-selective agonist baclofen and Δ9-THC using pharmacologically specific drug-discrimination procedures. Methods Eight cannabis users learned to discriminate 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50 mg), Δ9-THC (5, 15 and 30 mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Results Δ9-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50 mg) substituted for the Δ9-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ9-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ9-THC-like subjective responses when administered alone. Conclusions These results suggest that the GABAB receptor subtype is involved in the abuse-related effects of Δ9-THC, and that GABAB receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABAA) to determine the contribution of the different GABA receptors in the effects of Δ9-THC, and by extension cannabis, in humans. PMID:22699093

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

PubMed

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

2017-03-01

Women report greater sensitivity to the subjective effects of Δ 9 -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.

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

PubMed

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.

The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: A placebo-controlled, double-blind, crossover pilot trial.

PubMed

Englund, Amir; Atakan, Zerrin; Kralj, Aleksandra; Tunstall, Nigel; Murray, Robin; Morrison, Paul

2016-02-01

Cannabis is mostly grown under illegal and unregulated circumstances, which seems to favour a product increasingly high in its main cannabinoid ∆-9-tetrahydrocannabinol (THC). ∆-9-tetrahydrocannabivarin (THCV) is a relatively untested cannabinoid which is said to be a cannabinoid receptor neutral antagonist, and may inhibit the effects of THC. To explore the safety and tolerability of repeated THCV administration and its effects on symptoms normally induced by THC in a sample of healthy volunteers. Ten male cannabis users (<25 use occasions) were recruited for this within-subjects, placebo-controlled, double-blind, cross-over pilot study. 10mg oral pure THCV or placebo were administered daily for five days, followed by 1mg intravenous THC on the fifth day. THCV was well tolerated and subjectively indistinguishable from placebo. THC did not significantly increase psychotic symptoms, paranoia or impair short-term memory, while still producing significant intoxicating effects. Delayed verbal recall was impaired by THC and only occurred under placebo condition (Z=-2.201, p=0.028), suggesting a protective effect of THCV. THCV also inhibited THC-induced increased heart rate (Z=-2.193, p=0.028). Nine out of ten participants reported THC under THCV condition (compared to placebo) to be subjectively weaker or less intense (χ(2)=6.4, p=0.011). THCV in combination with THC significantly increased memory intrusions (Z=-2.155, p=0.031). In this first study of THC and THCV, THCV inhibited some of the well-known effects of THC, while potentiating others. These findings need to be interpreted with caution due to a small sample size and lack of THC-induced psychotomimetic and memory-impairing effect, probably owing to the choice of dose. © The Author(s) 2015.

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2012 CFR

2012-07-01

... requirements in Table 2 of this subpart based on THC CEMS data Collecting and recording the THC monitoring data... block average THC concentration in the exhaust gases less than or equal to the THC concentration...

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2013 CFR

2013-07-01

... requirements in Table 2 of this subpart based on THC CEMS data Collecting and recording the THC monitoring data... block average THC concentration in the exhaust gases less than or equal to the THC concentration...

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2014 CFR

2014-07-01

... requirements in Table 2 of this subpart based on THC CEMS data Collecting and recording the THC monitoring data... block average THC concentration in the exhaust gases less than or equal to the THC concentration...

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.

PubMed

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.

Ocular disposition of the hemiglutarate ester prodrug of ∆⁹-Tetrahydrocannabinol from various ophthalmic formulations.

PubMed

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

2013-08-01

The overall goal of this project is to enhance ocular delivery of ∆(9)-Tetrahydrocannabinol (THC) through the topical route. Solubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo. Aqueous solubility and stability and in vitro transcorneal permeability of THC-HG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber. In this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye.

Alteration in the level of endogenous hypothalamic prostaglandins induced by delta 9-tetrahydrocannabinol in the rat.

PubMed Central

Coupar, I. M.; Taylor, D. A.

1982-01-01

1 Whole brain and regional brain levels of prostaglandin E2 (PGE2)-like material have been determined following administration of delta 9-tetrahydrocannabinol (delta 9 -THC) in rats. 2 Intravenous administration of delta 9-THC 2 mg/kg, resulted in marked behavioural changes and hypothermia. The behavioural changes consisted mainly of catatonia (most apparent at 30 min after administration of delta 9-THC), followed by sedation (most evident at 60 min). Hypothermia was marked from 30 min after administration of delta 9-THC. 3 delta 9-THC did not after the whole brain levels of PGE2-like material 30, 60 or 120 min after administration. 4 delta 9-THC did not alter the levels of PGE2-like material in the medulla oblongata/pons, midbrain, cortex and cerebellum, 30 min after administration. However, there was a significant reduction of PGE2-like material in the hypothalamus, 30 min after delta 9-THC. 5 It is suggested that the delta 9-THC-induced decrease in hypothalamic PGE2-like material may contribute to the hypothermia observed following delta 9-THC administration. PMID:6282371

40 CFR 1065.303 - Summary of required calibration and verifications.

Code of Federal Regulations, 2012 CFR

2012-07-01

... initial installation and after major maintenance. THC FID optimization, and THC FID verification Optimize and determine CH4 response for THC FID analyzers: upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers: upon initial installation, within 185 days before...

40 CFR 1065.303 - Summary of required calibration and verifications.

Code of Federal Regulations, 2013 CFR

2013-07-01

... initial installation and after major maintenance. THC FID optimization, and THC FID verification Optimize and determine CH4 response for THC FID analyzers: upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers: upon initial installation, within 185 days before...

A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers.

PubMed

Stott, Colin; White, Linda; Wright, Stephen; Wilbraham, Darren; Guy, Geoffrey

2013-12-01

This Phase I study aimed to assess the potential drug-drug interactions (pharmacokinetic [PK] and safety profile) of Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex (®), nabiximols) in combination with cytochrome P450 (CYP450) inducer (rifampicin) or inhibitors (ketoconazole or omeprazole). Thirty-six healthy male subjects were divided into three groups of 12, and then randomized to one of two treatment sequences per group. Subjects received four sprays of THC/CBD (10.8/10 mg) alongside single doses of the CYP3A and 2C19 inducer rifampicin (600 mg), CYP3A inhibitor ketoconazole (400 mg) or CYP2C19 inhibitor omeprazole (40 mg). Plasma samples were analyzed for CBD, THC and its metabolite 11-hydroxy-THC (11-OH-THC). A single dose of four sprays of THC/CBD spray (10.8/10 mg) following repeated doses of rifampicin (600 mg) reduced the Cmax and AUC of all analytes. Cmax reduced from 2.94 to 1.88 ng/mL (-36%), 1.03 to 0.50 ng/mL (-52%) and 3.38 to 0.45 ng/mL (-87%) for THC, CBD and 11-OH-THC, respectively compared to single dose administration of THC/CBD spray alone. Ketoconazole co-administration with THC/CBD spray had the opposite effect, increasing the Cmax of the respective analytes from 2.65 to 3.36 ng/mL (+27%), 0.66 to 1.25 ng/mL (+89%) and 3.59 to 10.92 ng/mL (+204%). No significant deviations in Cmax or AUC for any analyte were observed when THC/CBD spray was co-administered with omeprazole. THC/CBD spray was well tolerated by the study subjects both alone and in combination with rifampicin, ketoconazole and omeprazole. Evaluation of the PKs of THC/CBD spray alone and in combination with CYP450 inhibitors/inducers suggests that all analytes are substrates for the isoenzyme CYP3A4, but not CYP2C19. On the basis of our findings, there is likely to be little impact on other drugs metabolized by CYP enzymes on the PK parameters of THC/CBD spray, but potential effects should be taken into consideration when co-administering THC/CBD spray with compounds which share the CYP3A4 pathway such as rifampicin or ketoconazole. NCT01323465.

Cost of Incremental Expansion of an Existing Family Medicine Residency Program.

PubMed

Ashkin, Evan A; Newton, Warren P; Toomey, Brian; Lingley, Ronald; Page, Cristen P

2017-07-01

Expanding residency training programs to address shortages in the primary care workforce is challenged by the present graduate medical education (GME) environment. The Medicare funding cap on new GME positions and reductions in the Health Resources and Services Administration (HRSA) Teaching Health Center (THC) GME program require innovative solutions to support primary care residency expansion. Sparse literature exists to assist in predicting the actual cost of incremental expansion of a family medicine residency program without federal or state GME support. In 2011 a collaboration to develop a community health center (CHC) academic medical partnership (CHAMP), was formed and created a THC as a training site for expansion of an existing family medicine residency program. The cost of expansion was a critical factor as no Federal GME funding or HRSA THC GME program support was available. Initial start-up costs were supported by a federal grant and local foundations. Careful financial analysis of the expansion has provided actual costs per resident of the incremental expansion of the residencyRESULTS: The CHAMP created a new THC and expanded the residency from eight to ten residents per year. The cost of expansion was approximately $72,000 per resident per year. The cost of incremental expansion of our residency program in the CHAMP model was more than 50% less than that of the recently reported cost of training in the HRSA THC GME program.

Cannabidiol reverses the reduction in social interaction produced by low dose Delta(9)-tetrahydrocannabinol in rats.

PubMed

Malone, Daniel Thomas; Jongejan, Dennis; Taylor, David Alan

2009-08-01

While Delta(9)-tetrahydrocannabinol (THC) is the main psychoactive constituent of the cannabis plant, a non-psychoactive constituent is cannabidiol (CBD). CBD has been implicated as a potential treatment of a number of disorders including schizophrenia and epilepsy and has been included with THC in a 1:1 combination for the treatment of conditions such as neuropathic pain. This study investigated the effect of THC and CBD, alone or in combination, on some objective behaviours of rats in the open field. Pairs of rats were injected with CBD or vehicle followed by THC or vehicle and behaviour in the open field was assessed for 10 min. In vehicle pretreated rats THC (1 mg/kg) significantly reduced social interaction between rat pairs. Treatment with CBD had no significant effect alone, but pretreatment with CBD (20 mg/kg) reversed the THC-induced decreases in social interaction. A higher dose of THC (10 mg/kg) produced no significant effect on social interaction. However, the combination of high dose CBD and high dose THC significantly reduced social interaction between rat pairs, as well as producing a significant decrease in locomotor activity. This data suggests that CBD can reverse social withdrawal induced by low dose THC, but the combination of high dose THC and CBD impairs social interaction, possibly by decreasing locomotor activity.

Is cannabis an effective treatment for joint pain?

PubMed

Miller, Richard J; Miller, Rachel E

2017-01-01

Cannabis has been used to treat pain for thousands of years. However, since the early part of the 20th century, laws restricting cannabis use have limited its evaluation using modern scientific criteria. Over the last decade, the situation has started to change because of the increased availability of cannabis in the United States for either medical or recreational purposes, making it important to provide the public with accurate information as to the effectiveness of the drug for joint pain among other indications. The major psychotropic component of cannabis is Δ9-tetrahydrocannabinol (THC), one of some 120 naturally occurring phytocannabinoids. Cannabidiol (CBD) is another molecule found in herbal cannabis in large amounts. Although CBD does not produce psychotropic effects, it has been shown to produce a variety of pharmacological effects. Hence, the overall effects of herbal cannabis represent the collective activity of THC, CBD and a number of minor components. The action of THC is mediated by two major G-protein coupled receptors, cannabinoid receptor type 1 (CB1) and CB2, and recent work has suggested that other targets may also exist. Arachidonic acid derived endocannabinoids are the normal physiological activators of the two cannabinoid receptors. Natural phytocannabinoids and synthetic derivatives have produced clear activity in a variety of models of joint pain in animals. These effects are the result of both inhibition of pain pathway signalling (mostly CB1) and anti-inflammatory effects (mostly CB2). There are also numerous anecdotal reports of the effectiveness of smoking cannabis for joint pain. Indeed, it is the largest medical request for the use of the drug. However, these reports generally do not extend to regulated clinical trials for rheumatic diseases. Nevertheless, the preclinical and human data that do exist indicate that the use of cannabis should be taken seriously as a potential treatment of joint pain.

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

PubMed

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.

The endocannabinoid system as a target for the treatment of neurodegenerative disease.

PubMed

Scotter, Emma L; Abood, Mary E; Glass, Michelle

2010-06-01

The Cannabis sativa plant has been exploited for medicinal, agricultural and spiritual purposes in diverse cultures over thousands of years. Cannabis has been used recreationally for its psychotropic properties, while effects such as stimulation of appetite, analgesia and anti-emesis have lead to the medicinal application of cannabis. Indeed, reports of medicinal efficacy of cannabis can been traced back as far as 2700 BC, and even at that time reports also suggested a neuroprotective effect of the cultivar. The discovery of the psychoactive component of cannabis resin, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) occurred long before the serendipitous identification of a G-protein coupled receptor at which Delta(9)-THC is active in the brain. The subsequent finding of endogenous cannabinoid compounds, the synthesis of which is directed by neuronal excitability and which in turn served to regulate that excitability, further widened the range of potential drug targets through which the endocannabinoid system can be manipulated. As a result of this, alterations in the endocannabinoid system have been extensively investigated in a range of neurodegenerative disorders. In this review we examine the evidence implicating the endocannabinoid system in the cause, symptomatology or treatment of neurodegenerative disease. We examine data from human patients and compare and contrast this with evidence from animal models of these diseases. On the basis of this evidence we discuss the likely efficacy of endocannabinoid-based therapies in each disease context.

Global Warming In A Regional Model of The Atlantic Ocean - Echam4/opyc3 In Flame 4/3

NASA Astrophysics Data System (ADS)

Schweckendiek, U.; Willebrand, J.

The reaction of the Thermohaline Circulation (THC) in most climate models on global warming scenarios is a weakening of the THC. An exception is the ECHAM4/OPYC3 simulation whose stable behaviour is traced back to a strongly enhanced evaporation and as a consequence to a development of a salt anomaly in the tropics and subtropics of the Atlantic Ocean (Latif et al.,2000). This salt signal is advected into convection regions and compensates the reduction of surface density due to surface heating and freshening. To examine this scenario for a more realistic ocean model, data from this model is used to drive a reginal model of the Atlantic Ocean. In order to test the crucial mechanisms for the maintainance of the meridional overturning, we have performed sensitivity studies by focussing on different combinations of the anomalous freshwater and heat fluxes. The results demonstrate that for the stabilising effect to become effective the salt sig- nal has to enter the GIN-Seas and subsequently the overflow waters, underlining the importance of the overflows for the THC. The Labrador Sea Convection is however uneffected by this stabilising salt signal and its convection ultimatly breaks down un- der surface warming and freshening.

40 CFR 1065.303 - Summary of required calibration and verifications.

Code of Federal Regulations, 2014 CFR

2014-07-01

...: FID calibrationTHC FID optimization, and THC FID verification Calibrate all FID analyzers: upon initial installation and after major maintenance.Optimize and determine CH4 response for THC FID analyzers: upon initial installation and after major maintenance. Verify CH4 response for THC FID analyzers: upon...

Synthetic Cannabinoids: Pharmacology, Behavioral Effects, and Abuse Potential

PubMed Central

Tai, Sherrica; Fantegrossi, William E.

2015-01-01

Cannabis has been used throughout the world for centuries. The psychoactive effects of cannabis are largely attributable to Δ9-tetrahydrocannabinol (Δ9-THC), the prototypical cannabinoid that occurs naturally in the plant. More recently, chemically- and pharmacologically-distinct synthetic cannabinoids (SCBs) have emerged as drugs of abuse. As compared to Δ9-THC, the distinct structures of these compounds allow them to avoid legal restrictions (at least initially) and detection in standard drug screens. This has contributed to the popularity of SCBs among drug users who seek to avoid positive drug screens. Importantly, the distinct structures of the SCBs also typically result in increased affinity for and efficacy at cannabinoid CB1 receptors, which are thought to be responsible for the psychoactive effects of Δ9-THC and its analogues. Accordingly, it seems likely that these more powerful cannabimimetic effects could result in increased adverse reactions and toxicities not elicited by Δ9-THC in cannabis. Animal models useful for the study of emerging SCBs include the cannabinoid tetrad, drug discrimination, and assays of tolerance, dependence, and withdrawal. However, these in vivo procedures have not been particularly informative with regards to drug efficacy, where the majority of SCB effects are comparable to those of Δ9-THC. In contrast, essentially all in vitro measures of drug efficacy confirm Δ9-THC as a relatively weak CB1 partial agonist, while the majority of the SCBs detected in commercial preparations are full agonists at the CB1 receptor. As use of these emerging SCBs continues to rise, there is an urgent need to better understand the pharmacology and toxicology of these novel compounds. PMID:26413452

Species-specific susceptibility to cannabis-induced convulsions.

PubMed

Whalley, Benjamin J; Lin, Hong; Bell, Lynne; Hill, Thomas; Patel, Amesha; Gray, Roy A; Elizabeth Roberts, C; Devinsky, Orrin; Bazelot, Michael; Williams, Claire M; Stephens, Gary J

2018-02-19

Numerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ 9 -tetrahydrocannabinol (THC), variously reported to be pro- and anticonvulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats and treatment-naïve rat, mouse, chicken, dog and human tissue. Prolonged exposure to cannabis extracts caused spontaneous, generalized seizures, subserved by epileptiform discharges in rats, but not dogs, and produced higher THC, but lower 11-hydroxy-THC (11-OH-THC) and CBD, plasma concentrations in rats versus dogs. In the same rats, prolonged exposure to cannabis also impaired cannabinoid type 1 receptor (CB 1 receptor)-mediated signalling. Profiling CB 1 receptor expression, basal activity, extent of activation and sensitivity to THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than one that did not (dog). Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models. © 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Suppression of human macrophage function in vitro by delta 9-tetrahydrocannabinol.

PubMed

Specter, S; Lancz, G; Goodfellow, D

1991-11-01

The ability of macrophages to function in the presence of delta 9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, was evaluated. THC added to macrophage cultures prepared from human peripheral blood inhibited macrophage spreading and phagocytosis of yeast. The effects of THC were concentration dependent, with inhibitory effects observed from 10 to 1 micrograms/ml or lower. These results suggest that macrophages are more sensitive to THC than are lymphocytes because macrophage functions were inhibited by THC at concentrations that did not affect lymphocyte function. Thus, inhibition of lymphocyte function(s) by THC could be attributed to a direct effect of the drug on macrophages which indirectly results in lowered lymphoid cell activity.

Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis.

PubMed

Morgan, Celia J A; Curran, H Valerie

2008-04-01

Cannabis contains various cannabinoids, two of which have almost opposing actions: Delta9-tetrahydrocannabinol (Delta9-THC) is psychotomimetic, whereas cannabidiol (CBD) has antipsychotic effects. Hair samples were analysed to examine levels of Delta9-THC and CBD in 140 individuals. Three clear groups emerged: ;THC only', ;THC+CBD' and those with no cannabinoid in hair. The THC only group showed higher levels of positive schizophrenia-like symptoms compared with the no cannabinoid and THC+CBD groups, and higher levels of delusions compared with the no cannabinoid group. This provides evidence of the divergent properties of cannabinoids and has important implications for research into the link between cannabis use and psychosis.

Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology.

PubMed

Schaefer, Nadine; Wojtyniak, Jan-Georg; Kettner, Mattias; Schlote, Julia; Laschke, Matthias W; Ewald, Andreas H; Lehr, Thorsten; Menger, Michael D; Maurer, Hans H; Schmidt, Peter H

2016-06-24

Synthetic cannabinoids (SCs) are gaining increasing importance in clinical and forensic toxicology. They are consumed without any preclinical safety studies. Thus, controlled human pharmacokinetic (PK) studies are not allowed, although being relevant for interpretation of analytical results in cases of misuse or poisoning. As alternative, in a controlled animal experiment, six pigs per drug received a single intravenous dose of 200μg/kg BW each of Δ(9)-tetrahydrocannabinol (THC), 4-ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210), or 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4). In addition, six pigs received a combination of the three drugs with the identical dose each. The drugs were determined in serum using LC-MS/MS. A population (pop) PK analysis revealed that a three-compartment model described best the PK data of all three cannabinoids. Central volumes of distribution were estimated at 0.29L/kg, 0.20L/kg, and 0.67L/kg for THC, JWH-210, and RCS-4, respectively. Clearances were 0.042L/min/kg, 0.048L/min/kg, and 0.093L/min/kg for THC, JWH-210, and RCS-4, respectively. The popPK THC pig model was upscaled to humans using allometric techniques. Comparison with published human data revealed that the concentration-time profiles could successfully be predicted. These findings indicate that pigs in conjunction with PK modeling technique may serve as a tool for prediction of human PK of SCs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Reasons for Synthetic THC Use among College Students

ERIC Educational Resources Information Center

Vidourek, Rebecca A.; King, Keith A.; Burbage, Michelle L.

2013-01-01

Synthetic THC, also known as fake marijuana, is used by college students in the United States. The present study examined reasons for recent synthetic THC use among college students (N = 339). Students completed a 3-page survey during regularly scheduled class times. Results indicated students reported using synthetic THC for curiosity, to get…

40 CFR 63.6620 - What performance tests and other procedures must I use?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Where: Ci = concentration of carbon monoxide (CO), total hydrocarbons (THC), or formaldehyde at the control device inlet, Co = concentration of CO, THC, or formaldehyde at the control device outlet, and R = percent reduction of CO, THC, or formaldehyde emissions. (2) You must normalize the CO, THC, or...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2010 CFR

2010-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a,b

Code of Federal Regulations, 2011 CFR

2011-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2012 CFR

2012-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

32 CFR 161.16 - Benefits for transitional health care members and dependents.

Code of Federal Regulations, 2014 CFR

2014-07-01

... members and dependents. This section shows the benefits for THC members and their eligible dependents. THC... Defense Authorization Act of for Fiscal Year 2005” made the THC program permanent and made the medical... years' commissary and exchange benefits to THC members. Section 734 of Public Law 110-417, “National...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a,b

Code of Federal Regulations, 2012 CFR

2012-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR 63.6620 - What performance tests and other procedures must I use?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Where: Ci = concentration of carbon monoxide (CO), total hydrocarbons (THC), or formaldehyde at the control device inlet, Co = concentration of CO, THC, or formaldehyde at the control device outlet, and R = percent reduction of CO, THC, or formaldehyde emissions. (2) You must normalize the CO, THC, or...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2011 CFR

2011-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a,b

Code of Federal Regulations, 2010 CFR

2010-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a b

Code of Federal Regulations, 2014 CFR

2014-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2011 CFR

2011-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR 86.137-94 - Dynamometer test run, gaseous and particulate emissions.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., if applicable), the temperature recorder, the vehicle cooling fan, and the heated THC analysis... diesel-cycle THC analyzer continuous sample line and filter, methanol-fueled vehicle THC, methanol and... measuring devices to zero. (i) For gaseous bag samples (except THC samples), the minimum flow rate is 0.17...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2010 CFR

2010-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2011 CFR

2011-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2014 CFR

2014-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

40 CFR Table 3 to Subpart Lllll of... - Requirements for Performance Tests a,b

Code of Federal Regulations, 2013 CFR

2013-07-01

..., THC destruction efficiency, THC outlet concentration, or combustion efficiency standards, the sampling... combustion efficiency or THC standards a. Measure the concentration of carbon dioxideb. Measure the... method 25A in appendix A to part 60 of this chapter 10. Each control device used to comply with the THC...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2013 CFR

2013-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2010 CFR

2010-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR 63.1349 - Performance testing requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

...)(1). (4)(i) THC CEMS relative accuracy test. (A) If you are subject to limitations on THC emissions... CEMS, the THC span value (as propane) is 50 ppmvd. You demonstrate compliance with a RATA when the... conducting the performance test for total organic HAP, you must also determine THC emissions by operating a...

40 CFR 63.1349 - Performance testing requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

...)(1). (4)(i) THC CEMS relative accuracy test. (A) If you are subject to limitations on THC emissions... CEMS, the THC span value (as propane) is 50 ppmvd. You demonstrate compliance with a RATA when the... conducting the performance test for total organic HAP, you must also determine THC emissions by operating a...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2012 CFR

2012-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

40 CFR Table 7 to Subpart Sssss of... - Continuous Compliance with Emission Limits

Code of Federal Regulations, 2013 CFR

2013-07-01

... average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC... other than a thermal or catalytic oxidizer The average THC concentration must not exceed 20 ppmvd, corrected to 18 percent oxygen; OR the average THC performance reduction must equal or exceed 95 percent...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2012 CFR

2012-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2013 CFR

2013-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

40 CFR 86.137-94 - Dynamometer test run, gaseous and particulate emissions.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., if applicable), the temperature recorder, the vehicle cooling fan, and the heated THC analysis... diesel-cycle THC analyzer continuous sample line and filter, methanol-fueled vehicle THC, methanol and... measuring devices to zero. (i) For gaseous bag samples (except THC samples), the minimum flow rate is 0.17...

40 CFR Table 4 to Subpart Lllll of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2014 CFR

2014-07-01

... auxiliary fuel achieving a THC destruction efficiency of 95.8 percent i. The THC destruction efficiency of..., and total hydrocarbon outlet concentrations over the performance test during which the THC destruction... table. c. Route the emissions to a combustion device that does not use auxiliary fuel achieving a THC...

40 CFR Table 3 to Subpart Ppppp of... - Requirements for Initial Compliance Demonstrations

Code of Federal Regulations, 2014 CFR

2014-07-01

... with . . . You must . . . Using . . . According to the following requirements . . . 1. The CO or THC outlet concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less i. EPA... CFR part 60 for THC measurement; or You must demonstrate that the outlet concentration of CO or THC...

Properties of the Only Thorium Fullerene, Th@C84, Uncovered.

PubMed

Kaminský, Jakub; Vícha, Jan; Bouř, Petr; Straka, Michal

2017-04-27

Only a single thorium fullerene, Th@C 84 , has been reported to date (Akiyama, K.; et al. J. Nucl. Radiochem. Sci. 2002, 3, 151-154). Although the system was characterized by UV-vis and XANES (X-ray absorption near edge structure) spectra, its structure and properties remain unknown. In this work we used the density functional calculations to identify molecular and electronic structure of the Th@C 84 . Series of molecular structures satisfying the ThC 84 stoichiometric formula were studied comprising 24 IPR and 110 non-IPR Th@C 84 isomers as well as 9 ThC 2 @C 82 IPR isomers. The lowest energy structure is Th@C 84 -C s (10) with the singlet ground state. Its predicted electronic absorption spectra are in agreement with the experimentally observed ones. The bonding between the cage and Th was characterized as polar covalent with Th in formal oxidation state IV. The NMR chemical shifts of Th@C 84 -C s (10) were predicted to guide the future experimental efforts in identification of this compound.

Effects of delta-9-tetrahydrocannabinol on evaluation of emotional images

PubMed Central

Ballard, Michael E; Bedi, Gillinder; de Wit, Harriet

2013-01-01

There is growing evidence that drugs of abuse alter processing of emotional information in ways that could be attractive to users. Our recent report that Δ9-tetrahydrocannabinol (THC) diminishes amygdalar activation in response to threat-related faces suggests that THC may modify evaluation of emotionally-salient, particularly negative or threatening, stimuli. In this study, we examined the effects of acute THC on evaluation of emotional images. Healthy volunteers received two doses of THC (7.5 and 15 mg; p.o.) and placebo across separate sessions before performing tasks assessing facial emotion recognition and emotional responses to pictures of emotional scenes. THC significantly impaired recognition of facial fear and anger, but it only marginally impaired recognition of sadness and happiness. The drug did not consistently affect ratings of emotional scenes. THC' effects on emotional evaluation were not clearly related to its mood-altering effects. These results support our previous work, and show that THC reduces perception of facial threat. Nevertheless, THC does not appear to positively bias evaluation of emotional stimuli in general PMID:22585232

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

PubMed

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.

