Influence of Cannabinoid Receptor 1 Genetic Variants on the Subjective Effects of Smoked Cannabis.
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ABSTRACT:
SUBMITTER: Murphy T
PROVIDER: S-EPMC8307475 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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/?g, 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.
| S-EPMC3758774 | biostudies-literature
Project description: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% ?(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.
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Project description:Genetic influences on acute responses to psychoactive drugs may contribute to individual variability in addiction risk. ABCB1 is a human gene that encodes P-glycoprotein, an ATP-dependent efflux pump that may influence the pharmacokinetics of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. Using data from 48 young adults (aged 19-25 years) reporting 1-4 days of cannabis use per week who completed a placebo-controlled human laboratory experiment, we tested the hypothesis that the rs2235048 polymorphism of ABCB1 would influence acute responses to smoked cannabis. C-allele carriers reported on average greater frequency of weekly cannabis use compared to the TT genotype carriers (TC/CC mean ± SEM = 2.74 ± 0.14, TT = 1.85 ± 0.24, p = 0.004). After smoking a single cannabis cigarette to their desired high, C-allele carriers had higher area-under-the-curve (AUC) of both THC metabolites (11-OH-THC TC/CC = 7.18 ± 9.64, TT = 3.28 ± 3.40, p = 0.05; THC-COOH TC/CC = 95.21 ± 116.12, TT = 45.92 ± 42.38, p = 0.043), and these results were impact by self-reported ethnicity. There were no significant differences in self-reported subjective drug effects except for a greater AUC of visual analogue scale rating of drug liking (TC/CC = 35,398.33 ± 37,233.72, TT = 15,895.56 ± 13,200.68, p = 0.017). Our preliminary findings suggest that further work in a larger sample should investigate whether human ABCB1 influences cannabis-related phenotypes and plays a role in the risk of developing a cannabis use disorder.
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Project description:BackgroundDespite the high prevalence of polysubstance use, outcomes and potential risks associated with common drug combinations are not well characterized. Many individuals who use cocaine also use cannabis, yet little is known about how interactions between the two drugs might contribute to continued co-use.MethodsThe aim of this double-blind, placebo-controlled study was to determine the physiological and subjective effects of smoked cannabis with smoked cocaine, to identify variables that may contribute to the continued use of this drug combination. Healthy, non-treatment seeking volunteers who reported smoking both cocaine and cannabis (N = 9, all males) completed a 13-day inpatient protocol. On session days, cannabis [0.0 or 5.6 % tetrahydrocannabinol (THC)] was administered 28 min prior to cocaine (0, 12, or 25 mg). Dependent measures included pharmacokinetic assessment of THC and cocaine and their respective metabolites, in addition to subjective and cardiovascular effects.ResultsActive cannabis (5.6 % THC) increased plasma levels of THC and the metabolite 11-nor-9-carboxy-Δ9-THC (THCCOOH), as well as subjective ratings of cannabis effects and heart rate relative to inactive cannabis. Cocaine dose-dependently increased plasma cocaine and metabolites and subjective ratings of cocaine effects. Active cannabis pre-treatment decreased plasma levels of cocaine and metabolites. Furthermore, active cannabis attenuated cocaine-related reductions in 'Hunger' and 'Calm.'ConclusionsCannabis pre-treatment altered the subjective experience of smoked cocaine and reduced peak plasma levels of cocaine. Future studies should explore additional doses of each drug and whether these changes also impact cocaine's reinforcing effects.
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Project description:Smoking cannabis daily doubles an individual's risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual's acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis-which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content-and also ± 7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.