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

PubMed

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.

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.

PubMed

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.

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

PubMed

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.

In Vitro Stability of Free and Glucuronidated Cannabinoids in Urine Following Controlled Smoked Cannabis

PubMed Central

Desrosiers, Nathalie A.; Lee, Dayong; Scheidweiler, Karl B.; Concheiro-Guisan, Marta; Gorelick, David A.; Huestis, Marilyn A.

2014-01-01

Analyte stability is an important factor in urine test interpretation, yet cannabinoid stability data are limited. A comprehensive study of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide, and THCCOOH-glucuronide stabilities in authentic urine was completed. Urine samples after ad libitum cannabis smoking were pooled to prepare low and high pools for each study participant; baseline concentrations were measured within 24h at room temperature (RT), 4°C and −20°C. Stability at RT, 4°C and −20°C was evaluated by Friedman tests for up to 1 year. THCCOOH, THC-glucuronide, and THCCOOH-glucuronide were quantified in baseline pools. RT THCCOOH baseline concentrations were significantly higher than −20°C, but not 4°C baseline concentrations. After 1 week at RT, THCCOOH increased, THCCOOH-glucuronide decreased, but THC-glucuronide was unchanged. In RT low pool, total THCCOOH (THCCOOH+THCCOOH-glucuronide) was significantly lower after 1 week. At 4°C, THCCOOH was stable 2 weeks, THCCOOH-glucuronide 1 month and THC-glucuronide for at least 6 months. THCCOOH was stable frozen for 1 year, but 6 months high pool results were significantly higher than baseline; THC-glucuronide and THCCOOH-glucuronide were stable for 6 months. Total THCCOOH was stable 6 months at 4°C, and frozen 6 months (low) and 1 year (high). THC, cannabidiol and cannabinol were never detected in urine; although not detected initially, 11-OH-THC was detected in 2 low and 3 high pools after one week at RT. Substantial THCCOOH-glucuronide deconjugation was observed at RT and 4°C. Analysis should be conducted within 3 months if non-hydrolyzed THCCOOH or THCCOOH-glucuronide quantification is required. PMID:24292435

Validation of an Enzyme Immunoassay for Detection and Semiquantification of Cannabinoids in Oral Fluid

PubMed Central

Schwope, David M.; Milman, Garry; Huestis, Marilyn A.

2011-01-01

BACKGROUND Oral fluid (OF) is gaining prominence as an alternative matrix for monitoring drugs of abuse in the workplace, criminal justice, and driving under the influence of drugs programs. It is important to characterize assay performance and limitations of screening techniques for Δ9-tetrahydrocannabinol (THC) in OF. METHODS We collected OF specimens by use of the Quantisal™ OF collection device from 13 daily cannabis users after controlled oral cannabinoid administration. All specimens were tested with the Immunalysis Sweat/OF THC Direct ELISA and confirmed by 2-dimensional GC-MS. RESULTS The limit of detection was <1 µg/L THC equivalent, and the assay demonstrated linearity from 1 to 50 µg/L, with semiquantification to 200 µg/L. Intraplate imprecision (n = 7) ranged from 2.9% to 7.7% CV, and interplate imprecision (n = 20) was 3.0%–9.1%. Cross-reactivities at 4 µg/L were as follows: 11-hydroxy-THC, 198%; Δ8-tetrahydrocannabinol (Δ8-THC), 128%; 11-nor-9-carboxy-THC (THCCOOH), 121%; THC (target), 98%; cannabinol, 87%; THCCOOH-glucuronide, 11%; THC-glucuronide, 10%; and cannabidiol, 2.4%. Of 499 tested OF specimens, 52 confirmed positive (THC 2.0–290 µg/L), with 100% diagnostic sensitivity at the proposed Substance Abuse and Mental Health Services Administration screening cutoff of 4 µg/L cannabinoids and GC-MS cutoff of 2 µg/L THC. Forty-seven specimens screened positive but were not confirmed by 2D-GC-MS, yielding 89.5% diagnostic specificity and 90.6% diagnostic efficiency. Thirty-one of 47 unconfirmed immunoassay positive specimens were from 1 individual and contained >400 ng/L THCCOOH, potentially contributing to cross-reactivity. CONCLUSIONS The Immunalysis Sweat/OF THC Direct ELISA is an effective screening procedure for detecting cannabinoids in OF. PMID:20360126

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

PubMed Central

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

2017-01-01

Background 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. Methods 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. Results 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. Conclusions 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. PMID:28130989

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

PubMed Central

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

2017-01-01

Background Acceptance of cannabis use is growing. However, prolonged use is associated with diminished psychosocial outcomes, potentially mediated by drug-induced cognitive impairments. Δ9-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. Methods 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. Results 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. Limitations Only male rats were investigated, and the THC/CBD coadministration experiment was carried out in a subset of individuals. Conclusion 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. PMID:28245177

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

PubMed Central

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

Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis.

PubMed

Syed, Yahiya Y; McKeage, Kate; Scott, Lesley J

2014-04-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) [Sativex®] is an oromucosal spray formulation that contains principally THC and CBD at an approximately 1:1 fixed ratio, derived from cloned Cannabis sativa L. plants. The main active substance, THC, acts as a partial agonist at human cannabinoid receptors (CB1 and CB2), and thus, may modulate the effects of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmitters. THC/CBD is approved in a number of countries, including Germany and the UK, as an add-on treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. In the largest multinational clinical trial that evaluated the approved THC/CBD regimen in this population, 12 weeks' double-blind treatment with THC/CBD significantly reduced spasticity severity (primary endpoint) compared with placebo in patients who achieved a clinically significant improvement in spasticity after 4 weeks' single-blind THC/CBD treatment, as assessed by a patient-rated numerical rating scale. A significantly greater proportion of THC/CBD than placebo recipients achieved a ≥ 30% reduction (a clinically relevant reduction) in spasticity severity. The efficacy of THC/CBD has been also shown in at least one everyday clinical practice study (MOVE 2). THC/CBD was generally well tolerated in clinical trials. Dizziness and fatigue were reported most frequently during the first 4 weeks of treatment and resolved within a few days even with continued treatment. Thus, add-on THC/CBD is a useful symptomatic treatment option for its approved indication.

Plasma Cannabinoid Pharmacokinetics following Controlled Oral Δ9-Tetrahydrocannabinol and Oromucosal Cannabis Extract Administration

PubMed Central

Karschner, Erin L.; Darwin, W. David; Goodwin, Robert S.; Wright, Stephen; Huestis, Marilyn A.

2013-01-01

BACKGROUND Sativex®, a cannabis extract oromucosal spray containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC’s effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. METHODS Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board–approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor-9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L. RESULTS Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (Cmax) and areas under the curve from 0–10.5 h postdose (AUC0→10.5) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in Cmax, time to maximum concentration or in the AUC0→10.5 between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. CONCLUSION These data suggest that CBD modulation of THC’s effects is not due to a pharmacokinetic interaction at these therapeutic doses. PMID:21078841

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

PubMed

Medveczky, Maria M; Sherwood, Tracy A; Klein, Thomas W; Friedman, Herman; Medveczky, Peter G

2004-09-15

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. 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. 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. 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. These studies may also provide the foundation for the development of antiviral strategies utilizing non-psychoactive derivatives of THC.

Identification of Psychoactive Degradants of Cannabidiol in Simulated Gastric and Physiological Fluid

PubMed Central

Merrick, John; Lane, Brian; Sebree, Terri; Yaksh, Tony; O'Neill, Carol; Banks, Stan L.

2016-01-01

Abstract Introduction: In recent research, orally administered cannabidiol (CBD) showed a relatively high incidence of somnolence in a pediatric population. Previous work has suggested that when CBD is exposed to an acidic environment, it degrades to Δ9-tetrahydrocannabinol (THC) and other psychoactive cannabinoids. To gain a better understanding of quantitative exposure, we completed an in vitro study by evaluating the formation of psychoactive cannabinoids when CBD is exposed to simulated gastric fluid (SGF). Methods: Materials included synthetic CBD, Δ8-THC, and Δ9-THC. Linearity was demonstrated for each component over the concentration range used in this study. CBD was spiked into media containing 1% sodium dodecyl sulfate (SDS). Samples were analyzed using chromatography with UV and mass spectrometry detection. An assessment time of 3 h was chosen as representative of the maximal duration of exposure to gastric fluid. Results: CBD in SGF with 1% SDS was degraded about 85% after 60 min and more than 98% at 120 min. The degradation followed first-order kinetics at a rate constant of −0.031 min−1 (R2=0.9933). The major products formed were Δ9-THC and Δ8-THC with less significant levels of other related cannabinoids. CBD in physiological buffer performed as a control did not convert to THC. Confirmation of THC formation was demonstrated by comparison of mass spectral analysis, mass identification, and retention time of Δ9-THC and Δ8-THC in the SGF samples against authentic reference standards. Conclusions: SGF converts CBD into the psychoactive components Δ9-THC and Δ8-THC. The first-order kinetics observed in this study allowed estimated levels to be calculated and indicated that the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a physiological response. Delivery methods that decrease the potential for formation of psychoactive cannabinoids should be explored. PMID:28861485

A phase I study to assess the effect of food on the single dose bioavailability of the THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-04-01

To assess the effect of food on the single-dose bioavailability of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, when administered to healthy male subjects. Twelve subjects took part in this fed-fasted cross-over study and received a single dose of THC/CBD spray (4 sprays = 10.8 mg THC + 10 mg CBD) in the fasted then fed state (or vice versa) with a 3-day wash-out period between treatments. Plasma samples were collected at designated time-points for analysis of CBD, THC, and its active metabolite, 11-hydroxy delta-9-tetrahydrocannabinol (11-OH-THC). Statistically significant increases in the mean area under the curve (AUC) and mean maximum plasma drug concentration (Cmax) were observed in subjects during fed conditions. Mean AUC and Cmax were one to three-fold higher for THC and 11-OH-THC, and five and three-fold higher for CBD respectively during fed conditions. A large inter-subject variability in exposure from the same dose was observed, particularly for THC. The Cmax for THC in fed versus fasted subjects was higher in 7 subjects (4.80-14.91 ng/ml) and lower in 5 subjects (2.81-3.51 ng/ml) compared with the mean Cmax of 3.98 ng/ml (range 0.97-9.34 ng/ml) observed in the fasted state. Increases in mean AUC(0-t), AUC(0-inf), and Cmax for THC, CBD, and 11-OH-THC in the fed state were within the range of inter-subject variability, which was considerable. Food also appeared to delay the time to peak concentration (Tmax) of all analytes by approximately 2-2.5 h. Only mild adverse events were reported. The THC/CBD spray was well tolerated in male subjects at a single dose of four sprays. The large inter-subject variability in exposure suggests that the changes observed are unlikely to be clinically relevant.

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a κ-Opioid Agonist in THC-Treated Mice.

PubMed

Chopda, Girish R; Parge, Viraj; Thakur, Ganesh A; Gatley, S John; Makriyannis, Alexandros; Paronis, Carol A

2016-08-01

Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of Δ(9)-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the κ-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to >90% of maximal possible effect. Treatment with THC produced 9- and 7-fold rightward shifts of the diuresis and antinociception dose-response curves for THC and, respectively, 7- and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to >35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the Bmax value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis dose-effect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ-9-tetrahydrocannabinol in humans

PubMed Central

Braley, Gabriel; Blaise, Rebecca; Vendetti, Michael; Oliver, Stephen; Pittman, Brian; Ranganathan, Mohini; Bhakta, Savita; Zimolo, Zoran; Cooper, Thomas; Perry, Edward

2010-01-01

Introduction Cannabinoids produce a spectrum of effects in humans including euphoria, cognitive impairments, psychotomimetic effects, and perceptual alterations. The extent to which dopaminergic systems contribute to the effects of Δ-9-tetrahydrocannabinol (Δ-9-THC) remains unclear. This study evaluated whether pretreatment with a dopamine receptor antagonist altered the effects of Δ-9-THC in humans. Materials and methods In a 2-test-day double-blind study, 28 subjects including healthy subjects (n=17) and frequent users of cannabis (n=11) were administered active (0.057 mg/kg) or placebo oral haloperidol in random order followed 90 and 215 min later by fixed order intravenous administration of placebo (vehicle) and active (0.0286 mg/kg) Δ-9-THC, respectively. Results Consistent with previous reports, intravenous Δ-9-THC produced psychotomimetic effects, perceptual alterations, and subjective effects including “high.” Δ-9-THC also impaired verbal recall and attention. Haloperidol pretreatment did not reduce any of the behavioral effects of Δ-9-THC. Haloperidol worsened the immediate free and delayed free and cued recall deficits produced by Δ-9-THC. Haloperidol and Δ-9-THC worsened distractibility and vigilance. Neither drug impaired performance on a motor screening task, the Stockings of Cambridge task, or the delayed match to sample task. Frequent users had lower baseline plasma prolactin levels and blunted Δ-9-THC induced memory impairments. Conclusions The deleterious effects of haloperidol pretreatment on the cognitive effects of Δ-9-THC are consistent with the preclinical literature in suggesting crosstalk between DAergic and CBergic systems. However, it is unlikely that DA D2 receptor mechanisms play a major role in mediating the psychotomimetic and perceptual altering effects of Δ-9-THC. Further investigation is warranted to understand the basis of the psychotomimetic effects of Δ-9-THC and to better understand the crosstalk between DAergic and CBergic systems. PMID:18228005

Work place drug testing of police officers after THC exposure during large volume cannabis seizures.

PubMed

Doran, Gregory S; Deans, Ralph; De Filippis, Carlo; Kostakis, Chris; Howitt, Julia A

2017-06-01

Police officers responsible for the seizure and removal of illegally grown cannabis plants from indoor and outdoor growing operations face the prospect of THC exposure while performing their work duties. As a result, a study investigating the amount of THC on hands and uniforms of officers during raids on cannabis growing houses (CGHs) and forest cannabis plantations (FCPs) and in the air at these sites was conducted. Swabs of gloves/hands, chests, and heads/necks were collected and analysed for THC. Results of hand swabs indicated that officers removing plants from FCPs were exposed to THC concentrations up to 20 times those involved in raids at CGHs, which was mainly associated with the number and size of plants seized. Air samples collected inside cannabis houses showed no detectable THC. Air samples collected inside the cargo area of the storage trucks used during FCP raids indicated that THC can be volatilised when lush plants are compressed by other seized plants loaded on top of them in the truck over a period of several days, allowing composting of plants at the bottom of the load to commence. The elevated temperature and humidity inside the truck may assist the decarboxylation of THCA to THC, as well as increasing the rate of volatilisation of THC. More than 100 urine samples were collected from officers in raids on both CGHs and FCPs and all tested negative for THC. Removal of cannabis plants by officers often resulted in cuts, abrasions and ruptured blisters on exposed skin surfaces, particularly at FCPs. The results in this study suggest that even when small areas of damaged skin are directly exposed to THC by contact transfer, the likelihood of showing a positive THC urine test is low. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

A Novel Observational Method for Assessing Acute Responses to Cannabis: Preliminary Validation Using Legal Market Strains.

PubMed

Bidwell, L Cinnamon; Mueller, Raeghan; YorkWilliams, Sophie L; Hagerty, Sarah; Bryan, Angela D; Hutchison, Kent E

2018-01-01

Background: The development of novel cannabis research methods that are compatible with current federal regulations is imperative to conduct studies of the effects of legal market cannabis. There is very little research on higher strength, higher Δ9-tetrahydrocannabinol (THC), which has become increasingly available since legalization. Research on strains containing cannabidiol (CBD), a second primary, but nonpsychotomimetic, cannabinoid, is very limited. Materials and Methods: Using a novel observational methodology, regular cannabis users were asked to use one of two legal market cannabis strains that they purchased from a local dispensary (one strain containing 8% THC and 16% CBD (THC+CBD) and one containing a 17% THC concentration, but no CBD (THC). After using their suggested cannabis strain as they typically would for a 3-day period, participants returned to the laboratory immediately after their final use. Measures included a blood draw to measure cannabinoid blood levels and circulating cytokines, self-reported subjective drug effects, and verbal recall memory. Results: Analysis of CBD/THC concentration levels in the blood following the 3-day strain manipulation suggests that all, but one participant ( n =23/24) followed instructions and used their assigned strain. Individuals in the THC group ( n =11) smoked no more than their usual amount, and participants who used the THC+CBD ( n =12) strain smoked more than their reported usual amount, but did not have significantly different THC+metabolite blood levels from the THC group. The THC+CBD strain was also associated with less desire to smoke, lower levels of subjective drug effects, and lower levels of circulating cytokines (TNF-α, IL-6, and IL-1β) immediately after use. Conclusions: Initial results support the feasibility of this novel observational methodology involving brief manipulation of strain use. Preliminary findings indicate that participants may self-titrate cannabis use based on cannabinoid concentration and the THC+CBD strain was associated with lower levels of cannabis craving, subjective intoxication, and circulating cytokines.

A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-05-01

A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. Δ(9)-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.

Validation of a two-dimensional gas chromatography mass spectrometry method for the simultaneous quantification of cannabidiol, Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC in plasma.

PubMed

Karschner, Erin L; Barnes, Allan J; Lowe, Ross H; Scheidweiler, Karl B; Huestis, Marilyn A

2010-05-01

A sensitive analytical method for simultaneous quantification of sub-nanogram concentrations of cannabidiol (CBD), Delta(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) in plasma is presented for monitoring cannabinoid pharmacotherapy and illicit cannabis use. Analytes were extracted from 1 mL plasma by solid-phase extraction, derivatized with N,O-bis(trimethylsilyl) trifluoroacetamide with 1% trimethylchlorosilane, and analyzed by two-dimensional gas chromatography mass spectrometry (2D-GCMS) with cryofocusing. The lower calibration curve was linear from 0.25-25 ng/mL for CBD and THC, 0.125-25 ng/mL for 11-OH-THC and 0.25-50 ng/mL for THCCOOH. A second higher linear range from 5-100 ng/mL, achieved through modification of injection parameters, was validated for THC, 11-OH-THC, and THCCOOH and was only implemented if concentrations exceeded the lower curve upper limit of linearity. This procedure prevented laborious re-extraction by allowing the same specimen to be re-injected for quantification on the high calibration curve. Intra- and inter-assay imprecision, determined at four quality control concentrations, were or=72.9% for all analytes. Analytes were stable when stored at 22 degrees C for 16 h, 4 degrees C for 48 h, after three freeze-thaw cycles at -20 degrees C and when stored on the autosampler for 48 h. This sensitive and specific 2D-GCMS assay provides a new means of simultaneously quantifying CBD, THC and metabolite biomarkers in clinical medicine, forensic toxicology, workplace drug testing, and driving under the influence of drugs programs.

Frequency and irregularity of heart rate in drivers suspected of driving under the influence of cannabis.

PubMed

Khiabani, Hassan Z; Mørland, Jørg; Bramness, Jørgen G

2008-12-01

Delta 9-tetrahydrocannabinol (THC) is the major active component of cannabis. Cardiovascular effects of THC have previously been reported: tachycardia after intake, but also bradycardia at higher doses. The purpose of this study was, firstly, to investigate the frequency and irregularity of heart rate in a group of cannabis users in their natural surroundings. We also compared THC-positive drivers with a regular pulse with THC-positive drivers with an irregular pulse. The division of Forensic Toxicology and Drug Abuse (DFTDA) at the Norwegian Institute of Public Heath analyzes blood samples from all drivers suspected of driving under the influence of drugs. We studied pulse rate and regularity in 502 THC-positive drivers who tested negative for other substances. As a control group, we randomly selected 125 drug-negative cases from the database of the DFTDA; no alcohol, narcotics, or medicinal drugs of abuse were detected. The Delta9-THC-positive drivers had a higher mean pulse rate than the control group [82.8 beats/min (SD 16.3) versus 75.6 beats/min (SD 9.2)] and more cases with tachycardia were detected in the Delta9-THC-positive group (19.4% versus 1.6%). There was only one driver with an irregular heart beat in the control group, while there were nine among the Delta9-THC-positive drivers. The drivers with an irregular pulse were over-represented amongst those with the lowest blood Delta9-THC concentrations. This report represents a large study of subjects in a real-life situation and includes observations on pulse frequency, regularity, and blood Delta9-THC concentration. A substantial fraction of Delta9-THC-positive drivers had tachycardia, but there was no correlation between blood Delta9-THC concentration and pulse rate in the present study. We had no further diagnostic information on the cause of the pulse irregularities, but our results indicate that occasional users of cannabis tend to have irregular heart rates at low THC concentrations and at low pulse rates.

A study investigating the acute dose-response effects of 13 mg and 17 mg Delta 9- tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana.

PubMed

Weinstein, A; Brickner, O; Lerman, H; Greemland, M; Bloch, M; Lester, H; Chisin, R; Sarne, Y; Mechoulam, R; Bar-Hamburger, R; Freedman, N; Even-Sapir, E

2008-06-01

Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana.

Hair analysis for delta(9)-THC, delta(9)-THC-COOH, CBN and CBD, by GC/MS-EI. Comparison with GC/MS-NCI for delta(9)-THC-COOH.

PubMed

Baptista, Maria João; Monsanto, Paula Verâncio; Pinho Marques, Estela Gouveia; Bermejo, Ana; Avila, Sofia; Castanheira, Alice Martelo; Margalho, Cláudia; Barroso, Mário; Vieira, Duarte Nuno

2002-08-14

A sensitive analytical method was developed for quantitative analysis of delta(9)-tetrahydrocannabinol (delta(9)-THC), 11-nor-delta(9)-tetrahydrocannabinol-carboxylic acid (delta(9)-THC-COOH), cannabinol (CBN) and cannabidiol (CBD) in human hair. The identification of delta(9)-THC-COOH in hair would document Cannabis use more effectively than the detection of parent drug (delta(9)-THC) which might have come from environmental exposure. Ketamine was added to hair samples as internal standard for CBN and CBD. Ketoprofen was added to hair samples as internal standard for the other compounds. Samples were hydrolyzed with beta-glucuronidase/arylsulfatase for 2h at 40 degrees C. After cooling, samples were extracted with a liquid-liquid extraction procedure (with chloroform/isopropyl alcohol, after alkalinization, and n-hexane/ethyl acetate, after acidification), which was developed in our laboratory. The extracts were analysed before and after derivatization with pentafluoropropionic anhydride (PFPA) and pentafluoropropanol (PFPOH) using a Hewlett Packard gas chromatographer/mass spectrometer detector, in electron impact mode (GC/MS-EI). Derivatized delta(9)-THC-COOH was also analysed using a Hewlett Packard gas chromatographer/mass spectrometer detector, in negative ion chemical ionization mode (GC/MS-NCI) using methane as the reagent gas. Responses were linear ranging from 0.10 to 5.00 ng/mg hair for delta(9)-THC and CBN, 0.10-10.00 ng/mg hair for CBD, 0.01-5.00 ng/mg for delta(9)-THC-COOH (r(2)>0.99). The intra-assay precisions ranged from <0.01 to 12.40%. Extraction recoveries ranged from 80.9 to 104.0% for delta(9)-THC, 85.9-100.0% for delta(9)-THC-COOH, 76.7-95.8% for CBN and 71.0-94.0% for CBD. The analytical method was applied to 87 human hair samples, obtained from individuals who testified in court of having committed drug related crimes. Quantification of delta(9)-THC-COOH using GC/MS-NCI was found to be more convenient than GC/MS-EI. The latter may give rise to false negatives due to the detection limit.

Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain.

PubMed

Johnson, Jeremy R; Burnell-Nugent, Mary; Lossignol, Dominique; Ganae-Motan, Elena Doina; Potts, Richard; Fallon, Marie T

2010-02-01

This study compared the efficacy of a tetrahydrocannabinol:cannabidiol (THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract, with placebo, in relieving pain in patients with advanced cancer. In total, 177 patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, entered a two-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. Patients were randomized to THC:CBD extract (n = 60), THC extract (n = 58), or placebo (n = 59). The primary analysis of change from baseline in mean pain Numerical Rating Scale (NRS) score was statistically significantly in favor of THC:CBD compared with placebo (improvement of -1.37 vs. -0.69), whereas the THC group showed a nonsignificant change (-1.01 vs. -0.69). Twice as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain NRS score when compared with placebo (23 [43%] vs. 12 [21%]). The associated odds ratio was statistically significant, whereas the number of THC group responders was similar to placebo (12 [23%] vs. 12 [21%]) and did not reach statistical significance. There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups. No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment. However, the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Questionnaire showed a worsening in nausea and vomiting with THC:CBD compared with placebo (P = 0.02), whereas THC had no difference (P = 1.0). Most drug-related adverse events were mild/moderate in severity. This study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids. Copyright 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Plasma and urine profiles of Delta9-tetrahydrocannabinol and its metabolites 11-hydroxy-Delta9-tetrahydrocannabinol and 11-nor-9-carboxy-Delta9-tetrahydrocannabinol after cannabis smoking by male volunteers to estimate recent consumption by athletes.

PubMed

Brenneisen, Rudolf; Meyer, Pascale; Chtioui, Haithem; Saugy, Martial; Kamber, Matthias

2010-04-01

Since 2004, cannabis has been prohibited by the World Anti-Doping Agency for all sports competitions. In the years since then, about half of all positive doping cases in Switzerland have been related to cannabis consumption. In doping urine analysis, the target analyte is 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), the cutoff being 15 ng/mL. However, the wide urinary detection window of the long-term metabolite of Delta(9)-tetrahydrocannabinol (THC) does not allow a conclusion to be drawn regarding the time of consumption or the impact on the physical performance. The purpose of the present study on light cannabis smokers was to evaluate target analytes with shorter urinary excretion times. Twelve male volunteers smoked a cannabis cigarette standardized to 70 mg THC per cigarette. Plasma and urine were collected up to 8 h and 11 days, respectively. Total THC, 11-hydroxy-Delta(9)-tetrahydrocannabinol (THC-OH), and THC-COOH were determined after hydrolysis followed by solid-phase extraction and gas chromatography/mass spectrometry. The limits of quantitation were 0.1-1.0 ng/mL. Eight puffs delivered a mean THC dose of 45 mg. Plasma levels of total THC, THC-OH, and THC-COOH were measured in the ranges 0.2-59.1, 0.1-3.9, and 0.4-16.4 ng/mL, respectively. Peak concentrations were observed at 5, 5-20, and 20-180 min. Urine levels were measured in the ranges 0.1-1.3, 0.1-14.4, and 0.5-38.2 ng/mL, peaking at 2, 2, and 6-24 h, respectively. The times of the last detectable levels were 2-8, 6-96, and 48-120 h. Besides high to very high THC-COOH levels (245 +/- 1,111 ng/mL), THC (3 +/- 8 ng/mL) and THC-OH (51 +/- 246 ng/mL) were found in 65 and 98% of cannabis-positive athletes' urine samples, respectively. In conclusion, in addition to THC-COOH, the pharmacologically active THC and THC-OH should be used as target analytes for doping urine analysis. In the case of light cannabis use, this may allow the estimation of more recent consumption, probably influencing performance during competitions. However, it is not possible to discriminate the intention of cannabis use, i.e., for recreational or doping purposes. Additionally, pharmacokinetic data of female volunteers are needed to interpret cannabis-positive doping cases of female athletes.

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.

PubMed

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 well. To the best of our knowledge, this is the first publication on a comprehensively automated classical liquid-liquid extraction workflow in the field of forensic toxicological analysis. Graphical abstract GC/MS with MPS Dual Head at the Institute of Legal Medicine, Giessen, Germany. Modules from left to right: (quick) Mix (for LLE), wash station, tray 1 (vials for extracts), solvent reservoir, (m) VAP (for extract evaporation), Solvent Filling Station (solvent supply), cooled tray 2 (vials for serum samples), and centrifuge (for phase separation).

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2010 CFR

2010-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR 86.158-08 - Supplemental Federal Test Procedures; overview.

Code of Federal Regulations, 2012 CFR

2012-07-01

... THC, CO, NOX, CH4, and CO2. For diesel-cycle vehicles, THC is sampled and analyzed continuously... for which THC is sampled and analyzed continuously according to the provisions of § 86.110, the analytical system shall be configured to calculate THC for the US06 City phase and the US06 Highway phase as...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2010 CFR

2010-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2012 CFR

2012-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2014 CFR

2014-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2012 CFR

2012-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR 63.1349 - Performance testing requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) THC emissions test. (i) If you are subject to limitations on THC emissions, you must operate a CEMS in... assurance evaluations for CEMS, the THC span value (as propane) is 50 ppmvd and the reference method (RM) is Method 25A of appendix A to part 60 of this chapter. (ii) Use the THC CEMS to conduct the initial...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2010 CFR

2010-07-01

... THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR part 60... the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2013 CFR

2013-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR 86.158-08 - Supplemental Federal Test Procedures; overview.

Code of Federal Regulations, 2014 CFR

2014-07-01

... THC, CO, NOX, CH4, and CO2. For diesel-cycle vehicles, THC is sampled and analyzed continuously... for which THC is sampled and analyzed continuously according to the provisions of § 86.110, the analytical system shall be configured to calculate THC for the US06 City phase and the US06 Highway phase as...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2013 CFR

2013-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2011 CFR

2011-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

40 CFR 86.158-08 - Supplemental Federal Test Procedures; overview.

Code of Federal Regulations, 2013 CFR

2013-07-01

... THC, CO, NOX, CH4, and CO2. For diesel-cycle vehicles, THC is sampled and analyzed continuously... for which THC is sampled and analyzed continuously according to the provisions of § 86.110, the analytical system shall be configured to calculate THC for the US06 City phase and the US06 Highway phase as...

40 CFR 63.8687 - What performance tests, design evaluations, and other procedures must I use?

Code of Federal Regulations, 2011 CFR

2011-07-01

.... THC = Total hydrocarbon concentration at the combustion device outlet, parts per million by volume... auxiliary fuel, you must use Equation 6 of this section as follows: ER29AP03.005 Where: THC DE = THC... the test method specified in Table 3 to this subpart. THC = Total hydrocarbon concentration at the...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2011 CFR

2011-07-01

... THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR part 60... the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR Table 5 to Subpart Ppppp of... - Continuous Compliance With Emission Limitations

Code of Federal Regulations, 2014 CFR

2014-07-01

... THC concentration emission limitation a. Demonstrate CO or THC emissions are 20 ppmvd or less over..., according to § 63.9320; 2. CO or THC percent reduction emission limitation a. Demonstrate a reduction in CO or THC of 96 percent or more over each 4-hour rolling averaging period i. Collecting the CPMS data...

Descending and Local Network Interactions Control Adaptive Locomotion

DTIC Science & Technology

2014-12-04

segment). The thorax-coxa ( ThC ) joint swings dramatically in the front leg, but hardly moves at all in the middle and hind legs. These observations...changes in the three degree of freedom thorax-coxa joint ( ThC ) (Fig. 1). Indeed we were able to describe which of the three degrees of freedom were...these actions are distinct. The T1 leg relies heavily on actions of the second and third degree of freedom of the ThC joint ( ThC 2 and ThC3) whereas in

Pharmacology, signaling and physiological relevance of the G protein-coupled receptor 55.

PubMed

Balenga, Nariman A B; Henstridge, Christopher M; Kargl, Julia; Waldhoer, Maria

2011-01-01

According to The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), ∼70 million European adults have consumed cannabis on at least one occasion. Cannabis consumption leads to a variety of psychoactive effects due to the presence of the constituent Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Δ(9)-THC interacts with the endocannabinoid system (ECS), which consists of the seven transmembrane spanning (7TM)/G protein-coupled receptors (GPCRs) CB(1) and CB(2), their respective ligands (endocannabinoids), and enzymes involved in their biosynthesis and degradation. This system plays a critical role in many physiological processes such as learning and memory, appetite control, pain sensation, motor coordination, lipogenesis, modulation of immune response, and the regulation of bone mass. Therefore, a huge effort has been spent trying to fully elucidate the composition and function of the ECS. The G protein-coupled receptor 55 (GPR55) was recently proposed as a novel component of this system; however, its classification as a cannabinoid receptor has been significantly hampered by its complex pharmacology, signaling, and cellular function. GPR55 is phylogenetically distinct from the traditional cannabinoid receptors, but in some experimental paradigms, it is activated by endocannabinoids, phytocannabinoids, and synthetic cannabinoid ligands. However, the most potent compound appears to be a lysophospholipid known as lysophosphatidylinositol (LPI). Here, we provide a comprehensive evaluation of the current pharmacology and signaling of GPR55 and review the proposed role of this receptor in a number of physiological and pathophysiological processes. Copyright © 2011 Elsevier Inc. All rights reserved.

Effect of Norbinaltorphimine on Δ9-Tetrahydrocannabinol (THC)-Induced Taste Avoidance in Adolescent and Adult Sprague-Dawley Rats

PubMed Central

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

2017-01-01

Rationale The aversive effects of Δ9-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. Objectives 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. Methods 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. Results 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. Conclusions 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. PMID:26025420

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

PubMed

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.

Residual cannabis levels in blood, urine and oral fluid following heavy cannabis use.

PubMed

Odell, Morris S; Frei, Matthew Y; Gerostamoulos, Dimitri; Chu, Mark; Lubman, Dan I

2015-04-01

An understanding of tetrahydrocannabinol (THC) kinetics and residual levels after cannabis use is essential in interpreting toxicology tests in body fluids from live subjects, particularly when used in forensic settings for drug abuse, traffic and interpersonal violence cases. However the current literature is largely based on laboratory studies using controlled cannabis dosages in experienced users, with limited research investigating the kinetics of residual THC concentrations in regular high dose cannabis users. Twenty-one dependent cannabis users were recruited at admission to two residential detoxification units in Melbourne, Australia. After being provided with information about, and consenting to, the study, subjects volunteered to provide once-daily blood, urine and oral fluid (saliva) samples for seven consecutive days following admission, involving cessation and abstinence from all cannabis use. Blood and oral fluid specimens were analysed for THC and urine specimens for the metabolite THC-COOH. In some subjects THC was detectable in blood for at least 7 days and oral fluid specimens were positive for THC up to 78 h after admission to the unit. Urinary THC-COOH concentrations exceeded 1000 ng/mL for some subjects 129 h after last use. The presented blood THC levels are higher and persist longer in some individuals than previously described, our understanding and interpretation of THC levels in long term heavy cannabis users may need to be reconsidered. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A low-Δ9 tetrahydrocannabinol cannabis extract induces hyperphagia in rats.

PubMed

Farrimond, Jonathan A; Whalley, Benjamin J; Williams, Claire M

2010-12-01

Appetite stimulation via partial agonism of cannabinoid type 1 receptors by Δtetrahydrocannabinol (ΔTHC) is well documented and can be modulated by non-ΔTHC phytocannabinoids. ΔTHC concentrations sufficient to elicit hyperphagia induce changes to both appetitive (reduced latency to feed) and consummatory (increased meal one size and duration) behaviours. Here, we show that a cannabis extract containing too little ΔTHC to stimulate appetite can induce hyperphagia solely by increasing appetitive behaviours. Twelve, male Lister hooded rats were presatiated before treatment with a low-ΔTHC cannabis extract (0.5, 1.0, 2.0 and 4.0 mg/kg). Hourly intake and meal pattern data were recorded and analyzed using one-way analyses of variance followed by Bonferroni post-hoc tests. The cannabis extract significantly increased food intake during the first hour of testing (at 4.0 mg/kg) and significantly reduced the latency to feed versus vehicle treatments (at doses ≥1.0 mg/kg). Meal size and duration were unaffected. These results show only the increase in appetitive behaviours, which could be attributed to non-ΔTHC phytocannabinoids in the extract rather than ΔTHC. Although further study is required to determine the constituents responsible for these effects, these results support the presence of non-ΔTHC cannabis constituent(s) that exert a stimulatory effect on appetite and likely lack the detrimental psychoactive effects of ΔTHC.

Identification and quantification of cannabinoids in Cannabis sativa L. plants by high performance liquid chromatography-mass spectrometry.

PubMed

Aizpurua-Olaizola, Oier; Omar, Jone; Navarro, Patricia; Olivares, Maitane; Etxebarria, Nestor; Usobiaga, Aresatz

2014-11-01

High performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) has been successfully applied to cannabis plant extracts in order to identify cannabinoid compounds after their quantitative isolation by means of supercritical fluid extraction (SFE). MS conditions were optimized by means of a central composite design (CCD) approach, and the analysis method was fully validated. Six major cannabinoids [tetrahydrocannabinolic acid (THCA), tetrahydrocannabinol (THC), cannabidiol (CBD), tetrahydrocannabivarin (THCV), cannabigerol (CBG), and cannabinol (CBN)] were quantified (RSD < 10%), and seven more cannabinoids were identified and verified by means of a liquid chromatograph coupled to a quadrupole-time-of-flight (Q-ToF) detector. Finally, based on the distribution of the analyzed cannabinoids in 30 Cannabis sativa L. plant varieties and the principal component analysis (PCA) of the resulting data, a clear difference was observed between outdoor and indoor grown plants, which was attributed to a higher concentration of THC, CBN, and CBD in outdoor grown plants.

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2013 CFR

2013-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR 86.159-00 - Exhaust emission test procedures for US06 emissions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... for THC, CO, CO2, CH4, and NOX. For petroleum-fueled diesel-cycle vehicles, THC is sampled and... analyzed for THC, CO, CO2, CH4, and NOX. (b) Dynamometer activities. (1) All official US06 tests shall be... pumps, the temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2010 CFR

2010-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2013 CFR

2013-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR 86.159-00 - Exhaust emission test procedures for US06 emissions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... for THC, CO, CO2, CH4, and NOX. For petroleum-fueled diesel-cycle vehicles, THC is sampled and... analyzed for THC, CO, CO2, CH4, and NOX. (b) Dynamometer activities. (1) All official US06 tests shall be... pumps, the temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2010 CFR

2010-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2011 CFR

2011-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2012 CFR

2012-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2011 CFR

2011-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2014 CFR

2014-07-01

... HAP as THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR... subtract the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2012 CFR

2012-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2013 CFR

2013-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2012 CFR

2012-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR 86.159-00 - Exhaust emission test procedures for US06 emissions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... for THC, CO, CO2, CH4, and NOX. For petroleum-fueled diesel-cycle vehicles, THC is sampled and... analyzed for THC, CO, CO2, CH4, and NOX. (b) Dynamometer activities. (1) All official US06 tests shall be... pumps, the temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel...

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2010 CFR

2010-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2011 CFR

2011-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2012 CFR

2012-07-01

... HAP as THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR... subtract the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR Table 4 to Subpart Dddd of... - Requirements for Performance Tests

Code of Federal Regulations, 2013 CFR

2013-07-01

... HAP as THC compliance option measure emissions of total HAP as THC Method 25A in appendix A to 40 CFR... subtract the methane emissions from the emissions of total HAP as THC. (6) each process unit subject to a... § 63.2240(c) establish the site-specific operating requirements (including the parameter limits or THC...

40 CFR Table 4 to Subpart Ppppp of... - Initial Compliance With Emission Limitations

Code of Federal Regulations, 2014 CFR

2014-07-01

... . . . 1. CO or THC concentration emission limitation The first 4-hour rolling average CO or THC concentration is 20 ppmvd or less, corrected to 15 percent O2 content. 2. CO or THC percent reduction emission limitation The first 4-hour rolling average reduction in CO or THC is 96 percent or more, dry basis...

40 CFR Table 4 to Subpart Sssss to... - Requirements for Performance Tests

Code of Federal Regulations, 2014 CFR

2014-07-01

... OM&M plan; and (6) If complying with the THC concentration or THC percentage reduction limits... continuous process unit that is subject to the THC emission limit listed in item 2.a., 3.a., 4, or 5 of Table 1 to this subpart a. Measure THC concentrations at the outlet of the control device or in the stack...

40 CFR 1039.240 - How do I demonstrate that my engine family complies with exhaust emission standards?

Code of Federal Regulations, 2014 CFR

2014-07-01

... compliance on total hydrocarbon (THC) emissions. Indicate in your application for certification if you are using this option. If you do, measure THC emissions and calculate NMHC emissions as 98 percent of THC emissions, as shown in the following equation: NMHC = (0.98) × (THC). [69 FR 39213, June 29, 2004, as...

40 CFR 86.159-00 - Exhaust emission test procedures for US06 emissions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... for THC, CO, CO2, CH4, and NOX. For petroleum-fueled diesel-cycle vehicles, THC is sampled and... analyzed for THC, CO, CO2, CH4, and NOX. (b) Dynamometer activities. (1) All official US06 tests shall be... pumps, the temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel...

Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol.

PubMed

Becker, Jérôme A J; Kieffer, Brigitte L; Le Merrer, Julie

2017-09-01

Unified theories of addiction are challenged by differing drug-seeking behaviors and neurobiological adaptations across drug classes, particularly for narcotics and psychostimulants. We previously showed that protracted abstinence to opiates leads to despair behavior and social withdrawal in mice, and we identified a transcriptional signature in the extended amygdala that was also present in animals abstinent from nicotine, Δ9-tetrahydrocannabinol (THC) and alcohol. Here we examined whether protracted abstinence to these four drugs would also share common behavioral features, and eventually differ from abstinence to the prototypic psychostimulant cocaine. We found similar reduced social recognition, increased motor stereotypies and increased anxiety with relevant c-fos response alterations in morphine, nicotine, THC and alcohol abstinent mice. Protracted abstinence to cocaine, however, led to strikingly distinct, mostly opposing adaptations at all levels, including behavioral responses, neuronal activation and gene expression. Together, these data further document the existence of common hallmarks for protracted abstinence to opiates, nicotine, THC and alcohol that develop within motivation/emotion brain circuits. In our model, however, these do not apply to cocaine, supporting the notion of unique mechanisms in psychostimulant abuse. © 2016 Society for the Study of Addiction.

Tetrahydrocannabinol-induced suppression of macrophage spreading and phagocytic activity in vitro.

PubMed

Lopez-Cepero, M; Friedman, M; Klein, T; Friedman, H

1986-06-01

The effects of tetrahydrocannabinol (THC) on several parameters of macrophage function in vitro were assessed. Delta 9 THC added to cultures of normal mouse peritoneal cells in vitro affected the ability of the cells to spread on glass surfaces and also had some effect on their ability to phagocytize yeast. These effects were dose related. A concentration of 20 micrograms of THC almost completely inhibited macrophage spreading, but it also decreased viability and the total number of these cells. Doses of 10 or 5 micrograms of THC also inhibited spreading but had little effect on cell viability or number. A dose of 1.0 microgram of THC had some inhibitory effect on spreading and the lowest dose affecting spreading appeared to be about 0.05 micrograms per culture. Higher doses of THC were necessary to inhibit phagocytosis of yeast particles as determined by direct microscopic examination or use of radiolabeled yeast as the test particles. These results indicate that several readily measured functions of macrophages may be suppressed by THC.

Brain imaging study of the acute effects of Delta9-tetrahydrocannabinol (THC) on attention and motor coordination in regular users of marijuana.

PubMed

Weinstein, Aviv; Brickner, Orit; Lerman, Hedva; Greemland, Mazal; Bloch, Miki; Lester, Hava; Chisin, Roland; Mechoulam, Raphael; Bar-Hamburger, Rachel; Freedman, Nanette; Even-Sapir, Einat

2008-01-01

Twelve regular users of marijuana underwent two positron emission tomography (PET) scans using [18F] Fluorodeoxyglucose (FDG), one while subject to the effects of 17 mg THC, the other without THC. In both sessions, a virtual reality maze task was performed during the FDG uptake period. When subject to the effects of 17 mg THC, regular marijuana smokers hit the walls more often on the virtual maze task than without THC. Compared to results without THC, 17 mg THC increased brain metabolism during task performance in areas that are associated with motor coordination and attention in the middle and medial frontal cortices and anterior cingulate, and reduced metabolism in areas that are related to visual integration of motion in the occipital lobes. These findings suggest that in regular marijuana users, the immediate effects of marijuana may impact on cognitive-motor skills and brain mechanisms that modulate coordinated movement and driving.

Evaluation of the Effects of Sativex (THC BDS: CBD BDS) on Inhibition of Spasticity in a Chronic Relapsing Experimental Allergic Autoimmune Encephalomyelitis: A Model of Multiple Sclerosis

PubMed Central

Hilliard, A.; Stott, C.; Wright, S.; Guy, G.; Pryce, G.; Al-Izki, S.; Bolton, C.; Giovannoni, G.

2012-01-01

This study investigated the antispasticity potential of Sativex in mice. Chronic relapsing experimental allergic encephalomyelitis was induced in adult ABH mice resulting in hind limb spasticity development. Vehicle, Sativex, and baclofen (as a positive control) were injected intravenously and the “stiffness” of limbs assessed by the resistance force against hind limb flexion. Vehicle alone caused no significant change in spasticity. Baclofen (5 mg/kg) induced approximately a 40% peak reduction in spasticity. Sativex dose dependently reduced spasticity; 5 mg/kg THC + 5 mg/kg CBD induced approximately a 20% peak reduction; 10 mg/kg THC + 10 mg/kg CBD produced approximately a 40% peak reduction in spasticity. Sativex has the potential to reduce spasticity in an experimental mouse model of multiple sclerosis (MS). Baclofen reduced spasticity and served as a positive control. Sativex (10 mg/kg) was just as effective as baclofen, providing supportive evidence for Sativex use in the treatment of spasticity in MS. PMID:22928118

40 CFR 1066.15 - Overview of test procedures.

Code of Federal Regulations, 2012 CFR

2012-07-01

... ways: (i) Total hydrocarbons, THC. (ii) Nonmethane hydrocarbons, NMHC, which results from subtracting methane (CH4) from THC. (iii) Total hydrocarbon-equivalent, THCE, which results from adjusting THC...

40 CFR 1066.15 - Overview of test procedures.

Code of Federal Regulations, 2013 CFR

2013-07-01

... ways: (i) Total hydrocarbons, THC. (ii) Nonmethane hydrocarbons, NMHC, which results from subtracting methane (CH4) from THC. (iii) Total hydrocarbon-equivalent, THCE, which results from adjusting THC...

[Time profile of serum THC levels in occasional and chronic marihuana smokers after acute drog use - implication for drivind motor vehicles].

PubMed

Balíková, Marie; Hložek, Tomáš; Páleníček, Tomáš; Tylš, Filip; Viktorinová, Michaela; Melicher, Tomáš; Androvičová, Renáta; Tomíček, Pavel; Roman, Michal; Horáček, Jiří

2014-01-01

Cannabis consumption has individual influence to cognitive and psychomotor functions of drivers and it has been generally accepted that driving under influence is risky in the perspective of traffic safety. However, rules how to assess fitness to drive are not quite clear. The psychoactive compound delta-9-tetrahydrocannabinol (THC) impairs cognition, psychomotor behaviour and driving performance in a dose-related manner approximately. After a single drug dose, THC blood concentration peaks within minutes, before the end of smoking, with a subsequent rapid decrease to the analytical limit of detection. Peak euphoria is delayed compared to THC peak blood concentration and physiological and behavioural effects return to baseline within 3-5 hours. In chronic users, the lipophilic THC accumulates in fat tissues, where its slow redistribution into blood is the rate limiting process in its terminal elimination. In our experimental study we have attempted to contribute to this discussion with results obtained from human volunteers - cannabis consumers in Czech Republic. Aim of our study was to document the time profile of serum THC level in occasional and chronic cannabis users. The observational interval covered the time immediately after the drug consumption (an own cigarette/joint) till 24 hours after. Our preliminary results have shown that in occasional users, THC serum levels cannot be detected already 4 hours after usual cannabis dose, whereas in chronic users measurable THC concentrations in serum persist longer. Moreover, some chronic consumers were practically with permanent THC detection during our observation period and also the chronic users consumed higher THC doses significantly related to doses in occasional ones. Presented results of the experimental study with human volunteers confirm a great individual variability of the kinetic profile of THC in blood due to complicated redistribution. The practical forensic question is how long the psychotropic effects of THC can persist after the last drug dose. In chronic users there are well documented indications of long term adverse effects to neurocognitive functions. THC blood level itself can not directly document the intensity of impairment of a driver. Moreover, the concentration of THC in blood at the time of driving is probably substantially higher than at the time of blood sampling. Therefore due to the prevention of traffic risk, some countries adopted per se traffic legislation based on analytical principle with minimum tolerance to illegal drugs in blood of drivers at driving. Low blood concentrations of THC close to the limit of detection of a specific toxicological method (GC-MS or LC-MS) are justified in an effective traffic legislation.

Oxidative stress and cannabinoid receptor expression in type-2 diabetic rat pancreas following treatment with Δ⁹-THC.

PubMed

Coskun, Zeynep Mine; Bolkent, Sema

2014-10-01

The objectives of study were (a) to determine alteration of feeding, glucose level and oxidative stress and (b) to investigate expression and localization of cannabinoid receptors in type-2 diabetic rat pancreas treated with Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Rats were randomly divided into four groups: control, Δ(9)-THC, diabetes and diabetes + Δ(9)-THC groups. Diabetic rats were treated with a single dose of nicotinamide (85 mg/kg) 15 min before injection of streptozotocin (65 mg/kg). Δ(9)-THC was administered intraperitoneally at 3 mg/kg/day for 7 days. Body weights and blood glucose level of rats in all groups were measured on days 0, 7, 14 and 21. On day 15 after the Δ(9)-THC injections, pancreatic tissues were removed. Blood glucose levels and body weights of diabetic rats treated with Δ(9)-THC did not show statistically significant changes when compared with the diabetic animals on days 7, 14 and 21. Treatment with Δ(9)-THC significantly increased pancreas glutathione levels, enzyme activities of superoxide dismutase and catalase in diabetes compared with non-treatment diabetes group. The cannabinoid 1 receptor was found in islets, whereas the cannabinoid 2 receptor was found in pancreatic ducts. Their localization in cells was both nuclear and cytoplasmic. We can suggest that Δ(9) -THC may be an important agent for the treatment of oxidative damages induced by diabetes. However, it must be supported with anti-hyperglycaemic agents. Furthermore, the present study for the first time emphasizes that Δ(9)-THC may improve pancreatic cells via cannabinoid receptors in diabetes. The aim of present study was to elucidate the effects of Δ(9)-THC, a natural cannabinoid receptor agonist, on the expression and localization of cannabinoid receptors, and oxidative stress statue in type-2 diabetic rat pancreas. Results demonstrate that the cannabinoid receptors are presented in both Langerhans islets and duct regions. The curative effects of Δ(9)-THC can be occurred via activation of cannabinoid receptors in diabetic rat pancreas. Moreover, it may provide a protective effect against oxidative damage induced by diabetes. Thus, it is suggested that Δ(9)-THC can be a candidate for therapeutic alternatives of diabetes symptoms. Copyright © 2014 John Wiley & Sons, Ltd.

Simultaneous quantification of cannabinoids and metabolites in oral fluid by two-dimensional gas chromatography mass spectrometry

PubMed Central

Milman, Garry; Barnes, Allan J.; Lowe, Ross H.; Huestis, Marilyn A.

2010-01-01

Development and validation of a method for simultaneous identification and quantification of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), and metabolites 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THCCOOH) in oral fluid. Simultaneous analysis was problematic due to different physicochemical characteristics and concentration ranges. Neutral analytes, such as THC and CBD, are present in ng/mL, rather than pg/mL concentrations, as observed for the acidic THCCOOH biomarker in oral fluid. THCCOOH is not present in cannabis smoke, definitively differentiating cannabis use from passive smoke exposure. THC, 11-OH-THC, THCCOOH, CBD, and CBN quantification was achieved in a single oral fluid specimen collected with the Quantisal™ device. One mL oral fluid/buffer solution (0.25mL oral fluid and 0.75mL buffer) was applied to conditioned CEREX® Polycrom™ THC solid phase extraction (SPE) columns. After washing, THC, 11-OH-THC, CBD, and CBN were eluted with hexane/acetone/ethyl acetate (60:30:20, v/v/v), derivatized with N, O-bis-(trimethylsilyl) trifluoroacetamide and quantified by two-dimensional gas chromatography electron ionization mass spectrometry (2D-GCMS) with cold trapping. Acidic THCCOOH was separately eluted with hexane/ethyl acetate/acetic acid (75:25:2.5, v/v/v), derivatized with trifluoroacetic anhydride and hexafluoroisopropanol, and quantified by the more sensitive 2D-GCMS–electron capture negative chemical ionization (NCI-MS). Linearity was 0.5-50ng/mL for THC, 11-OH-THC, CBD and 1-50ng/mL for CBN. The linear dynamic range for THCCOOH was 7.5–500pg/mL. Intra-and inter-assay imprecision as percent RSD at three concentrations across the linear dynamic range were 0.3%-6.6%. Analytical recovery was within 13.8% of target. This new SPE 2D-GCMS assay achieved efficient quantification of five cannabinoids in oral fluid, including pg/mL concentrations of THCCOOH by combining differential elution, 2D-GCMS with electron ionization and negative chemical ionization. This method will be applied to quantification of cannabinoids in oral fluid specimens from individuals participating in controlled cannabis and Sativex® (50% THC and 50% CBD) administration studies, and during cannabis withdrawal. PMID:20083251

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 12 2010-07-01 2010-07-01 true How do I determine the outlet THC.../outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and add-on control... section to determine either the outlet THC emissions or add-on control device emission destruction or...

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 13 2013-07-01 2012-07-01 true How do I determine the outlet THC... Control Efficiency/outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and... methods in this section to determine either the outlet THC emissions or add-on control device emission...

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 13 2014-07-01 2014-07-01 false How do I determine the outlet THC... Control Efficiency/outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and... methods in this section to determine either the outlet THC emissions or add-on control device emission...

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 12 2011-07-01 2009-07-01 true How do I determine the outlet THC.../outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and add-on control... section to determine either the outlet THC emissions or add-on control device emission destruction or...

40 CFR 63.3555 - How do I determine the outlet THC emissions and add-on control device emission destruction or...

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 13 2012-07-01 2012-07-01 false How do I determine the outlet THC... Control Efficiency/outlet Concentration Option § 63.3555 How do I determine the outlet THC emissions and... methods in this section to determine either the outlet THC emissions or add-on control device emission...

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2011 CFR

2011-07-01

... on THC CEMS data Collecting and recording the THC monitoring data listed in Table 2 to this subpart... according to calculations in § 63.2269(d); AND maintaining the 3-hour block average THC concentration in the exhaust gases less than or equal to the THC concentration established according to § 63.2262. (3) Each...

40 CFR Table 7 to Subpart Dddd of... - Continuous Compliance With the Compliance Options and Operating Requirements

Code of Federal Regulations, 2010 CFR

2010-07-01

... on THC CEMS data Collecting and recording the THC monitoring data listed in Table 2 to this subpart... according to calculations in § 63.2269(d); AND maintaining the 3-hour block average THC concentration in the exhaust gases less than or equal to the THC concentration established according to § 63.2262. (3) Each...

An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics.

PubMed

Johnson, Jeremy R; Lossignol, Dominique; Burnell-Nugent, Mary; Fallon, Marie T

2013-08-01

Chronic pain in patients with advanced cancer poses a serious clinical challenge. The Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (U.S. Adopted Name, nabiximols; Sativex(®)) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group. This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer. In total, 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing, who had participated in a previous three-arm (THC/CBD spray, THC spray, or placebo), two-week parent randomized controlled trial, entered this open-label, multicenter, follow-up study. Patients self-titrated THC/CBD spray (n=39) or THC spray (n=4) to symptom relief or maximum dose and were regularly reviewed for safety, tolerability, and evidence of clinical benefit. The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for "pain severity" and "worst pain" domains showed a decrease (i.e., improvement) at each visit in the THC/CBD spray patients. Similarly, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scores showed a decrease (i.e., improvement) from baseline in the domains of insomnia, pain, and fatigue. No new safety concerns associated with the extended use of THC/CBD spray arose from this study. This study showed that the long-term use of THC/CBD spray was generally well tolerated, with no evidence of a loss of effect for the relief of cancer-related pain with long-term use. Furthermore, patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit. Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Extended plasma cannabinoid excretion in chronic frequent cannabis smokers during sustained abstinence and correlation with psychomotor performance.

PubMed

Karschner, Erin L; Swortwood, Madeleine J; Hirvonen, Jussi; Goodwin, Robert S; Bosker, Wendy M; Ramaekers, Johannes G; Huestis, Marilyn A

2016-07-01

Cannabis smoking increases motor vehicle accident risk. Empirically defined cannabinoid detection windows are important to drugged driving legislation. Our aims were to establish plasma cannabinoid detection windows in frequent cannabis smokers and to determine if residual cannabinoid concentrations were correlated with psychomotor performance. Twenty-eight male chronic frequent cannabis smokers resided on a secure research unit for up to 33 days with daily blood collection. Plasma specimens were analyzed for Δ(9) -tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) by gas chromatography-mass spectrometry. Critical tracking and divided attention tasks were administered at baseline (after overnight stay to ensure lack of acute intoxication) and after 1, 2, and 3 weeks of cannabis abstinence. Twenty-seven of the twenty-eight participants were THC-positive at admission (median 4.2 µg/L). THC concentrations significantly decreased 24 h after admission, but were still ≥2 µg/L in 16 of the 28 participants 48 h after admission. THC was detected in 3 of 5 specimens on day 30. The last positive 11-OH-THC specimen was 15 days after admission. THCCOOH was measureable in 4 of 5 participants after 30 days of abstinence. Years of prior cannabis use significantly correlated with THC concentrations on admission, and days 7 and 14. Tracking error, evaluated by the Divided Attention Task, was the only evaluated psychomotor assessment significantly correlated with cannabinoid concentrations at baseline and day 8 (11-OH-THC only). Median THC was 0.3 µg/L in 5 chronic frequent cannabis smokers' plasma samples after 30 days of sustained abstinence. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

A novel fast method for aqueous derivatization of THC, OH-THC and THC-COOH in human whole blood and urine samples for routine forensic analyses.

PubMed

Stefanelli, Fabio; Pesci, Federica Giorgia; Giusiani, Mario; Chericoni, Silvio

2018-04-01

A novel aqueous in situ derivatization procedure with propyl chloroformate (PCF) for the simultaneous, quantitative analysis of Δ 9 -tetrahydrocannabinol (THC), 11-hydroxy-Δ 9 -tetrahydrocannabinol (OH-THC) and 11-nor-Δ 9 -tetrahydrocannabinol-carboxylic acid (THC-COOH) in human blood and urine is proposed. Unlike current methods based on the silylating agent [N,O-bis(trimethylsilyl)trifluoroacetamide] added in an anhydrous environment, this new proposed method allows the addition of the derivatizing agent (propyl chloroformate, PCF) directly to the deproteinized blood and recovery of the derivatives by liquid-liquid extraction. This novel method can be also used for hydrolyzed urine samples. It is faster than the traditional method involving a derivatization with trimethyloxonium tetrafluoroborate. The analytes are separated, detected and quantified by gas chromatography-mass spectrometry in selected ion monitoring mode (SIM). The method was validated in terms of selectivity, capacity of identification, limits of detection (LOD) and quantification (LOQ), carryover, linearity, intra-assay precision, inter-assay precision and accuracy. The LOD and LOQ in hydrolyzed urine were 0.5 and 1.3 ng/mL for THC and 1.2 and 2.6 ng/mL for THC-COOH, respectively. In blood, the LOD and LOQ were 0.2 and 0.5 ng/mL for THC, 0.2 and 0.6 ng/mL for OH-THC, and 0.9 and 2.4 ng/mL for THC-COOH, respectively. This method was applied to 35 urine samples and 50 blood samples resulting to be equivalent to the previously used ones with the advantage of a simpler method and faster sample processing time. We believe that this method will be a more convenient option for the routine analysis of cannabinoids in toxicological and forensic laboratories. Copyright © 2017 John Wiley & Sons, Ltd.

Recovery of spiked Δ9-tetrahydrocannabinol in oral fluid from polypropylene containers.

PubMed

Molnar, Anna; Lewis, John; Fu, Shanlin

2013-04-10

Oral fluid is currently used by Australian and international law enforcement agencies and employers to detect recent use of cannabis and other drugs of abuse. The main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol (THC), is highly lipophilic and losses occur when in contact with plastic, possibly due to its adsorption onto the plastic surface. This study aims to investigate factors governing the interaction of THC with plastic and search for ways of overcoming such interaction so to improve THC recovery. As polypropylene is one of the most common types of plastic used in collection devices, it was the focus of this study. All experiments were done by preparing neat oral fluid samples spiked with THC in 2-mL polypropylene centrifuge tubes. Samples were transferred with or without prior addition of Triton(®) X-100 (0.25%) to glass tubes containing d3-THC as internal standard and 0.1M phosphate buffer was then added. Samples were extracted by liquid-liquid extraction using hexane/ethyl acetate (9:1, v/v), dried and analysed by gas chromatography-mass spectrometry (GC-MS) after derivatisation. No significant difference was found in terms of THC loss to plastic when the concentration ranged from 25 to 1000 ng/mL in the same volume of oral fluid. Varying the oral fluid volume (0.5-1.5 mL) while keeping THC at a constant concentration showed an upward trend with more loss associated with lower volumes. The use of Triton(®) X-100 significantly decreased the adherence of THC to the plastic tubes and increased the THC transfer (>96%) at all volumes tested. Degradation of THC during storage was also studied over a 4-week period and it was found that azide did not seem to play a significant role in preserving THC in oral fluid. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats

PubMed Central

Shen, Erica Y.; Ali, Syed F.; Meyer, Jerrold S.

2011-01-01

Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or “ecstasy”) also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Δ9-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2 × 10 mg/kg × 4 h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5 mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA. PMID:21763331

Chronic administration of THC prevents the behavioral effects of intermittent adolescent MDMA administration and attenuates MDMA-induced hyperthermia and neurotoxicity in rats.

PubMed

Shen, Erica Y; Ali, Syed F; Meyer, Jerrold S

2011-12-01

Most recreational users of 3, 4-methylenedioxymethamphetamine (MDMA or "ecstasy") also take cannabis, in part because cannabis can reduce the dysphoric symptoms of the ecstasy come-down such as agitation and insomnia. Although previous animal studies have examined the acute effects of co-administering MDMA and Δ(9)-tetrahydrocannabinol (THC), which is the major psychoactive ingredient in cannabis, research on chronic exposure to this drug combination is lacking. Therefore, the present study was conducted to investigate the effects of chronic adolescent administration of both THC and MDMA on behavior and on regional serotonin transporter (SERT) binding and serotonin (5-HT) concentrations as indices of serotonergic system integrity. Male Sprague-Dawley rats were divided into four drug administration groups: (1) MDMA alone, (2) THC alone, (3) MDMA plus THC, and (4) vehicle controls. MDMA (2 × 10 mg/kg × 4 h) was administered every fifth day from postnatal day (PD) 35 to 60 to simulate intermittent recreational ecstasy use, whereas THC (5mg/kg) was given once daily over the same time period to simulate heavy cannabis use. THC unexpectedly produced a modest hyperthermic effect when administered alone, but in animals co-treated with both THC and MDMA, there was an attenuation of MDMA-induced hyperthermia on dosing days. Subsequent testing conducted after a drug washout period revealed that THC reduced MDMA-related behavioral changes in the emergence and social interaction tests of anxiety-like behavior and also blunted the MDMA-induced decrease in exploratory behavior in the hole-board test. THC additionally attenuated MDMA -induced decreases in 5-HT levels and in SERT binding in the frontal cortex, parietal cortex, and striatum, but not in the hippocampus. These results suggest that chronic co-administration of THC during adolescence can provide some protection against various adverse physiological, behavioral, and neurochemical effects produced by MDMA. Published by Elsevier Ltd.

Effects of tetrahydrocannabinol on glucose uptake in the rat brain.

PubMed

Miederer, I; Uebbing, K; Röhrich, J; Maus, S; Bausbacher, N; Krauter, K; Weyer-Elberich, V; Lutz, B; Schreckenberger, M; Urban, R

2017-05-01

Δ 9 -Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain. The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain. 21 male Sprague Dawley rats (12-13 w) were examined and received five different doses of THC ranging from 0.01 to 1 mg/kg. For data acquisition a Focus 120 small animal PET scanner was used and 24.1-28.0 MBq of [ 18 F]-fluoro-2-deoxy-d-glucose were injected. The data were acquired for 70 min and arterial blood samples were collected throughout the scan. THC, THC-OH and THC-COOH were determined at 55 min p.i. Nine volumes of interest were defined, and the cerebral glucose uptake was calculated for each brain region. Low blood THC levels of < 1 ng/ml (injected dose: ≤ 0.01 mg/kg) corresponded to an increased glucose uptake (6-30 %), particularly in the hypothalamus (p = 0.007), while blood THC levels > 10 ng/ml (injected dose: ≥ 0.05 mg/kg) coincided with a decreased glucose uptake (-2 to -22 %), especially in the cerebellar cortex (p = 0.008). The effective concentration in this region was estimated 2.4 ng/ml. This glucose PET study showed that stimulation of CB1 receptors by THC affects the glucose uptake in the rat brain, whereby the effect of THC is regionally different and dependent on dose - an effect that may be of relevance in behavioural studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

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.

PubMed

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.

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

PubMed Central

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

Separate and combined effects of the cannabinoid agonists nabilone and Δ⁹-THC in humans discriminating Δ⁹-THC.

PubMed

Lile, Joshua A; Kelly, Thomas H; Hays, Lon R

2011-07-01

Agonist replacement treatment is a promising strategy to manage cannabis-use disorders. The aim of this study was to assess the combined effects of the synthetic cannabinoid agonist nabilone and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) using drug-discrimination procedures, which are sensitive to drug interactions. Testing the concurrent administration of nabilone and Δ⁹-THC was also conducted to provide initial safety and tolerability data, which is important because cannabis users will likely lapse during treatment. Six cannabis users learned to discriminate 30 mg oral Δ⁹-THC from placebo and then received nabilone (0, 1 and 3mg) and Δ⁹-THC (0, 5, 15 and 30 mg), alone and in combination. Subjects completed the multiple-choice procedure to assess drug reinforcement, and self-report, task performance and physiological measures were collected. Δ⁹-THC and nabilone alone shared discriminative-stimulus effects with the training dose of Δ⁹-THC, increased crossover point on the multiple-choice procedure, produced overlapping subject ratings and decreased skin temperature. Nabilone alone also elevated heart rate. In combination, nabilone shifted the discriminative-stimulus effects of Δ⁹-THC leftward/upward and enhanced Δ⁹-THC effects on the other outcome measures. These results replicate a previous study demonstrating that nabilone shares agonist effects with the active constituent of cannabis in cannabis users, and contribute further by indicating that nabilone would likely be safe and well tolerated when combined with cannabis. These data support the conduct of future studies to determine if nabilone treatment would produce cross-tolerance to the abuse-related effects of cannabis and reduce cannabis use. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Tetrahydrocannabinol (THC) impairs encoding but not retrieval of verbal information.

PubMed

Ranganathan, Mohini; Radhakrishnan, Rajiv; Addy, Peter H; Schnakenberg-Martin, Ashley M; Williams, Ashley H; Carbuto, Michelle; Elander, Jacqueline; Pittman, Brian; Andrew Sewell, R; Skosnik, Patrick D; D'Souza, Deepak Cyril

2017-10-03

Cannabis and agonists of the brain cannabinoid receptor (CB 1 R) produce acute memory impairments in humans. However, the extent to which cannabinoids impair the component processes of encoding and retrieval has not been established in humans. The objective of this analysis was to determine whether the administration of Δ 9 -Tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, impairs encoding and/or retrieval of verbal information. Healthy subjects were recruited from the community. Subjects were administered the Rey-Auditory Verbal Learning Test (RAVLT) either before administration of THC (experiment #1) (n=38) or while under the influence of THC (experiment #2) (n=57). Immediate and delayed recall on the RAVLT was compared. Subjects received intravenous THC, in a placebo-controlled, double-blind, randomized manner at doses known to produce behavioral and subjective effects consistent with cannabis intoxication. Total immediate recall, short delayed recall, and long delayed recall were reduced in a statistically significant manner only when the RAVLT was administered to subjects while they were under the influence of THC (experiment #2) and not when the RAVLT was administered prior. THC acutely interferes with encoding of verbal memory without interfering with retrieval. These data suggest that learning information prior to the use of cannabis or cannabinoids is not likely to disrupt recall of that information. Future studies will be necessary to determine whether THC impairs encoding of non-verbal information, to what extent THC impairs memory consolidation, and the role of other cannabinoids in the memory-impairing effects of cannabis. Cannabinoids, Neural Synchrony, and Information Processing (THC-Gamma) http://clinicaltrials.gov/ct2/show/study/NCT00708994 NCT00708994 Pharmacogenetics of Cannabinoid Response http://clinicaltrials.gov/ct2/show/NCT00678730 NCT00678730. Copyright © 2017. Published by Elsevier Inc.

Persistent effects of chronic Δ9-THC exposure on motor impulsivity in rats.

PubMed

Irimia, Cristina; Polis, Ilham Y; Stouffer, David; Parsons, Loren H

2015-08-01

In humans, long-term marijuana use is associated with impaired impulse control and attentional capacity, though it has been difficult to distinguish pre-existing cognitive deficits from possible consequences of prolonged marijuana exposure. To evaluate the effects of long-term exposure to Δ9-Tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent in marijuana, on indices of impulse control and attentional capacity using the rat 5-Choice Serial Reaction Time Task (5-CSRTT). Ten 14-day cycles of Δ9-THC dosing and 5-CSRTT testing were employed, each comprised of 5-day Δ9-THC dosing (0.3 or 3 mg/kg b.i.d.) and 5-CSRTT testing during the 9 days of drug abstinence. Subsequent 5-CSRTT testing continued during 5 weeks of protracted abstinence. Dose-dependent increases in motor impulsivity (premature responses) and behavioral disinhibition (perseverative responses) emerged following 5 cycles of Δ9-THC exposure that persisted for the remaining dosing and testing cycles. Δ9-THC-related disruptions in motor impulsivity and behavioral inhibition were most pronounced during cognitively challenging 5-CSRTT sessions incorporating varying novel inter-trial intervals (ITIs), and these disruptions persisted for at least 5 weeks of Δ9-THC abstinence. Δ9-THC-related impairments in attentional capacity (response accuracy) were also evident during variable ITI challenge tests, though these attentional disruptions abated within 3 weeks of Δ9-THC abstinence. These observations demonstrate that long-term intermittent exposure to clinically meaningful Δ9-THC doses induces persistent impairments in impulse control and attentional function. If present in humans, these disruptions may impact academic and professional performance.

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

PubMed Central

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 experimental sessions wherein all combinations of placebo or 10 mg oral doses of delta-9-tetrahydocannibinol (THC); and 0 mg, 10 mg 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 10 mg THC + 0 mg, 10 mg, 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. PMID:25175495

Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew).

PubMed

Parker, Linda A; Kwiatkowska, Magdalena; Burton, Page; Mechoulam, Raphael

2004-01-01

Marijuana has been reported to interfere with nausea and vomiting in chemotherapy patients. The principal cannabinoids found in marijuana include the psychoactive compound Delta-9-tetrahydrocannabinol (THC) and the non-psychoactive compound cannabidiol (CBD). The experiments reported here evaluated the potential of THC and CBD to interfere with vomiting in the Suncus murinus (house musk shrew) produced by lithium chloride (LiCl), which is the most commonly employed unconditioned stimulus for taste avoidance. To evaluate the potential of the principal components of marijuana, THC and CBD, to suppress Li-induced vomiting in the house musk shrew. Shrews were injected with vehicle or one of two cannabinoids [Delta-9-THC (1-20 mg/kg), or CBD (2.5-40 mg/kg)] 10 min prior to an injection of LiCl (390 mg/kg of 0.15 M) and were then observed for 45 min. The frequency of vomiting episodes and the latency to the first episode were measured. The role of the CB1 receptor in these effects was also evaluated by pretreatment with SR-141716. Delta-9-THC produced a dose-dependent suppression of Li-induced vomiting, with higher doses producing greater suppression than lower doses. CBD produced a biphasic effect with lower doses producing suppression and higher doses producing enhancement of Li-induced vomiting. The suppression of Li-induced vomiting by THC, but not by CBD, was reversed by SR-141716. These results indicate that two major cannabinoid compounds found in marijuana, THC and CBD, are effective treatments for Li-induced vomiting; however, only THC acts by the CB1 receptor. The effects of THC and CBD on vomiting were dose dependent; with THC the effect was linear, but with CBD the effect was biphasic.

Cannabinoids in oral fluid following passive exposure to marijuana smoke.

PubMed

Moore, Christine; Coulter, Cynthia; Uges, Donald; Tuyay, James; van der Linde, Susanne; van Leeuwen, Arthur; Garnier, Margaux; Orbita, Jonathan

2011-10-10

The concentration of tetrahydrocannabinol (THC) and its main metabolite 11-nor-Δ(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 subjects, who were not marijuana smokers, volunteered to spend 3h in two different coffee shops in Groningen, The Netherlands. Subjects gave two oral fluid specimens at each time point: before entering the store, after 20 min, 40 min, 1h, 2h, and 3h of exposure. The specimens were collected outside the shop. Volunteers left the shop completely after 3h and also provided specimens approximately 12-22 h after beginning the exposure. The oral fluid specimens were subjected to immunoassay screening; confirmation for THC, cannabinol and cannabidiol using GC/MS; and THC-COOH using two-dimensional GC-GC/MS. THC was detectable in all oral fluid specimens taken 3h after exposure to smoke from recreationally used marijuana. In 50% of the volunteers, the concentration at the 3h time-point exceeded 4 ng/mL of THC, which is the current recommended cut-off concentration for immunoassay screening; the concentration of THC in 70% of the oral fluid specimens exceeded 2 ng/mL, currently proposed as the confirmatory cut-off concentration. THC-COOH was not detected in any specimens from passively exposed individuals. Therefore it is recommended that in order to avoid false positive oral fluid results assigned to marijuana use, by analyzing for only THC, the metabolite THC-COOH should also be monitored. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Molecularly imprinted solid phase extraction for simultaneous determination of Δ9-tetrahydrocannabinol and its main metabolites by gas chromatography-mass spectrometry in urine samples.

PubMed

Nestić, Marina; Babić, Sandra; Pavlović, Dragana Mutavdžić; Sutlović, Davorka

2013-09-10

In presented paper analytical method based on solid-phase extraction using molecularly imprinted polymer and gas chromatography-mass spectrometry has been developed and validated for the confirmation of THC, THC-OH and THC-COOH in urine samples. Non-covalent molecularly imprinted polymers of THC-OH were prepared using different functional monomers (methacrylic acid, 4-vinylpyridine, and 2-hydroxyethyl methacrylate), ethylene glycol dimethacrylate as a cross-linker and 2,2'-azobis-isobutyronitrile as an initiator of radical polymerization. Analytes were extracted from urine samples using prepared polymer sorbent with highest binding selectivity and capability. Before extraction, urine samples were hydrolyzed with alkaline. Elution was performed with chloroform:ethyl acetate (60:40, v/v). Dry extracts were silylated with BSTFA+1% TMCS. Detection and quantification were performed using gas chromatography-mass spectrometry in single ion recording mode. The developed method was linear over the range from LOQ to 150 ng mL(-1) for all three analytes. For THC, THC-OH and THC-COOH LOD was 2.5, 1 and 1 ng mL(-1), and LOQ was 3, 2 and 2 ng mL(-1), respectively. The precision, accuracy, recovery and matrix effect were investigated at 5, 25 and 50 ng mL(-1). In the investigated concentration range recoveries were 71.9% for THC, 78.6% for THC-OH and 75.2% for THC-COOH. Matrix effect was not significant (<10%) for all analytes in the concentration range from 5 ng mL(-1) to 50 ng mL(-1). Extraction recovery on non-imprinted polymer was relatively high indicating high non-specific binding. Optimized and validated method was applied to 15 post-mortem urine samples. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Psychotropic and nonpsychotropic cannabis derivatives inhibit human 5-HT(3A) receptors through a receptor desensitization-dependent mechanism.

PubMed

Xiong, W; Koo, B-N; Morton, R; Zhang, L

2011-06-16

Δ⁹ tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and nonpsychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT(3A) receptors (h5-HT(3A)Rs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC₅₀ values for CBD and THC-induced inhibition were 110 nM and 322 nM, respectively in HEK 293 cells expressing h5-HT(3A)Rs. In these cells, CBD and THC did not stimulate specific [³⁵S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT(3A)Rs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT(3A)R cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT(3A) receptors through a mechanism that is dependent on receptor desensitization. Published by Elsevier Ltd.

Psychotropic and Nonpsychotropic Cannabis Derivatives Inhibit Human 5-HT3A receptors through a Receptor Desensitization-Dependent Mechanism

PubMed Central

Xiong, Wei; Koo, Bon-Nyeo; Morton, Russell; Zhang, Li

2011-01-01

Δ9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are the principal psychoactive and non-psychoactive components of cannabis. While most THC-induced behavioral effects are thought to depend on endogenous cannabinoid 1 (CB1) receptors, the molecular targets for CBD remain unclear. Here, we report that CBD and THC inhibited the function of human 5-HT3A receptors (h5-HT3ARs) expressed in HEK 293 cells. The magnitude of THC and CBD inhibition was maximal 5 min after a continuous incubation with cannabinoids. The EC50 values for CBD and THC-induced inhibition were 110 nM and 322 nM respectively in HEK 293 cells expressing h5-HT3ARs. In these cells, CBD and THC did not stimulate specific [35S]-GTP-γs binding in membranes, suggesting that the inhibition by cannabinoids is unlikely mediated by a G-protein dependent mechanism. On the other hand, both CBD and THC accelerated receptor desensitization kinetics without significantly changing activation time. The extent of cannabinoid inhibition appeared to depend on receptor desensitization. Reducing receptor desensitization by nocodazole, 5-hydroxyindole and a point-mutation in the large cytoplasmic domain of the receptor significantly decreased CBD-induced inhibition. Similarly, the magnitude of THC and CBD-induced inhibition varied with the apparent desensitization rate of h5-HT3ARs expressed in Xenopus oocytes. For instance, with increasing amount of h5-HT3AR cRNA injected into the oocytes, the receptor desensitization rate at steady state decreased. THC and CBD-induced inhibition was correlated with the change in the receptor desensitization rate. Thus, CBD and THC inhibit h5-HT3A receptors through a mechanism that is dependent on receptor desensitization. PMID:21477640

Effect of oral THC pretreatment on marijuana cue-induced responses in cannabis dependent volunteers.

PubMed

Lundahl, Leslie H; Greenwald, Mark K

2015-04-01

The current study tested whether oral Δ(9)-tetrahydrocannabinol (THC: 0-, 10-, and 20-mg) pretreatment would attenuate polysensory cue-induced craving for marijuana. Cannabis dependent participants (7 males and 7 females, who smoked on average 5.4 ± 1.1 blunts daily) completed 3 experimental sessions (oral THC pretreatment dose; counterbalanced order) using a placebo-controlled within-subject crossover design. During each session, participants completed a baseline evaluation and were first exposed to neutral cues then marijuana cues while physiological measures and subjective ratings of mood, craving, and drug effect were recorded. Following placebo oral THC pretreatment, marijuana (vs. neutral) cues significantly increased ratings of marijuana craving (desire and urge to use, Marijuana Craving Questionnaire (MCQ)-Compulsivity scale), anxious mood and feeling hungry. Males also reported feeling more "Down" during marijuana cues relative to females. Pretreatment with oral THC (10-mg and/or 20-mg vs. placebo) significantly attenuated marijuana cue-induced increases in craving and anxiety but not hunger. Oral THC attenuation of the cue-induced increase in MCQ-Compulsivity ratings was observed in females only. Oral THC produced statistically (but not clinically) significant increases in heart rate and decreases in diastolic blood pressure, independent of cues. These marijuana-cue findings replicate earlier results and further demonstrate that oral THC can attenuate selected effects during marijuana multi-cue exposure, and that some of these effects may be sex-related. Results of this study suggest oral THC may be effective for reducing marijuana cue-elicited (conditioned) effects. Further study is needed to determine whether females may selectively benefit from oral THC for this purpose. Copyright © 2015. Published by Elsevier Ireland Ltd.

A thermodynamic study of the gaseous thorium carbides, ThC, ThC2, ThC3, ThC4, ThC5, and ThC6

NASA Astrophysics Data System (ADS)

Gupta, Satish K.; Gingerich, Karl A.

1980-02-01

Six gaseous carbides of thorium, ThCn(n=1-6), have been identified in a Knudsen effusion mass spectrometric investigation of the vapor phase above a thorium-uranium-rhodium-graphite system at high temperatures. The partial pressures of the thorium containing species were measured as a function of temperature in the 2300-2700 °K range. Third law enthalpies for the reactions Th(g)+nC(graphite) =ThCn, n=1 to 6, and of various other homogeneous and heterogeneous reactions were evaluated. By combining the experimental enthalpies with appropriate thermodynamic data taken from literature, the following values for the atomization energies ΔH °at,298, and standard heats of formation ΔH °f,298 of thorium carbides have been derived:

Sex-dimorphic psychomotor activation after perinatal exposure to (-)-delta 9-tetrahydrocannabinol. An ontogenic study in Wistar rats.

PubMed

Navarro, M; Rubio, P; Rodríguez de Fonseca, F

1994-12-01

The ontogeny and the adult expression of motor behaviors were studied in male and female rats born from mothers exposed to delta 9-tetrahydrocannabinol (THC, 5 mg/kg) during gestation and lactation. Perinatal exposure to THC increased both rearing and locomotor activities in males and females at immature preweanling ages (P-15 and P-20). These effects disappeared after ceasing THC exposure (postweaning ages), but they were observed again in adult (P-70) females. The effects appeared as persistently high motor activity in familiar environments, disappearing the characteristic habituation profile in locomotor and exploratory behaviors. In novel environment condition tests, adult (P-70) THC-exposed females, but not males, exhibited lower locomotor activity in the socio-sexual approach test, and an increase in the emergence latency in the dark-light emergence test. Additionally, animals of both sexes exposed to THC showed a increase in the time spent grooming measured in novelty conditions. These findings suggest that perinatal exposure to THC affects both the development and the adult expression of motor behaviors and it resulted in a sex-dimorphic psychomotor activation very similar to that observed after perinatal exposure to other drugs of abuse. A possible role of THC-induced pituitary-adrenal (PA) axis activation was also evaluated by measuring plasma corticosterone levels in adult animals perinatally exposed: THC-exposed females exhibit a clear increase of this adrenal hormone, whereas THC-exposed males displayed lower levels of this hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Tetrahydrocurcumin is more effective than curcumin in preventing azoxymethane-induced colon carcinogenesis.

PubMed

Lai, Ching-Shu; Wu, Jia-Ching; Yu, Shih-Feng; Badmaev, Vladimir; Nagabhushanam, Kalyanam; Ho, Chi-Tang; Pan, Min-Hsiung

2011-12-01

Tetrahydrocurcumin (THC), a major metabolite of curcumin (CUR), has been demonstrated to be anti-cancerogenic and anti-angiogenic and prevents type II diabetes. In this present study, we investigated the chemopreventive effects and underlying molecular mechanisms of dietary administration of CUR and THC in azoxymethane (AOM)-induced colon carcinogenesis in mice. All mice were sacrificed at 6 and 23 wk, and colonic tissue was collected and examined. We found that dietary administration of both CUR and THC could reduce aberrant crypt foci and polyps formation, while THC showed a better inhibitory effect than CUR. At the molecular level, results from Western blot analysis and immunohistochemistry staining showed that dietary CUR and THC exhibited anti-inflammatory activity by decreasing the levels of inducible NOS and COX-2 through downregulation of ERK1/2 activation. In addition, both dietary CUR and THC significantly decreased AOM-induced Wnt-1 and β-catenin protein expression, as well as the phosphorylation of GSK-3β in colonic tissue. Moreover, dietary feeding with CUR and THC markedly reduced the protein level of connexin-43, an important molecule of gap junctions, indicating that both CUR and THC might interfer with the intercellular communication of crypt cells. Taken together, these results demonstrated for the first time the in vivo chemopreventive efficacy and molecular mechanisms of dietary THC against AOM-induced colonic tumorigenesis. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Direct antigonadal activity of cannabinoids: suppression of rat granulosa cell functions.

PubMed

Adashi, E Y; Jones, P B; Hsueh, A J

1983-02-01

The direct effects of delta 9-tetrahydrocannabinol (THC) and related cannabinoids on ovarian granulosa cells were studied in vitro. Granulosa cells from immature, hypophysectomized, estrogen-treated rats were cultured for 2 days in an androstenedione-supplemented medium in the presence or absence of follicle-stimulating hormone (FSH) (10 ng/ml) with or without cannabinoids. FSH treatment increased progesterone and estrogen biosynthesis, whereas concomitant treatment with THC led to a dose-dependent inhibition of the FSH-stimulated accumulation of progesterone and estrogen with ED50 values of 3.5 +/- 0.3 X 10(-7) and 1.8 +/- 0.2 X 10(-6) M, respectively. Treatment with related but nonpsychoactive cannabinoids (cannabidiol, cannabinol, cannabigerol, or cannabichromene) was equally effective. The THC-induced inhibition of progesterone production was reversible and was associated with an inhibition of pregnenolone biosynthesis and a decrease of 3 beta-hydroxysteroid dehydrogenase activity. In addition, treatment with THC brought about a dose-dependent inhibition of the FSH-induced increase in luteinizing hormone (LH) receptors. The inhibitory effects of THC were not associated with changes in cell number, protein content, or cell viability. Thus, THC exerts direct inhibitory effects on FSH-dependent functions related to steroidogenesis and the acquisition of LH receptors, all of which are essential to follicular maturation. Because plasma concentrations of THC similar to those used in this study have been reported in human beings, repeated exposure of female users to THC may lead to ovarian dysfunction, due in part, to the direct antigonadal activity to THC.

A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray.

PubMed

Sellers, Edward M; Schoedel, Kerri; Bartlett, Cindy; Romach, Myroslava; Russo, Ethan B; Stott, Colin G; Wright, Stephen; White, Linda; Duncombe, Paul; Chen, Chien-Feng

2013-07-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain. A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers. The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed. Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day. In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies. © The Author(s) 2013.

Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats.

PubMed

Fadda, Paola; Robinson, Lianne; Fratta, Walter; Pertwee, Roger G; Riedel, Gernot

2004-12-01

Cannabinoid receptors in the brain (CB(1)) take part in modulation of learning, and are particularly important for working and short-term memory. Here, we employed a delayed-matching-to-place (DMTP) task in the open-field water maze and examined the effects of cannabis plant extracts rich in either Delta(9)-tetrahydrocannabinol (Delta(9)-THC), or rich in cannabidiol (CBD), on spatial working and short-term memory formation in rats. Delta(9)-THC-rich extracts impaired performance in the memory trial (trial 2) of the DMTP task in a dose-dependent but delay-independent manner. Deficits appeared at doses of 2 or 5 mg/kg (i.p.) at both 30 s and 4 h delays and were similar in severity compared with synthetic Delta(9)-THC. Despite considerable amounts of Delta(9)-THC present, CBD-rich extracts had no effect on spatial working/short-term memory, even at doses of up to 50 mg/kg. When given concomitantly, CBD-rich extracts did not reverse memory deficits of the additional Delta(9)-THC-rich extract. CBD-rich extracts also did not alter Delta(9)-THC-rich extract-induced catalepsy as revealed by the bar test. It appears that spatial working/short-term memory is not sensitive to CBD-rich extracts and that potentiation and antagonism of Delta(9)-THC-induced spatial memory deficits is dependent on the ratio between CBD and Delta(9)-THC.

The psychoactive substance of cannabis Δ9-tetrahydrocannabinol (THC) negatively regulates CFTR in airway cells.

PubMed

Chang, Sheng-Wei; Wellmerling, Jack; Zhang, Xiaoli; Rayner, Rachael E; Osman, Wissam; Mertz, Sara; Amer, Amal O; Peeples, Mark E; Boyaka, Prosper N; Cormet-Boyaka, Estelle

2018-06-18

Marijuana consumption is on the rise in the US but the health benefits of cannabis smoking are controversial and the impact of cannabis components on lung homeostasis is not well-understood. Lung function requires a fine regulation of the ion channel CFTR, which is responsible for fluid homeostasis and mucocilliary clearance. The goal of this study was to assess the effect that exposure to Δ9-tetrahydrocannabinol (THC), the psychoactive substance present in marijuana, has on CFTR expression and function. Cultures of human bronchial epithelial cell line 16HBE14o- and primary human airway epithelial cells were exposed to THC. The expression of CFTR protein was determined by immunoblotting and CFTR function was measured using Ussing chambers. We also used specific pharmacological inhibitors of EGFR and ERK to determine the role of this pathway in THC-induced regulation of CFTR. THC decreased CFTR protein expression in primary human bronchial epithelial cells. This decrease was associated with reduced CFTR-mediated short-circuit currents. THC also induced activation of the ERK MAPK pathway via activation of EGFR. Inhibition of EGFR or MEK/ERK prevented THC-induced down regulation of CFTR protein expression. THC negatively regulates CFTR and this is mediated through the EGFR/ERK axis. This study provides the first evidence that THC present in marijuana reduces the expression and function of CFTR in airway epithelial cells. Copyright © 2018. Published by Elsevier B.V.

Marijuana, receptors and immunomodulation.

PubMed

Friedman, H; Klein, T W; Newton, C; Daaka, Y

1995-01-01

THC, the major psychoactive component of marijuana, has been shown both in humans and experimental animals to have immunomodulatory properties. For example, marijuana smokers may show impaired immunological functions, including deficiency of blood leukocyte blastogenesis to mitogens. Detailed studies with mice have shown that animals given THC can show marked immunomodulation, including suppression of antibody formation, deficient cytokine production, etc. However, recent studies have also shown that lymphoid cells evince enhanced production or release or IL1, but suppression of IL2 and interferon production. Such lymphoid cells treated in vitro with THC also show suppressed blastogenesis to antigens and mitogens, suppressed NK activity, etc. In contrast, it has recently been shown that THC can enhance production or release of pro-inflammatory cytokines. This includes release of these cytokines from macrophages, including augmented release of IL1, TNF alpha, and IL6 activity. Susceptibility of mice to infection with opportunistic organisms such as L. pneumophila has been found and this increased susceptibility can be modulated by THC. A toxic shock-like death to Legionella has been induced by THC treatment given one day before and one day after infection. Receptors to THC have been detected in the brain as well as in peripheral tissues, including lymphoid cells. Thus, immunomodulation induced by THC may be related to receptor effects as well as unrelated to such receptors. It is clear that THC and other cannabinoids are excellent tools for studying the mechanisms of immune modulation, especially altered susceptibility to microbial infection.

Finding cannabinoids in hair does not prove cannabis consumption.

PubMed

Moosmann, Bjoern; Roth, Nadine; Auwärter, Volker

2015-10-07

Hair analysis for cannabinoids is extensively applied in workplace drug testing and in child protection cases, although valid data on incorporation of the main analytical targets, ∆9-tetrahydrocannabinol (THC) and 11-nor-9-carboxy-THC (THC-COOH), into human hair is widely missing. Furthermore, ∆9-tetrahydrocannabinolic acid A (THCA-A), the biogenetic precursor of THC, is found in the hair of persons who solely handled cannabis material. In the light of the serious consequences of positive test results the mechanisms of drug incorporation into hair urgently need scientific evaluation. Here we show that neither THC nor THCA-A are incorporated into human hair in relevant amounts after systemic uptake. THC-COOH, which is considered an incontestable proof of THC uptake according to the current scientific doctrine, was found in hair, but was also present in older hair segments, which already grew before the oral THC intake and in sebum/sweat samples. Our studies show that all three cannabinoids can be present in hair of non-consuming individuals because of transfer through cannabis consumers, via their hands, their sebum/sweat, or cannabis smoke. This is of concern for e.g. child-custody cases as cannabinoid findings in a child's hair may be caused by close contact to cannabis consumers rather than by inhalation of side-stream smoke.

Heat waves connect abrupt polar climate changes during the past 67ka: evidence from sediment core GeoB3912-1

NASA Astrophysics Data System (ADS)

Yang, X.; Rial, J. A.

2014-12-01

According to the hypothesis of polar synchronization, climate variations of Earth's poles are connected with a persistent phase lock of π/2 throughout the last glacial period. However, it is not clear yet how the Earth's two poles communicate with each other, the Thermohaline circulation (THC) being a possible candidate for signal carrier. Here we present a possible way of climate variation propagation through the Atlantic Ocean - likely in the form of heat or thermal wave (Cattaneo's solution) - based on lagged correlation between an organic carbon climate proxy record from the tropical Atlantic and the south-north polar temperature gradient. We further demonstrate that the speed of such propagation is frequency dependent, of which the wave of the longest period travels the fastest at the speed of ~32 km/year consistent with the estimated speed of the THC. The observed speed - frequency relationship can be successfully modeled as resulting from a propagating dispersive thermal wave initiated by the polar temperature gradient maximum. We show that such heat wave propagation is a potential mechanism to couple and synchronize the polar climates during the last glacial period and to force the occurrence of Heinrich events. To summarize, the polar temperature gradient anomalies are consequence of the π/2 phase lock between the polar climates, which is caused by polar synchronization maintained by the coupling, which is, as the data suggest, in the form of thermal waves. The spikes in organic carbon and the Fe/Ca ratio records in the core GeoB3912-1 can be thought of as snapshots of the passage of strong meteorological wavefronts through the equatorial region. The results strongly suggest that each peak in the organic carbon recorded a half-hemisphere-delayed passage of a wave-like disturbance through the equator carrying the south-north temperature gradient maxima. And each of these occurs within timing error of the Heinrich events H0-H6.

Medical Marijuana in Certain Neurological Disorders

MedlinePlus

... of chemicals in the plant: cannabidiol (CBD) and tetrahydrocannabinol (THC). CBD and THC are taken from the cannabis plant for use ... also can be created (synthesized) in a lab. THC has a stronger intoxicating effect than CBD. Is ...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

40 CFR 89.120 - Compliance with emission standards.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) The manufacturer may assume that up to two percent of the measured THC is methane (NMHC = 0.98 × THC... methane emissions from measured THC emissions. [59 FR 31335, June 17, 1994. Redesignated and amended at 63...

Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA.

PubMed

Gamage, Thomas F; Farquhar, Charlotte E; Lefever, Timothy W; Marusich, Julie A; Kevin, Richard C; McGregor, Iain S; Wiley, Jenny L; Thomas, Brian F

2018-05-01

Synthetic cannabinoids are a class of novel psychoactive substances that exhibit high affinity at the cannabinoid type-1 (CB 1 ) receptor and produce effects similar to those of Δ-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Illicit drug manufacturers are continually circumventing laws banning the sale of synthetic cannabinoids by synthesizing novel structures and doing so with little regard for the potential impact on pharmacological and toxicological effects. Synthetic cannabinoids produce a wide range of effects that include cardiotoxicity, seizure activity, and kidney damage, and they can cause death. Six synthetic cannabinoids, recently detected in illicit preparations, MMB-FUBINACA, MDMB-FUBINACA, CUMYL-PICA, 5F-CUMYL-PICA, NNEI, and MN-18 were assessed for: 1) receptor binding affinity at the human CB 1 and human CB 2 receptors, 2) function in [ 35 S]GTP γ S and cAMP signaling, and 3) THC-like effects in a mouse drug discrimination assay. All six synthetic cannabinoids exhibited high affinity for human cannabinoid receptors type-1 and type-2 and produced greater maximal effects than THC in [ 35 S]GTP γ S and cAMP signaling. Additionally, all six synthetic cannabinoids substituted for THC in drug discrimination, suggesting they probably possess subjective effects similar to those of cannabis. Notably, MDMB-FUBINACA, a methylated analog of MMB-FUBINACA, had higher affinity for CB 1 than the parent, showing that minor structural modifications being introduced can have a large impact on the pharmacological properties of these drugs. This study demonstrates that novel structures being sold and used illicitly as substitutes for cannabis are retaining high affinity at the CB 1 receptor, exhibiting greater efficacy than THC, and producing THC-like effects in models relevant to subjective effects in humans. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Controlled vaporized cannabis, with and without alcohol: subjective effects and oral fluid-blood cannabinoid relationships.

PubMed

Hartman, Rebecca L; Brown, Timothy L; Milavetz, Gary; Spurgin, Andrew; Gorelick, David A; Gaffney, Gary; Huestis, Marilyn A

2016-07-01

Vaporized cannabis and concurrent cannabis and alcohol intake are commonplace. We evaluated the subjective effects of cannabis, with and without alcohol, relative to blood and oral fluid (OF, advantageous for cannabis exposure screening) cannabinoid concentrations and OF/blood and OF/plasma vaporized-cannabinoid relationships. Healthy adult occasional-to-moderate cannabis smokers received a vaporized placebo or active cannabis (2.9% and 6.7% Δ(9) -tetrahydrocannabinol, THC) with or without oral low-dose alcohol (~0.065g/210L peak breath alcohol concentration [BrAC]) in a within-subjects design. Blood and OF were collected up to 8.3 h post-dose and subjective effects measured at matched time points with visual-analogue scales and 5-point Likert scales. Linear mixed models evaluated subjective effects by THC concentration, BrAC, and interactions. Effects by time point were evaluated by dose-wise analysis of variance (ANOVA). OF versus blood or plasma cannabinoid ratios and correlations were evaluated in paired-positive specimens. Nineteen participants (13 men) completed the study. Blood THC concentration or BrAC significantly associated with subjective effects including 'high', while OF contamination prevented significant OF concentration associations <1.4 h post-dose. Subjective effects persisted through 3.3-4.3 h, with alcohol potentiating the duration of the cannabis effects. Effect-versus-THC concentration and effect-versus-alcohol concentration hystereses were counterclockwise and clockwise, respectively. OF/blood and OF/plasma THC significantly correlated (all Spearman r≥0.71), but variability was high. Vaporized cannabis subjective effects were similar to those previously reported after smoking, with duration extended by concurrent alcohol. Cannabis intake was identified by OF testing, but OF concentration variability limited interpretation. Blood THC concentrations were more consistent across subjects and more accurate at predicting cannabis' subjective effects. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Δ9-Tetrahydrocannabinol and Endocannabinoid Degradative Enzyme Inhibitors Attenuate Intracranial Self-Stimulation in Mice

PubMed Central

Grim, Travis W.; Owens, Robert A.; Lazenka, Matthew F.; Sim-Selley, Laura J.; Abdullah, Rehab A.; Niphakis, Micah J.; Vann, Robert E.; Cravatt, Benjamin F.; Wiley, Jenny L.; Negus, S. Stevens; Lichtman, Aron H.

2015-01-01

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and nonreinforced behaviors. PMID:25398241

Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

PubMed

Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

2015-02-01

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and nonreinforced behaviors. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Suppressive effect of delta 9-tetrahydrocannabinol in vitro on phagocytosis by murine macrophages.

PubMed

Friedman, M; Cepero, M L; Klein, T; Friedman, H

1986-06-01

Incubation of normal mouse peritoneal cells consisting of over 90% phagocytizing macrophages with delta 9-tetrahydrocannabinol (THC) resulted in a inhibition of phagocytic function. The THC in a dose-related manner suppressed the percentage of macrophages per culture which ingested yeast and the average number of yeast particles ingested by the phagocytizing macrophages. The vehicle used to suspend the THC in vitro, i.e., DMSO, had no detectable effect on macrophage function. Suppression of phagocytosis with no effects on viability or cell number occurred with doses of 10 micrograms or less THC per milliliter culture medium. Measurable suppression also occurred after 24- to 48-hr treatment of the macrophages with the THC. This compound had little if any detectable effect on phagocytosis when added directly to the cultures shortly before testing for phagocytosis. Further studies concerning the effects of THC on macrophage function appear warranted.

An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition.

PubMed

Henquet, Cécile; Rosa, Araceli; Krabbendam, Lydia; Papiol, Sergi; Fananás, Lourdes; Drukker, Marjan; Ramaekers, Johannes G; van Os, Jim

2006-12-01

Observational studies have suggested that psychometric psychosis liability and a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderate the psychosis-inducing effect of cannabis. To replicate and extend this finding, a double-blind, placebo-controlled cross-over design was used in which patients with a psychotic disorder (n=30), relatives of patients with a psychotic disorder (n=12), and healthy controls (n=32) were exposed to Delta-9-tetrahydrocannabinol (Delta-9-THC, the principal component of cannabis) or placebo, followed by cognitive assessment and assessment of current psychotic experiences. Previous expression of psychometric psychosis liability was also assessed. Models of current psychotic experiences and cognition were examined with multilevel random regression analyses to assess (i) main effects of genotype and condition, (ii) interactions between condition and genotype, and (iii) three-way interactions between condition, genotype, and psychometric psychosis liability. Carriers of the Val allele were most sensitive to Delta-9-THC-induced psychotic experiences, but this was conditional on prior evidence of psychometric psychosis liability. Delta-9-THC impacted negatively on cognitive measures. Carriers of the Val allele were also more sensitive to Delta-9-THC-induced memory and attention impairments compared to carriers of the Met allele. Experimental effects of Delta-9-THC on cognition and psychosis are moderated by COMT Val(158)Met genotype, but the effects may in part be conditional on the additional presence of pre-existing psychosis liability. The association between cannabis and psychosis may represent higher order gene-environment and gene-gene interactions.

Has the intake of THC by cannabis users changed over the last decade? Evidence of increased exposure by analysis of blood THC concentrations in impaired drivers.

PubMed

Vindenes, Vigdis; Strand, Dag Helge; Kristoffersen, Lena; Boix, Fernando; Mørland, Jørg

2013-03-10

The main psychoactive substance, Δ9-tetrahydrocannabinol (THC) can be present in highly variable amounts in different cannabis preparations. An increase in THC content in cannabis products has been suggested, and reported from several countries. However, it has not yet been investigated if products with high potency lead to increased human exposure, and thus to higher risk of adverse effects. In this study, we examined the mean concentrations of THC in whole blood samples from drivers apprehended in Norway in the period between 2000 and 2010 suspected of driving under the influence of drugs. Cases with only THC (n=1747) have been compared to cases with only ethanol (n=38796) or amphetamines (n=2493). The increase in mean THC concentration measured from 2000 to 2010 was from 4.0 ± 0.3 to 6.6 ± 0.4 ng/ml (58%), compared to 3% for ethanol and 16% for the amphetamines. This increase in THC concentrations was to some extent paralleled by an increase in the percentage of drivers which were judged as lightly impaired by a physician. Monitoring concentrations of drugs of abuse in blood from apprehended drivers indicated an increasing exposure to THC in Norway. If similar trends are observed globally, it should be further explored if this type of information could be used to elucidate the drug consumption patterns in a population and accordingly the consequences with regard to adverse effects of cannabis from a public health perspective. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Sex differences in the subjective effects of oral Δ9-THC in cannabis users.

PubMed

Fogel, Jessica S; Kelly, Thomas H; Westgate, Philip M; Lile, Joshua A

2017-01-01

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ 9 -tetrahydrocannabinol (Δ 9 -THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ 9 -THC and placebo and then received a range of Δ 9 -THC doses (0, 5, 15 and a "high" dose of either 25 or 30mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ 9 -THC dose-dependently increased drug-appropriate responding, ratings on "positive" Visual Analog Scale (VAS) items (e.g., good effects, like drug, take again), and items related to intoxication (e.g., high, stoned). Δ 9 -THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5mg Δ 9 -THC dose, whereas men were more sensitive to the subjective effects of the 15mg dose of Δ 9 -THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ 9 -THC administration by sex, which might contribute to the differential development of problematic cannabis use. Copyright © 2015 Elsevier Inc. All rights reserved.

Tolerance to effects of high-dose oral δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers.

PubMed

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.

ABCB1 C3435T polymorphism is associated with tetrahydrocannabinol blood levels in heavy cannabis users.

PubMed

Kebir, Oussama; Lafaye, Genevieve; Blecha, Lisa; Chaumette, Boris; Mouaffak, Fayçal; Laqueille, Xavier; Benyamina, Amine

2018-04-01

ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T (rs1045642) polymorphism may modulate Δ9-Tetrahydrocannabinol (THC) blood levels in a sample of heavy cannabis users. The study sample includes 39 Caucasian individuals, recruited in two French addictology centres, with isolated cannabis dependence and heavy use (defined as ≥ 7 joints per week). Each underwent clinical evaluation, cannabis blood metabolite dosage (THC, 11-OH-THC, and THC-COOH) and genotyping of ABCB1 C3435T polymorphism. In this population (males: 74.4%, average age 29.5 +/- 9), average cannabis use was 21 joints per week (median 12; range 7 - 80). T carriers (TT/CT) had significantly lower plasma THC levels (ng/ml) versus non T carriers (8 vs 15.70, significant), controlling for level of weekly use, 11-OH-THC and THC-COOH levels. Our results show that ABCB1 C3435T polymorphism may modulate serum THC levels in chronic heavy cannabis users. The exact mechanisms and roles that this may play in cannabis dependence genesis and evolution remain to be elucidated. These results should be controlled in a replication study using a larger population. Copyright © 2017 Elsevier B.V. All rights reserved.

Death by self-mutilation after oral cannabis consumption.

PubMed

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.

Clinical experience with THC:CBD oromucosal spray in patients with multiple sclerosis-related spasticity.

PubMed

Koehler, Jürgen; Feneberg, Wolfgang; Meier, Martin; Pöllmann, Walter

2014-09-01

This detailed medical charts' data collection study conducted at a multiple sclerosis (MS) clinic in Germany evaluated the effectiveness of tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray in patients with resistant MS spasticity. Over a 15-month timeframe, THC:CBD spray was initiated in 166 patients. Mean follow-up was 9 months. In all, 120 patients remained on treatment for a response rate of 72%. THC:CBD spray was used as add-on therapy in 95 patients and as monotherapy in 25 patients to achieve best-possible therapeutic results. Among responders, the mean spasticity 0-10 numerical rating scale (NRS) score decreased by 57%, from 7.0 before treatment to 3.0 within 10 days of starting THC:CBD spray. The mean dosage was 4 sprays/day. Most patients who withdrew from treatment (40/46) had been receiving THC:CBD spray for less than 60 days. Main reasons for treatment discontinuation were: adverse drug reactions, mainly dizziness, fatigue and oral discomfort (23 patients; 13.9%); lack of efficacy (14 patients; 8.4%); or need for a baclofen pump (9 patients; 5.4%). No new safety signals were noted with THC:CBD spray during the evaluation period. In this routine clinical practice setting at an MS clinic in Germany, THC:CBD spray was effective and well tolerated as add-on therapy or as monotherapy in a relevant proportion of patients with resistant MS spasticity.

Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex.

PubMed

Rubino, Tiziana; Prini, Pamela; Piscitelli, Fabiana; Zamberletti, Erica; Trusel, Massimo; Melis, Miriam; Sagheddu, Claudia; Ligresti, Alessia; Tonini, Raffaella; Di Marzo, Vincenzo; Parolaro, Daniela

2015-01-01

Current concepts suggest that exposure to THC during adolescence may act as a risk factor for the development of psychiatric disorders later in life. However, the molecular underpinnings of this vulnerability are still poorly understood. To analyze this, we investigated whether and how THC exposure in female rats interferes with different maturational events occurring in the prefrontal cortex during adolescence through biochemical, pharmacological and electrophysiological means. We found that the endocannabinoid system undergoes maturational processes during adolescence and that THC exposure disrupts them, leading to impairment of both endocannabinoid signaling and endocannabinoid-mediated LTD in the adult prefrontal cortex. THC also altered the maturational fluctuations of NMDA subunits, leading to larger amounts of gluN2B at adulthood. Adult animals exposed to THC during adolescence also showed increased AMPA gluA1 with no changes in gluA2 subunits. Finally, adolescent THC exposure altered cognition at adulthood. All these effects seem to be triggered by the disruption of the physiological role played by the endocannabinoid system during adolescence. Indeed, blockade of CB1 receptors from early to late adolescence seems to prevent the occurrence of pruning at glutamatergic synapses. These results suggest that vulnerability of adolescent female rats to long-lasting THC adverse effects might partly reside in disruption of the pivotal role played by the endocannabinoid system in the prefrontal cortex maturation. Copyright © 2014 Elsevier Inc. All rights reserved.

Is 2-Hydroxypropyl-β-cyclodextrin a Suitable Carrier for Central Administration of Δ9 -Tetrahydrocannabinol? Preclinical Evidence.

PubMed

Agabio, R; Sanna, F; Lobina, C; Monduzzi, M; Nairi, V; Cugia, F; Mameli, S; Pisanu, G M; Gessa, G L; Melis, M R

2017-12-01

Preclinical Research Δ 9 -Tetrahydrocannabinol (THC) is a hydrophobic compound that has a potent antinociceptive effect in animals after intrathecal (IT) or intracerebroventricular (ICV) administration. The lack of a suitable solvent precludes its IT administration in humans. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) increases the water solubility of hydrophobic drugs and is approved for IT administration in humans. To investigate whether HPβCD might be a suitable carrier for ICV administration of THC in rats, two formulations containing THC complexed with HPβCD (30 and 135 μg of THC per animal) and vehicle were administered to Wistar rats. The antinociceptive effect (using the tail flick test), locomotor activity, and body temperature were evaluated. ICV injection of 135 μg of THC/HPβCD complex increased tail flick latency, reduced locomotor activity, and had a dual effect on body temperature. The 30 μg THC/HPβCD formulation only produced a hyperthermic effect. All animals appeared healthy, with no difference between the groups. These results were similar to those obtained in other preclinical studies in which THC was administered centrally using solvents that are unsuitable for IT administration in humans because of their toxicity. Our findings suggest that HPβCD may be a useful carrier for IT administration of THC in humans. Drug Dev Res 78 : 411-419, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Cannabis with high δ9-THC contents affects perception and visual selective attention acutely: an event-related potential study.

PubMed

Böcker, K B E; Gerritsen, J; Hunault, C C; Kruidenier, M; Mensinga, Tj T; Kenemans, J L

2010-07-01

Cannabis intake has been reported to affect cognitive functions such as selective attention. This study addressed the effects of exposure to cannabis with up to 69.4mg Delta(9)-tetrahydrocannabinol (THC) on Event-Related Potentials (ERPs) recorded during a visual selective attention task. Twenty-four participants smoked cannabis cigarettes with four doses of THC on four test days in a randomized, double blind, placebo-controlled, crossover study. Two hours after THC exposure the participants performed a visual selective attention task and concomitant ERPs were recorded. Accuracy decreased linearly and reaction times increased linearly with THC dose. However, performance measures and most of the ERP components related specifically to selective attention did not show significant dose effects. Only in relatively light cannabis users the Occipital Selection Negativity decreased linearly with dose. Furthermore, ERP components reflecting perceptual processing, as well as the P300 component, decreased in amplitude after THC exposure. Only the former effect showed a linear dose-response relation. The decrements in performance and ERP amplitudes induced by exposure to cannabis with high THC content resulted from a non-selective decrease in attentional or processing resources. Performance requiring attentional resources, such as vehicle control, may be compromised several hours after smoking cannabis cigarettes containing high doses of THC, as presently available in Europe and Northern America. Copyright 2010 Elsevier Inc. All rights reserved.

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

PubMed

Pitsilis, George; Spyridakos, Dimitrios; Nomikos, George G; Panagis, George

2017-01-01

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 Δ 9 -tetrahydrocannabinol (Δ 9 -THC) induces transgenerational effects on the reward-facilitating effects of Δ 9 -THC and d -amphetamine in their adult male offspring. Female Sprague-Dawley rats received Δ 9 -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 Δ 9 -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 Δ 9 -THC was abolished in the F1 offspring of females that were exposed to Δ 9 -THC (0.1 or 1 mg/kg), whereas the reward-attenuating effect of the 1 mg dose of Δ 9 -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 Δ 9 -THC (1 mg/kg and 0.1 or 1 mg, respectively). The present results reveal that female Δ 9 -THC exposure during adolescence can diminish the reward-facilitating effects of Δ 9 -THC and d -amphetamine in the adult male offspring. These transgenerational effects occur in the absence of in utero exposure. It is speculated that Δ 9 -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.

In vitro maturation of immature thymocytes into immunocompetent T cells in the absence of direct thymic influence.

PubMed

Irlé, C; Piguet, P F; Vassalli, P

1978-07-01

Peanut lectin (PNL) binds to a majority of mouse thymocytes (Thc) in suspension. By using cell affinity chromatography on a column of anti-PNL antibody, Thc populations at least 96 percent pure in PNL + or - cells, as judged by immunofluorescence, were obtained. PNL(+) cells are rich in Thy 1 and poor in H(2) antigens, cortisone sensitive, unresponsive to phytohemagglutinin (PHA), and immunologically incompetent, as judged by mixed lymphocyte reaction, popliteal lymph node graft-versus-host assay, and by testing helper activity in a primary in vitro antibody response to sheep erythrocytes; the converse is true of PNL(-) cells. Thus, PNL(+) and (-) cells appear to correspond to cortical and medullary Thc, respectively, as previously suggested. In culture, PNL(+) Thc show poor viability and a weak proliferative response to concanavalin A (Con A), except when supernate (SUP) of 24 h Con A stimulated lymph node lymphocyte cultures, or irradiated lymph node cells, are added, in which cases a strong proliferative response to the mitogen is observed. A variety of control experiments showed that the proliferating cells did not result from preferential stimulation of a few contaminating PNL(-) Thc present in the PNL(+) Thc cultures. The blasts resulting from PNL(+) Thc proliferation display mitogen-induced cytotoxicity, and give rise to a population of medium-sized lymphocytes, mostly PNL(-), poor in Thy 1 and rich in H(2) antigens, PHA responsive, and immunologically competent in the above-mentioned assays. Fresh PNL(+) Thc responded in mixed lymphocyte reaction in the presence of SUP (lectin depleted) and since incubation in SUP alone did not confer reactivity on PNL(+) Thc, it appears therefore that (a) immature Thc possess alloantigen and mitogen-specific surface receptors but lack the capacity to respond by proliferation to receptor triggering without the help of extracellular factor(s) released by mature lymphoid cells stimulated by mitogens (b) cell division is associated with the acquisition of immunological responsiveness, characteristic of mature T lymphocytes. The implications of these findings for the ontogenesis of thymus-derived lymphocytes, and for the possible traffic of Thc within and from the thymus, are discussed.

Detection time for THC in oral fluid after frequent cannabis smoking.

PubMed

Andås, Hilde T; Krabseth, Hege-Merete; Enger, Asle; Marcussen, Bjarne N; Haneborg, An-Magritt; Christophersen, Asbjørg S; Vindenes, Vigdis; Øiestad, Elisabeth L

2014-12-01

The use of oral fluid for detecting drugs of abuse has become increasingly more frequent. Few studies have, however, investigated the detection times for drugs of abuse in oral fluid, compared with that of in urine or in blood. Cannabis is the world's most widely used drug of abuse, and the detection times for cannabis, in different types of matrixes, are therefore important information to the laboratories or institutions performing and evaluating drugs of abuse analyses. It is well known that frequent use of high dosages of cannabis, for longer periods of time, might lead to prolonged detection times for THC-COOH in urine. Cannabis intake is detected in oral fluid as THC, and a positive finding is considered to be a result of recent smoking, although some studies have already reported longer detection times. The aim of this study was to investigate the detection time for THC in oral fluid, collected from drug addicts admitted for detoxification. Findings in oral fluid were compared with findings in urine, among 26 patients admitted to a closed detoxification unit. The study, being the first in doing so, describes the concentration-time profiles for THC in oral fluid among chronic cannabis users, during monitored abstinence, using the Intercept collection kit. The study also includes the concentration-time profiles for creatinine-corrected THC-COOH ratios in urine samples, included to monitor for the possibility of new intakes. THC was detected in oral fluid collected from 11 of the 26 patients in the study. The elimination curves for THC in oral fluid revealed that negative samples could be interspersed among positive samples several days after cessation, whereas the THC-COOH concentrations in urine were decreasing. THC was, in this study, detected in oral fluid for up to 8 days after admission. The study shows that frequent use of high dosages of cannabis may lead to prolonged detection times, and that positive samples can be interspersed among negative samples. These results are of great importance when THC results from oral fluid analyses are to be interpreted.

Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

PubMed Central

D'Souza, Deepak Cyril; Fridberg, Daniel J; Skosnik, Patrick D; Williams, Ashley; Roach, Brian; Singh, Nagendra; Carbuto, Michelle; Elander, Jacqueline; Schnakenberg, Ashley; Pittman, Brian; Sewell, R Andrew; Ranganathan, Mohini; Mathalon, Daniel

2012-01-01

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball' P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high' in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact. Collectively, the findings suggest that CB1R systems modulate top-down and bottom-up processing. PMID:22334121

Cannabis, cannabidiol, and epilepsy--from receptors to clinical response.

PubMed

Szaflarski, Jerzy P; Bebin, E Martina

2014-12-01

Recreational cannabis use in adults with epilepsy is widespread. The use of cannabis for medicinal purposes is also becoming more prevalent. For this purpose, various preparations of cannabis of varying strengths and content are being used. The recent changes in the legal environment have improved the availability of products with high cannabidiol (CBD) and low tetrahydrocannabinol (THC) concentrations. There is some anecdotal evidence of their potential efficacy, but the mechanisms of such action are not entirely clear. Some suspect an existence of synergy or "entourage effect" between CBD and THC. There is strong evidence that THC acts via the cannabinoid receptor CB1. The mechanism of action of CBD is less clear but is likely polypharmacological. The scientific data support the role of the endocannabinoid system in seizure generation, maintenance, and control in animal models of epilepsy. There are clear data for the negative effects of cannabis on the developing and mature brain though these effects appear to be relatively mild in most cases. Further data from well-designed studies are needed regarding short- and long-term efficacy and side effects of CBD or high-CBD/low-THC products for the treatment of seizures and epilepsy in children and adults. Copyright © 2014 Elsevier Inc. All rights reserved.

THC Prevents MDMA Neurotoxicity in Mice.

PubMed

Touriño, Clara; Zimmer, Andreas; Valverde, Olga

2010-02-10

The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg x 4) were pretreated with THC (3 mg/kg x 4) at room (21 degrees C) and at warm (26 degrees C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB(1) receptor antagonist AM251 and the CB(2) receptor antagonist AM630, as well as in CB(1), CB(2) and CB(1)/CB(2) deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB(1) receptor antagonist AM251, neither in CB(1) and CB(1)/CB(2) knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB(2) cannabinoid antagonist and in CB(2) knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB(1) receptor, although CB(2) receptors may also contribute to attenuate neuroinflammation in this process.

THC Prevents MDMA Neurotoxicity in Mice

PubMed Central

Touriño, Clara; Zimmer, Andreas; Valverde, Olga

2010-01-01

The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg ×4) were pretreated with THC (3 mg/kg ×4) at room (21°C) and at warm (26°C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB1 receptor antagonist AM251 and the CB2 receptor antagonist AM630, as well as in CB1, CB2 and CB1/CB2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB1 receptor antagonist AM251, neither in CB1 and CB1/CB2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB2 cannabinoid antagonist and in CB2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB1 receptor, although CB2 receptors may also contribute to attenuate neuroinflammation in this process. PMID:20174577

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

PubMed Central

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

Functional interaction and cross-tolerance between ethanol and Δ9-THC: possible modulation by mouse cerebellar adenosinergic A1/GABAergic-A receptors.

PubMed

Dar, M Saeed

2014-08-15

We have previously shown a functional motor interaction between ethanol and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) that involved cerebellar adenosinergic A1 and GABAergic A receptor modulation. We now report the development of cross-tolerance between intracerebellar Δ(9)-THC and intraperitoneal ethanol using ataxia as the test response in male CD-1 mice. The drugs [Δ(9)-THC (20 μg), N(6)-cyclohexyladenosine, CHA (12 ng), muscimol (20 ng)] used in the study were directly microinfused stereotaxically via guide cannulas into the cerebellum except ethanol. Δ(9)-THC, infused once daily for 5 days followed 16 h after the last infusion by acute ethanol (2g/kg) and Rotorod evaluation, virtually abolished ethanol ataxia indicating development of cross-tolerance. The cross-tolerance was also observed when the order of ethanol and Δ(9)-THC treatment was reversed, i.e., ethanol injected once daily for 5 days followed 16 h after the last ethanol injection by Δ(9)-THC infusion. The cross-tolerance appeared within 24-48 h, lasted over 72 h and was maximal in 5-day ethanol/Δ(9)-THC-treated animals. Finally, tolerance in chronic ethanol/Δ(9)-THC/-treated animals developed not only to ethanol/Δ(9)-THC-induced ataxia, respectively, but also to the ataxia potentiating effect of CHA and muscimol, indicating modulation by cerebellar adenosinergic A1 and GABAA receptors. A practical implication of these results could be that marijuana smokers may experience little or no negative effects such as ataxia following alcohol consumption. Clinically, such antagonism of ethanol-induced ataxia can be observed in marijuana users thereby encouraging more alcohol consumption and thus may represent a risk factor for the development of alcoholism in this segment of population. Copyright © 2014 Elsevier B.V. All rights reserved.

Oral fluid/plasma cannabinoid ratios following controlled oral THC and smoked cannabis administration.

PubMed

Lee, Dayong; Vandrey, Ryan; Milman, Garry; Bergamaschi, Mateus; Mendu, Damodara R; Murray, Jeannie A; Barnes, Allan J; Huestis, Marilyn A

2013-09-01

Oral fluid (OF) is a valuable biological alternative for clinical and forensic drug testing. Evaluating OF to plasma (OF/P) cannabinoid ratios provides important pharmacokinetic data on the disposition of drug and factors influencing partition between matrices. Eleven chronic cannabis smokers resided on a closed research unit for 51 days. There were four 5-day sessions of 0, 30, 60, and 120 mg oral ∆(9)-tetrahydrocannabinol (THC)/day followed by a five-puff smoked cannabis challenge on Day 5. Each session was separated by 9 days ad libitum cannabis smoking. OF and plasma specimens were analyzed for THC and metabolites. During ad libitum smoking, OF/P THC ratios were high (median, 6.1; range, 0.2-348.5) within 1 h after last smoking, decreasing to 0.1-20.7 (median, 2.1) by 13.0-17.1 h. OF/P THC ratios also decreased during 5-days oral THC dosing, and after the smoked cannabis challenge, median OF/P THC ratios decreased from 1.4 to 5.5 (0.04-245.6) at 0.25 h to 0.12 to 0.17 (0.04-5.1) at 10.5 h post-smoking. In other studies, longer exposure to more potent cannabis smoke and oromucosal cannabis spray was associated with increased OF/P THC peak ratios. Median OF/P 11-nor-9-carboxy-THC (THCCOOH) ratios were 0.3-2.5 (range, 0.1-14.7) ng/μg, much more consistent in various dosing conditions over time. OF/P THC, but not THCCOOH, ratios were significantly influenced by oral cavity contamination after smoking or oromucosal spray of cannabinoid products, followed by time-dependent decreases. Establishing relationships between OF and plasma cannabinoid concentrations is essential for making inferences of impairment or other clinical outcomes from OF concentrations.

Oral fluid/plasma cannabinoid ratios following controlled oral THC and smoked cannabis administration

PubMed Central

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

2013-01-01

BACKGROUND Oral fluid (OF) is a valuable biological alternative for clinical and forensic drug testing. Evaluating OF to plasma (OF/P) cannabinoid ratios provides important pharmacokinetic data on the disposition of drug and factors influencing partition between matrices. METHODS Eleven chronic cannabis smokers resided on a closed research unit for 51 days. There were four 5-day sessions of 0, 30, 60, and 120 mg oral Δ9-tetrahydrocannabinol (THC)/per day followed by a 5-puff smoked cannabis challenge on Day 5. Each session was separated by 9 days ad-libitum cannabis smoking. OF and plasma specimens were analyzed for THC and metabolites. RESULTS During ad-libitum smoking, OF/P THC ratios were high (median 6.1, range 0.2– 348.5) within 1 h after last smoking, decreasing to 0.1–20.7 (median 2.1) by 13.0–17.1 h. OF/P THC ratios also decreased during 5-days oral THC dosing, and after the smoked cannabis challenge, median OF/P THC ratios decreased from 1.4–5.5 (0.04–245.6) at 0.25 h to 0.12–0.17 (0.04–5.1) at 10.5 h post smoking. In other studies, longer exposure to more potent cannabis smoke and oromucosal cannabis spray was associated with increased OF/P THC peak ratios. Median OF/P 11-nor-9-carboxy-THC (THCCOOH) ratios were 0.3–2.5 (range 0.1–14.7) ng/µg, much more consistent in various dosing conditions over time. CONCLUSIONS OF/P THC, but not THCCOOH, ratios were significantly influenced by oral cavity contamination after smoking or oromucosal spray of cannabinoid products, followed by time-dependent decreases. Establishing relationships between OF and plasma cannabinoid concentrations is essential for making inferences of impairment or other clinical outcomes from OF concentrations. PMID:23831756

A galenical produced from Ba-Wei-Die-Huang-Wan (THC-002) provides resistance to the cold stress-induced detrusor overactivity in conscious rats.

PubMed

Imamura, Tetsuya; Ishizuka, Osamu; Sudha, Gautam Silwal; Lei, Zhang; Hosoda, Tomoka; Noguchi, Wataru; Yamagishi, Takahiro; Yokoyama, Hitoshi; Kurizaki, Yoshiki; Nishizawa, Osamu

2013-06-01

We determined if THC-002, a galenical produced from Ba-Wei-Die-Huang-Wan, could increase skin temperature and inhibit detrusor overactivity induced by sudden whole body cooling. Further, we determined if THC-002 could decrease expression of transient receptor potential melastatin 8 (TRPM8) channels associated with the cold responses. Hind leg skin temperature of female 10-week-old Sprague-Dawley rats was measured by thermal imaging. Experimental rats (n = 12) were given oral 100 mg/kg THC-002 daily for one week, and controls (n = 12) were similarly treated with THC-002-free solution. Afterwards, thermal imaging and cystometric investigations of the freely moving conscious rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then transferred to a low temperature (LT, 4 ± 2°C) environment during which thermal imaging and cystometric measurements were taken at 5, 10, 20, 30, and 40 min. Afterward, the skin tissues were harvested to estimate expression levels of TRPM8 channels by immunohistochemistry and real-time reverse-transcription polymerase chain reaction. The RT skin temperature of THC-002-treated rats was significantly higher than controls. During the first 20 min under LT, the control rats exhibited cold stress-induced detrusor overactivity such as decreased voiding interval and bladder capacity. THC-002 partially inhibited the detrusor overactivity patterns. During the second 20 min, skin temperature was relatively stable, and the detrusor overactivity of both groups slowly disappeared. THC-002 significantly reduced expression of TRPM8 channel protein and mRNA. THC-002 inhibited cold stress-induced detrusor overactivity resulting from decreasing skin temperature. Therefore, THC-002 might provide resistance to cold stress-exacerbated lower urinary tract symptoms. Copyright © 2012 Wiley Periodicals, Inc.

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.

PubMed

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.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ngaotepprutaram, Thitirat; Center for Integrative Toxicology, Michigan State University; Kaplan, Barbara L.F.

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{supmore » 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.« less

Effect of the psychoactive metabolite of marijuana, delta 9-tetrahydrocannabinol (THC), on the synthesis of tumor necrosis factor by human large granular lymphocytes.

PubMed

Kusher, D I; Dawson, L O; Taylor, A C; Djeu, J Y

1994-03-01

The natural killer cell (NK)/3polymorphonuclear neutrophil axis has recently been identified to be important in early defense against the opportunistic fungi, Candida albicans. Repression of this system is therefore likely to contribute to susceptibility to opportunistic infections. delta 9-Tetrahydrocannabinol (THC), an active constituent of marijuana, has been reported to be immunosuppressive at concentrations that exceed attainable plasma levels. In this report, we examine the possibility that human large granular lymphocytes (LGL) can be immunosuppressed by exposure to THC at physiologically relevant concentrations and probed two functions associated with LGL, i.e., cytokine production and tumoricidal activity. We find that these low levels of THC inhibit tumor necrosis factor-alpha (TNF) induction from LGL by C. albicans and are dependent upon THC dose (0.005-5.0 micrograms/ml) and length of exposure (0.05-3.0 hr). Northern blot analysis indicates that the downregulation of TNF production from LGL by THC resides at the mRNA level. Moreover, exposure of LGL to physiological THC concentrations (0.01-2.0 micrograms/ml) diminishes their cytolytic activity against K562 tumor cells.

[Testing the pharmacological activity of some synthetic cannabinoids in mice (author's transl)].

PubMed

Ganz, A J; Waser, P G

1980-01-01

A series of synthetic cannabinoids were tested in mice for analgesic, anticonvulsant, sedative and reserpine antagonistic properties as well as for influence on body temperature and on motor coordination and compared with the natural delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC) and cannabidiol (CBD). All cannabinoids were injected s.c. or i.p. in mice as solutions in olive oil. The synthetic cannabinoids, with the exception of the lipophilic ones, were less active than the natural delta 9-THC. 1',1'-dimethyl-delta 8-tetrahydrocannabinol (DM-delta 8-THC) has an analgesic ED 50 of 16 mg/kg s.c. (writhing test) and is three times more active than delta 9-THC, but also eight times less active than morphine. The lipophilic derivatives of delta 8-THC prolonged pentobarbitone narcosis and diminished locomotor activity in mice. Anticonvulsant activities could never be detected; all cannabinoids slightly diminished body temperature and antagonized weakly the hypothermia induced by reserpine. The trained capacity of remaining on the rotating rod was severely shortened for a long time after application of all cannabinoids but mainly by the lipophilic ones. The influence of derivation on the activity of delta 9-THC is discussed.

Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology.

PubMed

Potter, David J; Clark, Peter; Brown, Marc B

2008-01-01

Gas chromatography was used to study the cannabinoid content ("potency") of illicit cannabis seized by police in England in 2004/5. Of the four hundred and fifty two samples, indoor-grown unpollinated female cannabis ("sinsemilla") was the most frequent form, followed by resin (hashish) and imported outdoor-grown herbal cannabis (marijuana). The content of the psychoactive cannabinoid delta 9-tetrahydrocannabinol (THC) varied widely. The median THC content of herbal cannabis and resin was 2.1% and 3.5%, respectively. The median 13.9% THC content of sinsemilla was significantly higher than that recorded in the UK in 1996/8. In sinsemilla and imported herbal cannabis, the content of the antipsychotic cannabinoid cannabidiol (CBD) was extremely low. In resin, however, the average CBD content exceeded that of THC, and the relative proportions of the two cannabinoids varied widely between samples. The increases in average THC content and relative popularity of sinsemilla cannabis, combined with the absence of the anti-psychotic cannabinoid CBD, suggest that the current trends in cannabis use pose an increasing risk to those users susceptible to the harmful psychological effects associated with high doses of THC.

[Neuropsychopharmacology of delta-9-tetrahydrocannabinol].

PubMed

Costentin, J

2008-08-01

Today, the main route of introduction of tetrahydrocannabinol (THC), the main active substance of cannabis, into the human body is via the lungs, from smokes produced by combustion of a haschich-tobacco mixture. The use of a water pipe (nargileh-like) intensifies its fast supply to the body. THC reaches the brain easily where it stimulates CB1 receptors; their ubiquity underlies a wide variety of effects. THC disappears from extracellular spaces by dissolving in lipid rich membranes, and not by excretion from the body. This is followed by a slow release, leading to long lasting effects originating from brain areas containing a large proportion of spare receptors ("reserve receptors"). Far from mimicking the effects of endocannabinoids, THC caricatures and disturbs them. It induces both psychical and physical dependencies, but the perception of withdrawal is weak on account of its very slow elimination. THC disturbs cognition. Acutely, it develops anxiolytic- and antidepressant-like effects, which causes a lot of users to abuse THC, thus leading to a tolerance (desensitization of CB1 receptors) making anxiety and depression to reappear more intensely than originally. THC has close relationships with schizophrenia. It incites to tobacco, alcohol and heroine abuses.

Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L.

PubMed

Formukong, E A; Evans, A T; Evans, F J

1988-02-01

Tetrahydrocannabinol (THC) induced catalepsy in mice, whereas a cannabis oil (6.68% w/w THC), four cannabinoids and a synthetic mixture did not. Cannabinol (CBN) and olivetol inhibited THC-induced catalepsy in the mornings and the evenings, but cannabidiol (CBD) exhibited this effect only in the evenings. A combination of CBN and CBD inhibited THC-induced catalepsy equal to that of CBN alone in the mornings, but this inhibition was greater than that produced by CBN alone in the evenings.

40 CFR 1066.635 - NMOG determination.

Code of Federal Regulations, 2014 CFR

2014-07-01

... calculated using Eq. 1066.605-1. r OCHi = the C1-equivalent density of oxygenated species i. RF OHCi[THC-FID] = the response factor of a THC-FID to oxygenated species i relative to propane on a C1-equivalent basis....0002 g m C2H5OH = 0.0009 g m CH2O = 0.0001 g m C2H4O = 0.00005 g RF CH3OH[THC-FID] = 0.63 RF C2H5OH[THC...

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

PubMed

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.

Significant enhancement of 11-Hydroxy-THC detection by formation of picolinic acid esters and application of liquid chromatography/multi stage mass spectrometry (LC-MS(3) ): Application to hair and oral fluid analysis.

PubMed

Thieme, Detlef; Sachs, Ulf; Sachs, Hans; Moore, Christine

2015-07-01

Formation of picolinic acid esters of hydroxylated drugs or their biotransformation products is a promising tool to improve their mass spectrometric ionization efficiency, alter their fragmentation behaviour and enhance sensitivity and specificity of their detection. The procedure was optimized and tested for the detection of cannabinoids, which proved to be most challenging when dealing with alternative specimens, for example hair and oral fluid. In particular, the detection of the THC metabolites hydroxyl-THC and carboxy-THC requires ultimate sensitivity because of their poor incorporation into hair or saliva. Both biotransformation products are widely accepted as incorporation markers to distinguish drug consumption from passive contamination. The derivatization procedure was carried out by adding a mixture of picolinic acid, 4-(dimethylamino)pyridine and 2-methyl-6-nitrobenzoic anhydride in tetrahydrofuran/triethylamine to the dry extraction residues. Resulting derivatives were found to be very stable and could be reconstituted in aqueous or organic buffers and subsequently analyzed by liquid chromatography-mass spectrometry (LC-MS). Owing to the complex consecutive fragmentation patterns, the application of multistage MS3 proved to be extremely useful for a sensitive identification of doubly picolinated hydroxy-THC in complex matrices. The detection limits - estimated by comparison of corresponding signal-to-noise ratios - increased by a factor of 100 following picolination. All other species examined, like cannabinol, THC, cannabidiol, and carboxy-THC, could also be derivatized exhibiting only moderate sensitivity improvements. The assay was systematically tested using hair samples and exemplarily applied to oral fluid. Concentrations of OH-THC identified in THC-positive hair samples ranged from 0.02 to 0.29pg/mg. Copyright © 2014 John Wiley & Sons, Ltd.

Chronic marijuana smoke exposure in the rhesus monkey. IV: Neurochemical effects and comparison to acute and chronic exposure to delta-9-tetrahydrocannabinol (THC) in rats.

PubMed

Ali, S F; Newport, G D; Scallet, A C; Paule, M G; Bailey, J R; Slikker, W

1991-11-01

THC is the major psychoactive constituent of marijuana and is known to produce psychopharmacological effects in humans. These studies were designed to determine whether acute or chronic exposure to marijuana smoke or THC produces in vitro or in vivo neurochemical alterations in rat or monkey brain. For the in vitro study, THC was added (1-100 nM) to membranes prepared from different regions of the rat brain and muscarinic cholinergic (MCh) receptor binding was measured. For the acute in vivo study, rats were injected IP with vehicle, 1, 3, 10, or 30 mg THC/kg and sacrificed 2 h later. For the chronic study, rats were gavaged with vehicle or 10 or 20 mg THC/kg daily, 5 days/week for 90 days and sacrificed either 24 h or 2 months later. Rhesus monkeys were exposed to the smoke of a single 2.6% THC cigarette once a day, 2 or 7 days a week for 1 year. Approximately 7 months after the last exposure, animals were sacrificed by overdose with pentobarbital for neurochemical analyses. In vitro exposure to THC produced a dose-dependent inhibition of MCh receptor binding in several brain areas. This inhibition of MCh receptor binding, however, was also observed with two other nonpsychoactive derivatives of marijuana, cannabidiol and cannabinol. In the rat in vivo study, we found no significant changes in MCh or other neurotransmitter receptor binding in hippocampus, frontal cortex or caudate nucleus after acute or chronic exposure to THC. In the monkey brain, we found no alterations in the concentration of neurotransmitters in caudate nucleus, frontal cortex, hypothalamus or brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis-related spasticity.

PubMed

Celius, Elisabeth G; Vila, Carlos

2018-05-01

Driving ability is a key function for the majority of patients with multiple sclerosis (MS) to help maintain daily interactions. Both physical and cognitive disability, as well as treatments, may affect the ability to drive. Spasticity is a common symptom associated with MS, and it may affect driving performance either directly or via the medications used to treat it. In this article, we review the evidence relating the antispasticity medicine, Δ 9 -tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex ® ), and its potential impact on driving performance. Articles were identified by searching PubMed from 1/1/2000 to 30/6/2017 using a specified list of search terms. The articles identified using these search terms were augmented with relevant references from these papers and other articles known to the authors. The results from THC:CBD oromucosal spray driving studies and real-world registries did not show any evidence of an increase in motor vehicle accidents associated with THC:CBD oromucosal spray. The majority of patients reported an improvement in driving ability after starting THC:CBD oromucosal spray, and it was speculated that this may be related to reduced spasticity and/or better cognitive function. It should be noted that THC blood levels are significantly lower than the levels associated with recreational use of herbal cannabis. THC:CBD oromucosal spray was shown not to impair driving performance. However, periodic assessment of patients with MS driving ability is recommended, especially after relapses and changes in treatment. Blood THC measurements might be above authorized thresholds for some countries following administration of THC:CBD oromucosal spray, thus specific knowledge of each country's driving regulations and a medical certificate are recommended.

Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users.

PubMed

Hindocha, Chandni; Freeman, Tom P; Schafer, Grainne; Gardener, Chelsea; Das, Ravi K; Morgan, Celia J A; Curran, H Valerie

2015-03-01

Acute administration of the primary psychoactive constituent of cannabis, Δ-9-tetrahydrocannabinol (THC), impairs human facial affect recognition, implicating the endocannabinoid system in emotional processing. Another main constituent of cannabis, cannabidiol (CBD), has seemingly opposite functional effects on the brain. This study aimed to determine the effects of THC and CBD, both alone and in combination on emotional facial affect recognition. 48 volunteers, selected for high and low frequency of cannabis use and schizotypy, were administered, THC (8mg), CBD (16mg), THC+CBD (8mg+16mg) and placebo, by inhalation, in a 4-way, double-blind, placebo-controlled crossover design. They completed an emotional facial affect recognition task including fearful, angry, happy, sad, surprise and disgust faces varying in intensity from 20% to 100%. A visual analogue scale (VAS) of feeling 'stoned' was also completed. In comparison to placebo, CBD improved emotional facial affect recognition at 60% emotional intensity; THC was detrimental to the recognition of ambiguous faces of 40% intensity. The combination of THC+CBD produced no impairment. Relative to placebo, both THC alone and combined THC+CBD equally increased feelings of being 'stoned'. CBD did not influence feelings of 'stoned'. No effects of frequency of use or schizotypy were found. In conclusion, CBD improves recognition of emotional facial affect and attenuates the impairment induced by THC. This is the first human study examining the effects of different cannabinoids on emotional processing. It provides preliminary evidence that different pharmacological agents acting upon the endocannabinoid system can both improve and impair recognition of emotional faces. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: A randomised, double-blind, placebo-controlled study in cannabis users

PubMed Central

Hindocha, Chandni; Freeman, Tom P.; Schafer, Grainne; Gardener, Chelsea; Das, Ravi K.; Morgan, Celia J.A.; Curran, H. Valerie

2015-01-01

Acute administration of the primary psychoactive constituent of cannabis, Δ-9-tetrahydrocannabinol (THC), impairs human facial affect recognition, implicating the endocannabinoid system in emotional processing. Another main constituent of cannabis, cannabidiol (CBD), has seemingly opposite functional effects on the brain. This study aimed to determine the effects of THC and CBD, both alone and in combination on emotional facial affect recognition. 48 volunteers, selected for high and low frequency of cannabis use and schizotypy, were administered, THC (8 mg), CBD (16 mg), THC+CBD (8 mg+16 mg) and placebo, by inhalation, in a 4-way, double-blind, placebo-controlled crossover design. They completed an emotional facial affect recognition task including fearful, angry, happy, sad, surprise and disgust faces varying in intensity from 20% to 100%. A visual analogue scale (VAS) of feeling ‘stoned’ was also completed. In comparison to placebo, CBD improved emotional facial affect recognition at 60% emotional intensity; THC was detrimental to the recognition of ambiguous faces of 40% intensity. The combination of THC+CBD produced no impairment. Relative to placebo, both THC alone and combined THC+CBD equally increased feelings of being ‘stoned’. CBD did not influence feelings of ‘stoned’. No effects of frequency of use or schizotypy were found. In conclusion, CBD improves recognition of emotional facial affect and attenuates the impairment induced by THC. This is the first human study examining the effects of different cannabinoids on emotional processing. It provides preliminary evidence that different pharmacological agents acting upon the endocannabinoid system can both improve and impair recognition of emotional faces. PMID:25534187

A novel component of cannabis extract potentiates excitatory synaptic transmission in rat olfactory cortex in vitro.

PubMed

Whalley, Benjamin J; Wilkinson, Jonathan D; Williamson, Elizabeth M; Constanti, Andrew

2004-07-15

Cannabis is a potential treatment for epilepsy, although the few human studies supporting this use have proved inconclusive. Previously, we showed that a standardized cannabis extract (SCE), isolated Delta9-tetrahydrocannabinol (Delta9-THC), and even Delta9-THC-free SCE inhibited muscarinic agonist-induced epileptiform bursting in rat olfactory cortical brain slices, acting via CB1 receptors. The present work demonstrates that although Delta9-THC (1 microM) significantly depressed evoked depolarizing postsynaptic potentials (PSPs) in rat olfactory cortex neurones, both SCE and Delta9-THC-free SCE significantly potentiated evoked PSPs (all results were fully reversed by the CB1 receptor antagonist SR141716A, 1 microM); interestingly, the potentiation by Delta9-THC-free SCE was greater than that produced by SCE. On comparing the effects of Delta9-THC-free SCE upon evoked PSPs and artificial PSPs (aPSPs; evoked electrotonically following brief intracellular current injection), PSPs were enhanced, whereas aPSPs were unaffected, suggesting that the effect was not due to changes in background input resistance. Similar recordings made using CB1 receptor-deficient knockout mice (CB1-/-) and wild-type littermate controls revealed cannabinoid or extract-induced changes in membrane resistance, cell excitability and synaptic transmission in wild-type mice that were similar to those seen in rat neurones, but no effect on these properties were seen in CB1-/- cells. It appears that the unknown extract constituent(s) effects over-rode the suppressive effects of Delta9-THC on excitatory neurotransmitter release, which may explain some patients' preference for herbal cannabis rather than isolated Delta9-THC (due to attenuation of some of the central Delta9-THC side effects) and possibly account for the rare incidence of seizures in some individuals taking cannabis recreationally.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ali, S.F.; Newport, G.D.; Scallet, A.C.

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 weremore » 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.« less

Analysis of cannabis seizures in NSW, Australia: cannabis potency and cannabinoid profile.

PubMed

Swift, Wendy; Wong, Alex; Li, Kong M; Arnold, Jonathon C; McGregor, Iain S

2013-01-01

Recent analysis of the cannabinoid content of cannabis plants suggests a shift towards use of high potency plant material with high levels of Δ(9)-tetrahydrocannabinol (THC) and low levels of other phytocannabinoids, particularly cannabidiol (CBD). Use of this type of cannabis is thought by some to predispose to greater adverse outcomes on mental health and fewer therapeutic benefits. Australia has one of the highest per capita rates of cannabis use in the world yet there has been no previous systematic analysis of the cannabis being used. In the present study we examined the cannabinoid content of 206 cannabis samples that had been confiscated by police from recreational users holding 15 g of cannabis or less, under the New South Wales "Cannabis Cautioning" scheme. A further 26 "Known Provenance" samples were analysed that had been seized by police from larger indoor or outdoor cultivation sites rather than from street level users. An HPLC method was used to determine the content of 9 cannabinoids: THC, CBD, cannabigerol (CBG), and their plant-based carboxylic acid precursors THC-A, CBD-A and CBG-A, as well as cannabichromene (CBC), cannabinol (CBN) and tetrahydrocannabivarin (THC-V). The "Cannabis Cautioning" samples showed high mean THC content (THC+THC-A = 14.88%) and low mean CBD content (CBD+CBD-A = 0.14%). A modest level of CBG was detected (CBG+CBG-A = 1.18%) and very low levels of CBC, CBN and THC-V (<0.1%). "Known Provenance" samples showed no significant differences in THC content between those seized from indoor versus outdoor cultivation sites. The present analysis echoes trends reported in other countries towards the use of high potency cannabis with very low CBD content. The implications for public health outcomes and harm reduction strategies are discussed.

Inhalation exposure to jet fuel (JP8) among U.S. Air Force personnel.

PubMed

Smith, Kristen W; Proctor, Susan P; Ozonoff, Al; McClean, Michael D

2010-10-01

As jet fuel is a common occupational exposure among military and civilian populations, this study was conducted to characterize jet fuel (JP8) exposure among active duty U.S. Air Force personnel. Personnel (n = 24) were divided a priori into high, moderate, and low exposure groups. Questionnaires and personal air samples (breathing zone) were collected from each worker over 3 consecutive days (72 worker-days) and analyzed for total hydrocarbons (THC), benzene, toluene, ethylbenzene, xylenes, and naphthalene. Air samples were collected from inside the fuel tank and analyzed for the same analytes. Linear mixed-effects models were used to evaluate the exposure data. Our results show that the correlation of THC (a measure of overall JP8 inhalation exposure) with all other analytes was moderate to strong in the a priori high and moderate exposure groups combined. Inhalation exposure to all analytes varied significantly by self-reported JP8 exposure (THC levels higher among workers reporting JP8 exposure), a priori exposure group (THC levels in high group > moderate group > low group), and more specific job task groupings (THC levels among workers in fuel systems hangar group > refueling maintenance group > fuel systems office group > fuel handling group > clinic group), with task groupings explaining the most between-worker variability. Among highly exposed workers, statistically significant job task-related predictors of inhalation exposure to THC indicated that increased time in the hangar, working close to the fuel tank (inside > less than 25 ft > greater than 25 ft), primary job (entrant > attendant/runner/fireguard > outside hangar), and performing various tasks near the fuel tank, such as searching for a leak, resulted in higher JP8 exposure. This study shows that while a priori exposure groups were useful in distinguishing JP8 exposure levels, job task-based categories should be considered in epidemiologic study designs to improve exposure classification. Finally, the strong correlation of THC with naphthalene suggests that naphthalene may be an appropriate surrogate of JP8 exposure. [Supplementary materials are available for this article. Go to the publisher's online edition of the Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a pdf file containing a table detailing concentrations of JP8 components.].

40 CFR 1065.650 - Emission calculations.

Code of Federal Regulations, 2011 CFR

2011-07-01

... following sequence of preliminary calculations on recorded concentrations: (i) Correct all THC and CH4.... (iii) Calculate all THC and NMHC concentrations, including dilution air background concentrations, as... NMHC to background corrected mass of THC. If the background corrected mass of NMHC is greater than 0.98...

TORONTO HARBOUR COMMISSIONERS (THC) SOIL RECYCLE TREATMENT TRAIN - APPLICATIONS ANALYSIS REPORT

EPA Science Inventory

The Toronto Harbour Commissioners (THC) have developed a soil treatment train designed to treat inorganic and organic contaminants in soils. THC has conducted a large-scale demonstration of these technologies in an attempt to establish that contaminated soils at the Toronto Port ...

A preliminary investigation on the distribution of cannabinoids in man.

PubMed

Gronewold, Antonia; Skopp, Gisela

2011-07-15

An LC/MS/MS procedure to determine THC along with its major metabolites 11-OH-THC, THC-COOH and its glucuronide as well as the cannabinoids CBD and CBN was applied to 5 post mortem cases to study their distribution into some less commonly studied matrices. Analytes were determined in fluids and tissue homogenates following protein precipitation and liquid-liquid extraction. Gall bladder fluid exhibited maximum concentrations of all analytes except THC, which was detectable in high concentrations in muscle tissue along with CBD. THC was also present in lung specimens, whereas its concentration in liver samples was low or not detectable at all. Liver und kidney specimens contained appreciable amounts of THC-COOglu. Findings from bile support extensive enterohepatic recirculation of the glucuronide. Muscle tissue seems an interesting specimen to detect multiple cannabis use, and brain may serve as an alternative specimen for blood; nevertheless, the present findings should be substantiated by further investigations. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Short-Term Genetic Selection for Adolescent Locomotor Sensitivity to Delta9-Tetrahydrocannabinol (THC).

PubMed

Kasten, Chelsea R; Zhang, Yanping; Mackie, Ken; Boehm, Stephen L

2018-05-01

Cannabis use is linked to positive and negative outcomes. Identifying genetic targets of susceptibility to the negative effects of cannabinoid use is of growing importance. The current study sought to complete short-term selective breeding for adolescent sensitivity and resistance to the locomotor effects of a single 10 mg/kg THC dose in the open field. Selection for THC-locomotor sensitivity was moderately heritable, with the greatest estimates of heritability seen in females from the F2 to S3 generations. Selection for locomotor sensitivity also resulted in increased anxiety-like activity in the open field. These results are the first to indicate that adolescent THC-locomotor sensitivity can be influenced via selective breeding. Development of lines with a genetic predisposition for THC-sensitivity or resistance to locomotor effects allow for investigation of risk factors, differences in consequences of THC use, identification of correlated behavioral responses, and detection of genetic targets that may contribute to heightened cannabinoid sensitivity.

Medicinal applications of delta-9-tetrahydrocannabinol and marijuana.

PubMed

Voth, E A; Schwartz, R H

1997-05-15

The use of crude marijuana for herbal medicinal applications is now being widely discussed in both the medical and lay literature. Ballot initiatives in California and Arizona have recently made crude marijuana accessible to patients under certain circumstances. As medicinal applications of pure forms of delta-9-tetrahydrocannabinol (THC) and crude marijuana are being considered, the most promising uses of any form of THC are to counteract the nausea associated with cancer chemotherapy and to stimulate appetite. We evaluated the relevant research published between 1975 and 1996 on the medical applications, physical complications, and legal precedents for the use of pure THC or crude marijuana. Our review focused on the medical use of THC derivatives for nausea associated with cancer chemotherapy, glaucoma, stimulation of appetite, and spinal cord spasticity. Despite the toxicity of THC delivered in any form, evidence supports the selective use of pure THC preparations to treat nausea associated with cancer chemotherapy and to stimulate appetite. The evidence does not support the reclassification of crude marijuana as a prescribable medicine.

Cannabidiol enhances the inhibitory effects of Δ9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival

PubMed Central

Marcu, Jahan P.; Christian, Rigel T.; Lau, Darryl; Zielinski, Anne J.; Horowitz, Maxx P.; Lee, Jasmine; Pakdel, Arash; Allison, Juanita; Limbad, Chandani; Moore, Dan H.; Yount, Garret L.; Desprez, Pierre-Yves; McAllister, Sean D.

2009-01-01

The cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonist, Δ9-tetrahydrocannabinol (THC), has been shown to be a broad range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma. It has been suggested that other plant-derived cannabinoids, which do not interact efficiently with CB1 and CB2 receptors, can modulate the actions of Δ9-THC. However, there are conflicting reports as to what extent other cannabinoids can modulate Δ9-THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Δ9-THC. We therefore tested cannabidiol (CBD), the second most abundant plant derived cannabiniod, in combination with Δ9-THC. In U251 and SF126 glioblastoma cell lines, Δ9-THC and CBD acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species (ROS) and apoptosis as well as specific modulations of extracellular signal-regulated kinase (ERK) and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of CBD to Δ9-THC may improve the overall effectiveness of Δ9-THC in the treatment of glioblastoma in cancer patients. PMID:20053780

Cannabinoid administration attenuates the progression of simian immunodeficiency virus.

PubMed

Molina, Patricia E; Winsauer, Peter; Zhang, Ping; Walker, Edith; Birke, Leslie; Amedee, Angela; Stouwe, Curtis Vande; Troxclair, Dana; McGoey, Robin; Varner, Kurt; Byerley, Lauri; LaMotte, Lynn

2011-06-01

Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), the primary psychoactive component in marijuana, is FDA approved to ameliorate AIDS-associated wasting. Because cannabinoid receptors are expressed on cells of the immune system, chronic Δ(9)-THC use may impact HIV disease progression. We examined the impact of chronic Δ(9)-THC administration (0.32 mg/kg im, 2 × daily), starting 28 days prior to inoculation with simian immunodeficiency virus (SIV(mac251); 100 TCID(50)/ml, iv), on immune and metabolic indicators of disease during the initial 6 month asymptomatic phase of infection in rhesus macaques. SIV(mac251) inoculation resulted in measurable viral load, decreased lymphocyte CD4(+)/CD8(+) ratio, and increased CD8(+) proliferation. Δ(9)-THC treatment of SIV-infected animals produced minor to no effects in these parameters. However, chronic Δ(9)-THC administration decreased early mortality from SIV infection (p = 0.039), and this was associated with attenuation of plasma and CSF viral load and retention of body mass (p = NS). In vitro, Δ(9)-THC (10 μm) decreased SIV (10 TCID(50)) viral replication in MT4-R5 cells. These results indicate that chronic Δ(9)-THC does not increase viral load or aggravate morbidity and may actually ameliorate SIV disease progression. We speculate that reduced levels of SIV, retention of body mass, and attenuation of inflammation are likely mechanisms for Δ(9)-THC-mediated modulation of disease progression that warrant further study.

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment.

PubMed

Englund, Amir; Morrison, Paul D; Nottage, Judith; Hague, Dominic; Kane, Fergus; Bonaccorso, Stefania; Stone, James M; Reichenberg, Avi; Brenneisen, Rudolf; Holt, David; Feilding, Amanda; Walker, Lucy; Murray, Robin M; Kapur, Shitij

2013-01-01

Community-based studies suggest that cannabis products that are high in Δ⁹-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥ 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ²=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 ± 18.9%) compared with the CBD group (-0.4% ± 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Exposure of Adolescent Mice to Delta-9-Tetrahydrocannabinol Induces Long-Lasting Modulation of Pro- and Anti-Inflammatory Cytokines in Hypothalamus and Hippocampus Similar to that Observed for Peripheral Macrophages.

PubMed

Moretti, Sarah; Franchi, Silvia; Castelli, Mara; Amodeo, Giada; Somaini, Lorenzo; Panerai, Alberto; Sacerdote, Paola

2015-06-01

Cannabis use is frequent among adolescents. Its main component, delta-9-tetrahydrocannabinol (THC), affects the immune system. We recently demonstrated that chronic exposure of adolescent mice to THC suppressed immunity immediately after treatment but that after a washout period THC induced a long-lasting opposite modulation towards a proinflammatory and T-helper-1 phenotype in adulthood. The main objective of this study was to investigate whether the same effect was also present in brain regions such as the hypothalamus and hippocampus. Thirty-three-day-old adolescent and 80-day-old adult male mice were used. Acute THC administration induced a similar reduction of macrophage proinflammatory cytokines and an IL-10 increase in adult and adolescent mice. THC did not affect brain cytokines in adult mice, but a proinflammatory cytokine decrease was evident in the adolescent brain. A similar effect was present in the hypothalamus and hippocampus after 10 days' THC administration. In contrast, when brain cytokines were measured 47 days after the final THC administration, we observed an inverted effect in adult mice treated as adolescents, i.e., IL-1β and TNF-α increased and IL-10 decreased, indicating a shift toward neuroinflammation. These data suggest that THC exposure in adolescence has long-lasting effects on brain cytokines that parallel those present in the periphery. This modulation may affect vulnerability to immune and behavioural diseases in adulthood.

40 CFR 1066.15 - Overview of test procedures.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) Hydrocarbons, HC, which may be expressed in the following ways: (i) Total hydrocarbons, THC. (ii) Nonmethane hydrocarbons, NMHC, which results from subtracting methane, CH4, from THC. (iii) Total hydrocarbon-equivalent, THCE, which results from adjusting THC mathematically to be equivalent on a carbon-mass basis. (iv...

The detection of THC, CBD and CBN in the oral fluid of Sativex® patients using two on-site screening tests and LC-MS/MS.

PubMed

Molnar, Anna; Fu, Shanlin; Lewis, John; Allsop, David J; Copeland, Jan

2014-05-01

Sativex(®) is an oromucosal spray used to treat spasticity in multiple sclerosis sufferers in some European countries, the United Kingdom, Canada and New Zealand. The drug has also recently been registered by the Therapeutic Goods Administration (TGA) in Australia for treatment of multiple sclerosis. Sativex(®) contains high concentrations of Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), with the former being the subject of random roadside drug tests across Australia to detect cannabis use. This pilot study aims to determine whether or not patients taking Sativex(®) will test positive to THC using these roadside screening tests. Detectable levels of THC, CBD and cannabinol (CBN) in their oral fluid were also confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study was a double-blind, placebo controlled design. Oral fluid was tested prior to and immediately after dosing with either Sativex(®) or placebo at intervals up to 2h after the dose. Two Sativex(®) doses were studied. The low dose contained 5.4mg THC, the high dose 21.6mg THC. Results indicate that the primary screening test used in Australian roadside drug testing, the DrugWipe(®) II Twin, often gave a false negative response for THC, even with high concentrations present. However, secondary screening test, Cozart(®) DDS (used by police after a DrugWipe test gives a positive result), gave true positive results in all cases where patients were being treated with Sativex(®). Confirmatory testing showed high concentrations of THC and CBD (>5356ng/mL THC and >3826ng/mL CBD) in the oral fluid shortly after dosing and also elevated concentrations of CBN. Levels dropped quickly but remained at detectable concentrations (>67.6ng/mL) two hours after drug administration. The average concentration ratio of THC/CBD across all positive samples was 1.10 (%RSD 19.9) reflecting the composition of the Sativex(®) spray. In conclusion, Sativex(®) users may test positive for THC by roadside drug testing within 2-3h of use. Confirmatory analysis can identify Sativex(®) treatment through use of THC/CBD ratios, however, these ratios would unlikely be sufficient to differentiate non-medicinal cannabis use from Sativex(®) use if both are taken concurrently. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Examination of the effects of cannabinoid ligands on decision making in a rat gambling task.

PubMed

Ferland, Jacqueline-Marie N; Carr, Madison R; Lee, Angela M; Hoogeland, Myrthe E; Winstanley, Catharine A; Pattij, Tommy

2018-07-01

Although exposure to delta-9-tetrahydrocannabinol (THC) is perceived to be relatively harmless, mounting evidence has begun to show that it is associated with a variety of cognitive deficits, including poor decision making. THC-induced impairments in decision making are thought to be the result of cannabinoid CB1 receptor activation, and although clinical literature suggests that chronic activation via THC contributes to perturbations in decision making, acute CB1 receptor modulation has yielded mixed results. Using an animal model to examine how CB1-specific ligands impact choice biases would provide significant insight as to how recruitment of the endocannabinoid system may influence decision making. Here, we used the rat gambling task (rGT), a validated analogue of the human Iowa Gambling Task, to assess baseline decision making preferences in male Wistar rats. After acquisition rGT performance was measured. Animals were challenged with the CB1 receptor antagonist rimonabant, the partial agonist THC, and the synthetic agonist WIN55,212-2. Animals were also treated acutely with the fatty acid amide hydrolase (FAAH) inhibitor URB597 to selectively upregulate the endocannabinoid anandamide. Blockade of the CB1 receptor produced a trend improvement in decision making in animals who preferred the advantageous task options, yet left choice unaffected in risk-prone rats. Neither CB1 receptor agonist had strong effects on decision making, but a high dose THC decreased premature responses, whereas WIN55,212-2 did the opposite. URB597 did not affect task performance. These results indicate that although chronic CB1 receptor activation may be associated with impaired decision making, acute modulation has modest effects on choice and instead may play a substantive role in regulating impulsive responding. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Tensor hypercontracted ppRPA: Reducing the cost of the particle-particle random phase approximation from O(r {sup 6}) to O(r {sup 4})

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shenvi, Neil; Yang, Yang; Yang, Weitao

In recent years, interest in the random-phase approximation (RPA) has grown rapidly. At the same time, tensor hypercontraction has emerged as an intriguing method to reduce the computational cost of electronic structure algorithms. In this paper, we combine the particle-particle random phase approximation with tensor hypercontraction to produce the tensor-hypercontracted particle-particle RPA (THC-ppRPA) algorithm. Unlike previous implementations of ppRPA which scale as O(r{sup 6}), the THC-ppRPA algorithm scales asymptotically as only O(r{sup 4}), albeit with a much larger prefactor than the traditional algorithm. We apply THC-ppRPA to several model systems and show that it yields the same results as traditionalmore » ppRPA to within mH accuracy. Our method opens the door to the development of post-Kohn Sham functionals based on ppRPA without the excessive asymptotic cost of traditional ppRPA implementations.« less

Tensor hypercontracted ppRPA: Reducing the cost of the particle-particle random phase approximation from O(r 6) to O(r 4)

NASA Astrophysics Data System (ADS)

Shenvi, Neil; van Aggelen, Helen; Yang, Yang; Yang, Weitao

2014-07-01

In recent years, interest in the random-phase approximation (RPA) has grown rapidly. At the same time, tensor hypercontraction has emerged as an intriguing method to reduce the computational cost of electronic structure algorithms. In this paper, we combine the particle-particle random phase approximation with tensor hypercontraction to produce the tensor-hypercontracted particle-particle RPA (THC-ppRPA) algorithm. Unlike previous implementations of ppRPA which scale as O(r6), the THC-ppRPA algorithm scales asymptotically as only O(r4), albeit with a much larger prefactor than the traditional algorithm. We apply THC-ppRPA to several model systems and show that it yields the same results as traditional ppRPA to within mH accuracy. Our method opens the door to the development of post-Kohn Sham functionals based on ppRPA without the excessive asymptotic cost of traditional ppRPA implementations.

40 CFR 63.9320 - What procedures must I use?

Code of Federal Regulations, 2014 CFR

2014-07-01

... the carbon monoxide (CO) or total hydrocarbon (THC) concentration limitation consists of the first 4-hour rolling average CO or THC concentration recorded after completion of the CEMS performance evaluation. You must correct the CO or THC concentration at the outlet of the engine test cell/stand or the...

40 CFR Table 2 to Subpart Dddd of... - Operating Requirements

Code of Federal Regulations, 2012 CFR

2012-07-01

... THC concentration a in the thermal oxidizer exhaust below the maximum concentration established during... average THC concentration a in the catalytic oxidizer exhaust below the maximum concentration established... the range established according to § 63.2262(m) Maintain the 24-hour block average THC concentration a...

76 FR 8788 - Riverside Casualty, Inc.; Notice of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-15

.../search/search.htm or by calling (202) 551-8090. Applicant's Representations 1. The Haskell Company (``THC..., construction, real estate and facility management services. All of the outstanding shares of THC's common stock are owned by The Haskell Company Employee Stock Ownership Trust (``THC ESOP''); Preston H. Haskell III...

Evaluation of 25-Percent ATJ Fuel Blends in the John Deere 4045HF 280 Engine

DTIC Science & Technology

2014-08-01

25% ATJ Blend ........ 26 Figure 16 . THC Emissions, Pre-Test, Ambient Temperature ...................................................... 28 Figure...17 . THC Emissions, Pre-Test, Desert Temperature ......................................................... 28 Figure 18 . NOx Emissions, Pre-Test...Emissions, Pre-Test, Desert Temperature (Scaled) ............................................. 32 Figure 23 . THC Emissions, Post-Test, Ambient

40 CFR Table 2 to Subpart Dddd of... - Operating Requirements

Code of Federal Regulations, 2013 CFR

2013-07-01

... THC concentration a in the thermal oxidizer exhaust below the maximum concentration established during... average THC concentration a in the catalytic oxidizer exhaust below the maximum concentration established... the range established according to § 63.2262(m) Maintain the 24-hour block average THC concentration a...

40 CFR Table 4 to Subpart Zzzz of... - Requirements for Performance Tests

Code of Federal Regulations, 2013 CFR

2013-07-01

... determine O2 concentration must be made at the same time as the measurements for formaldehyde or THC... formaldehyde or THC concentration. iv. If demonstrating compliance with the formaldehyde percent reduction...-hour or longer runs. v. If demonstrating compliance with the THC percent reduction requirement, measure...

40 CFR 63.9320 - What procedures must I use?

Code of Federal Regulations, 2011 CFR

2011-07-01

... the carbon monoxide (CO) or total hydrocarbon (THC) concentration limitation consists of the first 4-hour rolling average CO or THC concentration recorded after completion of the CEMS performance evaluation. You must correct the CO or THC concentration at the outlet of the engine test cell/stand or the...

40 CFR 86.135-90 - Dynamometer procedure.

Code of Federal Regulations, 2014 CFR

2014-07-01

... petroleum gas-fueled Otto-cycle vehicles, the composite samples collected in bags are analyzed for THC, CO..., liquefied petroleum gas-fueled and methanol-fueled diesel-cycle vehicles), THC is sampled and analyzed... analyzed for THC, CO, CO2, CH4, and NOX. (3) For natural gas-fueled, liquefied petroleum gas-fueled and...

40 CFR 63.9320 - What procedures must I use?

Code of Federal Regulations, 2012 CFR

2012-07-01

... the carbon monoxide (CO) or total hydrocarbon (THC) concentration limitation consists of the first 4-hour rolling average CO or THC concentration recorded after completion of the CEMS performance evaluation. You must correct the CO or THC concentration at the outlet of the engine test cell/stand or the...

40 CFR Table 2 to Subpart Dddd of... - Operating Requirements

Code of Federal Regulations, 2014 CFR

2014-07-01

... THC concentration a in the thermal oxidizer exhaust below the maximum concentration established during... average THC concentration a in the catalytic oxidizer exhaust below the maximum concentration established... the range established according to § 63.2262(m) Maintain the 24-hour block average THC concentration a...

40 CFR 63.9320 - What procedures must I use?

Code of Federal Regulations, 2013 CFR

2013-07-01

... the carbon monoxide (CO) or total hydrocarbon (THC) concentration limitation consists of the first 4-hour rolling average CO or THC concentration recorded after completion of the CEMS performance evaluation. You must correct the CO or THC concentration at the outlet of the engine test cell/stand or the...

40 CFR 86.237-08 - Dynamometer test run, gaseous emissions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel-cycle only). (The heat exchanger of the constant volume sampler, if used, petroleum-fueled diesel-cycle THC analyzer continuous sample line and filter, methanol-fueled vehicle THC, methanol and formaldehyde sample lines, if...

40 CFR Table 4 to Subpart Zzzz of... - Requirements for Performance Tests

Code of Federal Regulations, 2014 CFR

2014-07-01

... determine O2 concentration must be made at the same time as the measurements for formaldehyde or THC... formaldehyde or THC concentration. iv. If demonstrating compliance with the formaldehyde percent reduction...-hour or longer runs. v. If demonstrating compliance with the THC percent reduction requirement, measure...

40 CFR 63.9320 - What procedures must I use?

Code of Federal Regulations, 2010 CFR

2010-07-01

... the carbon monoxide (CO) or total hydrocarbon (THC) concentration limitation consists of the first 4-hour rolling average CO or THC concentration recorded after completion of the CEMS performance evaluation. You must correct the CO or THC concentration at the outlet of the engine test cell/stand or the...

40 CFR 86.237-08 - Dynamometer test run, gaseous emissions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... temperature recorder, the vehicle cooling fan, and the heated THC analysis recorder (diesel-cycle only). (The heat exchanger of the constant volume sampler, if used, petroleum-fueled diesel-cycle THC analyzer continuous sample line and filter, methanol-fueled vehicle THC, methanol and formaldehyde sample lines, if...

Rapid elimination of Carboxy-THC in a cohort of chronic cannabis users.

PubMed

Lewis, John; Molnar, Anna; Allsop, David; Copeland, Jan; Fu, Shanlin

2016-01-01

Urinary 11-nor-Δ(9)-tetrahydrocannabinol-9-carboxylic acid (Carboxy-THC) concentrations, normalised to creatinine output, have been demonstrated to be a useful tool in the interpretation of the results of a series of urine tests for cannabis. These tests, often termed historical data, can be used to identify potential chronic cannabis users who may present occupational health and safety risks within the workplace. Conversely, the data can also be used to support employee claims of previous regular, rather than recent, cannabis use. This study aimed at examining the mean elimination of Carboxy-THC in 37 chronic users undergoing voluntary abstinence over a 2-week period. Urine specimens were collected prior to the study and after 1 and 2 weeks of abstinence. Carboxy-THC levels in urine were measured by gas chromatography-mass spectrometry (GC-MS) following alkaline hydrolysis, organic solvent extraction and derivatisation to form its pentafluoropropionic derivative. The creatinine-normalised Carboxy-THC concentrations declined rapidly over the 2 weeks of abstinence period and the majority of chronic cannabis users (73%) reduced their urinary Carboxy-THC levels to below the 15-μg/L confirmatory cutoff within that time. The study further highlights the value of historical urinary Carboxy-THC data as a means of identifying potential occupational health and safety risks among chronic cannabis users.

Acute Δ-9-tetrahydrocannabinol administration in female rats attenuates immediate responses following losses but not multi-trial reinforcement learning from wins.

PubMed

Wong, Scott A; Randolph, Sienna H; Ivan, Victorita E; Gruber, Aaron J

2017-09-29

Δ-9-Tetrahydrocannabinol (THC) is the main psychoactive component of marijuana and has potent effects on decision-making, including a proposed reduction in cognitive flexibility. We demonstrate here that acute THC administration differentially affects some of the processes that contribute to cognitive flexibility. Specifically, THC reduces lose-shift responding in which female rats tend to immediately shift choice responses away from options that result in reward omission on the previous trial. THC, however, did not impair the ability of rats to flexibly bias responses toward feeders with higher probability of reward in a reversal task. This response adaptation developed over several trials, suggesting that THC did not impair slower forms of reinforcement learning needed to choose among options with unequal utility. This dissociation of THC's effects on innate/rapid and learned/gradual decision-making processes was unexpected, but is supported by emerging evidence that lose-shift responding is mediated by neural mechanisms distinct from those involved in other forms of reinforcement learning. The present data suggest that, at least in some tasks, the apparent reductions in cognitive flexibility by THC may be explained by the immediate effects on loss sensitivity, rather than impairments of all processes used for choice adaptation. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol.

PubMed

Boggs, Douglas L; Nguyen, Jacques D; Morgenson, Daralyn; Taffe, Michael A; Ranganathan, Mohini

2018-01-01

The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are >550 chemical compounds and >100 phytocannabinoids isolated from cannabis, including Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC-induced anxiety, psychosis, and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from preclinical and human studies, particularly with reference to anxiety and psychosis-like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings, including the individual and interactive effects of CBD and THC.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johansson, E.; Gillespie, H.K.; Halldin, M.M.

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 weremore » 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.« less

Effects of oxidizing adulterants on detection of 11-nor-delta9-THC-9-carboxylic acid in urine.

PubMed

Paul, Buddha D; Jacobs, Aaron

2002-10-01

Bleach, nitrite, chromate, and hydrogen peroxide-peroxidase are effective urine adulterants used by the illicit drug users to conceal marijuana-positive results. Methods for detecting nitrite and chromate are available. Effects of other oxidizing agents that could possibly be used as adulterants and are difficult to detect or measure are presented in this report. Urine samples containing 40 ng/mL of 11-nor-delta9-THC-9-carboxylic acid (THC-acid) were treated with 10 mmol/L of commonly available oxidizing agents. Effects of horseradish peroxidase of activity 10 unit/mL and extracts from 2.5 g of red radish (Raphanus sativus, Radicula group), horseradish (Armoracia rusticana), Japanese radish (Raphanus sativus, Daikon group), and black mustard seeds (Brassica nigra), all with 10 mmol/L of hydrogen peroxide, were also examined. After 5 min, 16 h and 48 h of exposure at room temperature (23 degrees C) the specimens were tested by a gas chromatographic-mass spectrometric method for THC-acid. A control group treated with sodium hydrosulfite to reduce the oxidants, was also tested to investigate the effect of oxidizing agents on THC-acid in the extraction method. THC-acid was lost completely in the extraction method when treated with chromate, nitrite, oxone, and hydrogen peroxide/ferrous ammonium sulfate (Fenton's reagent). Some losses were also observed with persulfate and periodate (up to 25%). These oxidants, and other oxidizing agents like permanganate, periodate, peroxidase, and extracts from red radish, horseradish, Japanese radish and black mustard seeds destroyed most of the THC-acid (> 94%) within 48 h of exposure. Chlorate, perchlorate, iodate, and oxychloride under these conditions showed little or no effect. Complete loss was observed when THC-acid was exposed to 50 mmol/L of oxychloride for 48 h. Several oxidizing adulterants that are difficult to test by the present urine adulterant testing methods showed considerable effects on the destruction of THC-acid. The time and temperature for these effects were similar to those used by most laboratories to collect and test specimens. In several cases, the loss of THC-acid was > 94%.

Characteristics of cannabinoids composition of Cannabis plants grown in Northern Thailand and its forensic application.

PubMed

Tipparat, Prapatsorn; Natakankitkul, Surapol; Chamnivikaipong, Pipop; Chutiwat, Sirot

2012-02-10

The Thai government has recognized the possibility for legitimate cultivation of hemp. Further study of certain cannabinoid characteristics is necessary in establishing criteria for regulation of cannabis cultivation in Thailand. For this purpose, factors affecting characteristics of cannabinoids composition of Thai-grown cannabis were investigated. Plants were cultivated from seeds derived from the previous studies under the same conditions. 372 cannabis samples from landraces, three different trial fields and seized marijuana were collected. 100g of each sample was dried, ground and quantitatively analyzed for THC, CBD and CBN contents by GC-FID. The results showed that cannabis grown during March-June which had longer vegetative stages and longer photoperiod exposure, had higher cannabinoids contents than those grown in August. The male plants grown in trial fields had the range of THC contents from 0.722% to 0.848% d.w. and average THC/CBD ratio of 1.9. Cannabis in landraces at traditional harvest time of 75 days had a range of THC contents from 0.874% to 1.480% d.w. and an average THC/CBD ratio of 2.6. The THC contents and THC/CBD ratios of cannabis in second generation crops grown in the same growing season were found to be lower than those grown in the first generation, unless fairly high temperatures and a lesser amount of rainfall were present. The average THC content in seized fresh marijuana was 2.068% d.w. while THC/CBD ratios were between 12.6 and 84.09, which is 10-45 times greater than those of similar studied cannabis samples from the previous study. However, most Thai cannabis in landraces and in trial fields giving a low log(10) value of THC/CBD ratio at below 1 may be classified as intermediate type, whereas seized marijuana giving a higher log(10) value at above 1 could be classified as drug type. Therefore, the expanded information provided by the current study will assist in the development of criteria for regulation of hemp cultivation in Thailand. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Pharmacokinetic Profile of Oral Cannabis in Humans: Blood and Oral Fluid Disposition and Relation to Pharmacodynamic Outcomes

PubMed Central

Vandrey, Ryan; Herrmann, Evan S.; Mitchell, John M.; Bigelow, George E.; Flegel, Ronald; LoDico, Charles; Cone, Edward J.

2017-01-01

Abstract Most research on cannabis pharmacokinetics has evaluated inhaled cannabis, but oral (“edible”) preparations comprise an increasing segment of the cannabis market. To assess oral cannabis pharmacokinetics and pharmacodynamics, healthy adults (N = 6 per dose) were administered cannabis brownies containing 10, 25 or 50 mg 9-tetrahydrocannabinol (THC). Whole blood and oral fluid specimens were obtained at baseline and then for 9 days post-exposure; 6 days in a residential research setting and 3 days as outpatients. Measures of subjective, cardiovascular and performance effects were obtained at baseline and for 8 h post-ingestion. The mean Cmax for THC in whole blood was 1, 3.5 and 3.3 ng/mL for the 10, 25 and 50 mg THC doses, respectively. The mean maximum concentration (Cmax) and mean time to maximum concentration (Tmax) of 11-OH-THC in whole blood were similar to THC. Cmax blood concentrations of THCCOOH were generally higher than THC and had longer Tmax values. The mean Tmax for THC in oral fluid occurred immediately following oral dose administration, and appear to reflect local topical residue rather than systemic bioavailbility. Mean Cmax oral fluid concentrations of THCCOOH were lower than THC, erratic over time and mean Tmax occurred at longer times than THC. The window of THC detection ranged from 0 to 22 h for whole blood (limit of quantitation (LOQ) = 0.5 ng/mL) and 1.9 to 22 h for oral fluid (LOQ = 1.0 ng/mL). Subjective drug and cognitive performance effects were generally dose dependent, peaked at 1.5–3 h post-administration, and lasted 6–8 h. Whole blood cannabinoid concentrations were significantly correlated with subjective drug effects. Correlations between blood cannabinoids and cognitive performance measures, and between oral fluid and all pharmacodynamic outcomes were either non-significant or not orderly by dose. Quantitative levels of cannabinoids in whole blood and oral fluid were low compared with levels observed following inhalation of cannabis. The route of administration is important for interpretation of cannabinoid toxicology. PMID:28158482

Evaluation of fatty acid amides in the carrageenan-induced paw edema model.

PubMed

Wise, Laura E; Cannavacciulo, Roberta; Cravatt, Benjamin F; Martin, Billy F; Lichtman, Aron H

2008-01-01

While it has long been recognized that Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild-type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal anti-edema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this assay.

Even High Doses of Oral Cannabidiol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016;1(1):102–112; DOI: 10.1089/can.2015.0004

PubMed Central

Grotenhermen, Franjo; Russo, Ethan; Zuardi, Antonio Waldo

2017-01-01

Abstract This short communication examines the question whether the experimental data presented in a study by Merrick et al. are of clinical relevance. These authors found that cannabidiol (CBD), a major cannabinoid of the cannabis plant devoid of psychotropic effects and of great interest for therapeutic use in several medical conditions, may be converted in gastric fluid into the psychoactive cannabinoids delta-8-THC and delta-9-THC to a relevant degree. They concluded that “the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a positive physiological response.” They issued a warning concerning oral use of CBD and recommend the development of other delivery methods. However, the available clinical data do not support this conclusion and recommendation, since even high doses of oral CBD do not cause psychological, psychomotor, cognitive, or physical effects that are characteristic for THC or cannabis rich in THC. On the contrary, in the past decades and by several groups, high doses of oral CBD were consistently shown to cause opposite effects to those of THC in clinical studies. In addition, administration of CBD did not result in detectable THC blood concentrations. Thus, there is no reason to avoid oral use of CBD, which has been demonstrated to be a safe means of administration of CBD, even at very high doses. PMID:28861499

Chronic THC during adolescence increases the vulnerability to stress-induced relapse to heroin seeking in adult rats.

PubMed

Stopponi, Serena; Soverchia, Laura; Ubaldi, Massimo; Cippitelli, Andrea; Serpelloni, Giovanni; Ciccocioppo, Roberto

2014-07-01

Cannabis derivatives are among the most widely used illicit substances among young people. The addictive potential of delta-9-tetrahydrocannabinol (THC), the major active ingredient of cannabis is well documented in scientific literature. However, the consequence of THC exposure during adolescence on occurrence of addiction for other drugs of abuse later in life is still controversial. To explore this aspect of THC pharmacology, in the present study, we treated adolescent rats from postnatal day (PND) 35 to PND-46 with increasing daily doses of THC (2.5-10mg/kg). One week after intoxication, the rats were tested for anxiety-like behavior in the elevated plus maze (EPM) test. One month later (starting from PND 75), rats were trained to operantly self-administer heroin intravenously. Finally, following extinction phase, reinstatement of lever pressing elicited by the pharmacological stressor, yohimbine (1.25mg/kg) was evaluated. Data revealed that in comparison to controls, animals treated with chronic THC during adolescence showed a higher level of anxiety-like behavior. When tested for heroin (20μg per infusion) self-administration, no significant differences were observed in both the acquisition of operant responding and heroin intake at baseline. Noteworthy, following the extinction phase, administration of yohimbine elicited a significantly higher level of heroin seeking in rats previously exposed to THC. Altogether these findings demonstrate that chronic exposure to THC during adolescence is responsible for heightened anxiety and increased vulnerability to drug relapse in adulthood. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

The relationship between observed signs of impairment and THC concentration in oral fluid.

PubMed

Fierro, Inmaculada; González-Luque, Juan Carlos; Alvarez, F Javier

2014-11-01

Studies have shown that cannabis intake increases the risk of traffic accidents. Controlled experiments support these findings and have shown a positive dose-effect relationship. In this retrospective cross-sectional study of data from a roadside survey, we investigated whether a police officer's judgment regarding signs of impairment is related to the concentration of delta-9-tetrahydrocannabinol (THC) in the oral fluid (OF). We investigated 2,632 cases from a representative sample of 3,302 Spanish drivers: 253 drivers positive for THC only, 32 positive for THC and ethanol, 201 with only ethanol detected in their breath, and 2,146 drivers who tested negative for ethanol in breath and drugs in OF. Recorded data comprised breath alcohol concentrations, THC concentrations in the OF, and the 31 observed signs of impairment. Subject groups were compared using the chi-square test, and logistic regression was used to examine the risk of being categorized as exhibiting signs of impairment. A relationship was found between the OF THC concentration and some observed signs of impairment. Eye signs were noticeable from a THC concentration >3.0 ng/ml in OF, and >25 ng/ml was related to behavior, facial expression, and speech signs. Alcohol and THC contribute to impairment independently and, when taken simultaneously, the effects are comparable to the sum of the effects when consumed separately. The observation of signs of impairment due to cannabis occurs in an OF concentration-related manner but, as a clinical test, OF has low sensitivity and specificity in a random roadside survey. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Morphine decreases social interaction of adult male rats, while THC does not affect it.

PubMed

Šlamberová, R; Mikulecká, A; Macúchová, E; Hrebíčková, I; Ševčíková, M; Nohejlová, K; Pometlová, M

2016-12-22

The aim of the present study was to compare effect of three low doses of morphine (MOR) and delta9-tetrahydrocannabinol (THC) on social behavior tested in Social interaction test (SIT). 45 min prior to testing adult male rats received one of the drugs or solvents: MOR (1; 2.5; 5 mg/kg); saline as a solvent for MOR; THC (0.5; 1; 2 mg/kg); ethanol as a solvent for THC. Occurrence and time spent in specific patterns of social interactions (SI) and non-social activities (locomotion and rearing) was video-recorded for 5 min and then analyzed. MOR in doses of 1 and 2.5 mg/kg displayed decreased SI in total. Detailed analysis of specific patterns of SI revealed decrease in mutual sniffing and allo-grooming after all doses of MOR. The highest dose (5 mg/kg) of MOR decreased following and increased genital investigation. Rearing activity was increased by lower doses of MOR (1 and 2.5 mg/kg). THC, in each of the tested doses, did not induce any specific changes when compared to matching control group (ethanol). However, an additional statistical analysis showed differences between all THC groups and their ethanol control group when compared to saline controls. There was lower SI in total, lower mutual sniffing and allo-grooming, but higher rearing in THC and ethanol groups than in saline control group. Thus, changes seen in THC and ethanol groups are seemed to be attributed mainly to the effect of the ethanol. Based on the present results we can assume that opioids affect SI more than cannabinoid.

Simultaneous Quantification of Free and Glucuronidated Cannabinoids in Human Urine by Liquid Chromatography-Tandem Mass Spectrometry

PubMed Central

Scheidweiler, Karl B.; Desrosiers, Nathalie A.; Huestis, Marilyn A.

2012-01-01

Background Cannabis is the most commonly abused drug of abuse and is commonly quantified during urine drug testing. We conducted a controlled drug administration studies investigating efficacy of urinary cannabinoid glucuronide metabolites for documenting recency of cannabis intake and for determining stability of urinary cannabinoids. Methods A liquid chromatography tandem mass spectrometry method was developed and validated quantifying Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol, cannabinol, THC-glucuronide and THCCOOH-glucuronide in 0.5 ml human urine via supported-liquid extraction. Chromatography was performed on an Ultra Biphenyl column with a gradient of 10 mmol/l ammonium acetate, pH 6.15 and 15% methanol in acetonitrile at 0. 4ml/min. Analytes were monitored by positive and negative mode electrospray ionization and multiple reaction monitoring mass spectrometry. Results Linear ranges were 0.5–50 ng/ml for THC-glucuronide, 1–100 ng/ml for THCCOOH, 11-OH-THC and cannabidiol, 2–100 ng/ml for THC and cannabinol, and 5–500 ng/ml for THCCOOH-glucuronide (R2>0.99). Mean extraction efficiencies were 34–73% with analytical recovery (bias) 80.5–118.0% and total imprecision 3.0–10.2% coefficient of variation. Conclusion This method simultaneously quantifies urinary cannabinoids and phase II glucuronide metabolites, and enables evaluation of urinary cannabinoid glucuronides for documenting recency of cannabis intake and cannabinoid stability. The assay is applicable for routine urine cannabinoid testing. PMID:22771478

How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆9-Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to Paranoia

PubMed Central

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.

2015-01-01

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. PMID:25031222

Even High Doses of Oral Cannabidol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016;1(1):102-112; DOI: 10.1089/can.2015.0004.

PubMed

Grotenhermen, Franjo; Russo, Ethan; Zuardi, Antonio Waldo

2017-01-01

This short communication examines the question whether the experimental data presented in a study by Merrick et al. are of clinical relevance. These authors found that cannabidiol (CBD), a major cannabinoid of the cannabis plant devoid of psychotropic effects and of great interest for therapeutic use in several medical conditions, may be converted in gastric fluid into the psychoactive cannabinoids delta-8-THC and delta-9-THC to a relevant degree. They concluded that "the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a positive physiological response." They issued a warning concerning oral use of CBD and recommend the development of other delivery methods. However, the available clinical data do not support this conclusion and recommendation, since even high doses of oral CBD do not cause psychological, psychomotor, cognitive, or physical effects that are characteristic for THC or cannabis rich in THC. On the contrary, in the past decades and by several groups, high doses of oral CBD were consistently shown to cause opposite effects to those of THC in clinical studies. In addition, administration of CBD did not result in detectable THC blood concentrations. Thus, there is no reason to avoid oral use of CBD, which has been demonstrated to be a safe means of administration of CBD, even at very high doses.

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

PubMed

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 Δ 9 -tetrahydrocannabinol (Δ 9 -THC). In Canada, this limit is 10 μg of Δ 9 -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 Δ 9 -THC and cannabidiol (CBD). Discussion: We discovered that Δ 9 -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. Δ 9 -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, Δ 9 -THC concentrations were higher than the legal limit. These quantities of total Δ 9 -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 Δ 9 -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.

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

PubMed

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.

Delta-9-Tetrahydrocannabinol Potentiates Fear Memory Salience Through Functional Modulation of Mesolimbic Dopaminergic Activity States.

PubMed

Fitoussi, Aurelie; Zunder, Jordan; Tan, Huibing; Laviolette, Steven R

2018-05-18

Chronic or acute exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side-effects, including dysregulation of emotional processing and associative memory formation. Clinical and pre-clinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear-related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra-NASh THC dose-dependently potentiates the emotional salience of normally sub-threshold fear-conditioning cues. These effects were dependent upon intra-VTA transmission through GABAergic receptor mechanisms and intra-NASh DAergic transmission. Furthermore, doses of intra-NASh THC that potentiated fear memory salience were found to modulate intra-VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurons whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurons. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Acute effects of THC on time perception in frequent and infrequent cannabis users.

PubMed

Sewell, R Andrew; Schnakenberg, Ashley; Elander, Jacqueline; Radhakrishnan, Rajiv; Williams, Ashley; Skosnik, Patrick D; Pittman, Brian; Ranganathan, Mohini; D'Souza, D Cyril

2013-03-01

Cannabinoids have been shown to alter time perception, but existing literature has several limitations. Few studies have included both time estimation and production tasks, few control for subvocal counting, most had small sample sizes, some did not record subjects' cannabis use, many tested only one dose, and used either oral or inhaled administration of Δ⁹-tetrahydrocannabinol (THC), leading to variable pharmacokinetics, and some used whole-plant cannabis containing cannabinoids other than THC. Our study attempted to address these limitations. This study aims to characterize the acute effects of THC and frequent cannabis use on seconds-range time perception. THC was hypothesized to produce transient, dose-related time overestimation and underproduction. Frequent cannabis smokers were hypothesized to show blunted responses to these alterations. IV THC was administered at doses from 0.015 to 0.05 mg/kg to 44 subjects who participated in several double-blind, randomized, counterbalanced, crossover, placebo-controlled studies. Visual time estimation and production tasks in the seconds range were presented to subjects three times on each test day. All doses induced time overestimation and underproduction. Chronic cannabis use had no effect on baseline time perception. While infrequent/nonsmokers showed temporal overestimation at medium and high doses and temporal underproduction at all doses, frequent cannabis users showed no differences. THC effects on time perception were not dose related. A psychoactive dose of THC increases internal clock speed as indicated by time overestimation and underproduction. This effect is not dose related and is blunted in chronic cannabis smokers who did not otherwise have altered baseline time perception.