| S-EPMC4872423 | biostudies-literature
Project description:?9-Tetrahydrocannabinol (THC), the primary psychoactive constituent in cannabis, impairs psychomotor performance, cognition and driving ability; thus, driving under the influence of cannabis is a public safety concern. We documented cannabis' psychomotor, neurocognitive, subjective and physiological effects in occasional and frequent smokers to investigate potential differences between these smokers. Fourteen frequent (?4x/week) and 11 occasional (<2x/week) cannabis smokers entered a secure research unit ?19 h prior to smoking one 6.8% THC cigarette. Cognitive and psychomotor performance was evaluated with the critical tracking (CTT), divided attention (DAT), n-back (working memory) and Balloon Analog Risk (BART) (risk-taking) tasks at -1.75, 1.5, 3.5, 5.5 and 22.5 h after starting smoking. GLM (General Linear Model) repeated measures ANOVA was utilized to compare scores. Occasional smokers had significantly more difficulty compensating for CTT tracking error compared with frequent smokers 1.5 h after smoking. Divided attention performance declined significantly especially in occasional smokers, with session × group effects for tracking error, hits, false alarms and reaction time. Cannabis smoking did not elicit session × group effects on the n-back or BART. Controlled cannabis smoking impaired psychomotor function, more so in occasional smokers, suggesting some tolerance to psychomotor impairment in frequent users. These data have implications for cannabis-associated impairment in driving under the influence of cannabis cases.
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Project description:ImportanceVaporization is an increasingly popular method for cannabis administration, and policy changes have increased adult access to cannabis drastically. Controlled examinations of cannabis vaporization among adults with infrequent current cannabis use patterns (>30 days since last use) are needed.ObjectiveTo evaluate the acute dose effects of smoked and vaporized cannabis using controlled administration methods.Design, setting, and participantsThis within-participant, double-blind, crossover study was conducted from June 2016 to January 2017 at the Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine, and included 17 healthy adults. Six smoked and vaporized outpatient experimental sessions (1-week washout between sessions) were completed in clusters (order counterbalanced across participants); dose order was randomized within each cluster.InterventionsCannabis containing Δ9-tetrahydrocannabinol (THC) doses of 0 mg, 10 mg, and 25 mg was vaporized and smoked by each participant.Main outcomes and measuresChange from baseline scores for subjective drug effects, cognitive and psychomotor performance, vital signs, and blood THC concentration.ResultsThe sample included 17 healthy adults (mean [SD] age, 27.3 [5.7] years; 9 men and 8 women) with no cannabis use in the prior month (mean [SD] days since last cannabis use, 398 [437] days). Inhalation of cannabis containing 10 mg of THC produced discriminative drug effects (mean [SD] ratings on a 100-point visual analog scale, smoked: 46 [26]; vaporized: 69 [26]) and modest impairment of cognitive functioning. The 25-mg dose produced significant drug effects (mean [SD] ratings, smoked: 66 [29]; vaporized: 78 [24]), increased incidence of adverse effects, and pronounced impairment of cognitive and psychomotor ability (eg, significant decreased task performance compared with placebo in vaporized conditions). Vaporized cannabis resulted in qualitatively stronger drug effects for most pharmacodynamic outcomes and higher peak concentrations of THC in blood, compared with equal doses of smoked cannabis (25-mg dose: smoked, 10.2 ng/mL; vaporized, 14.4 ng/mL). Blood THC concentrations and heart rate peaked within 30 minutes after cannabis administration and returned to baseline within 3 to 4 hours. Several subjective drug effects and observed cognitive and psychomotor impairments persisted for up to 6 hours on average.Conclusions and relevanceVaporized and smoked cannabis produced dose-orderly drug effects, which were stronger when vaporized. These data can inform regulatory and clinical decisions surrounding the use of cannabis among adults with little or no prior cannabis exposure.Trial registrationClinicalTrials.gov Identifier: NCT03676166.
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Project description:IntroductionDespite decreasing consumption by general populations, use of synthetic cannabinoid receptor agonists (SCRAs) persists in some marginalised groups, including those who use other substances. This article explores SCRA consumption in an Australian cannabis treatment sample, comparing those who report ever using SCRAs with those who have never used SCRAs.MethodsA questionnaire orally administered in person to a convenience sample of 154 cannabis treatment service clients from New South Wales, Australia (71% male, median age 35) collected information regarding cannabis and SCRA use including motivations, effects and health-related consequences of use, demographics, other substance use and overall health. Demographic profiles and between-group differences were explored. McNemar tests compared effects of SCRA and cannabis. Logistic regression analysis determined predictors of SCRA use.ResultsHalf (53%) reported lifetime SCRA use; 20% reported previous-month use. The SCRA + cannabis group displayed greater polysubstance use and psychological distress. Reduced dependence on cannabis but higher levels of other substance use may predict SCRA use. Although curiosity motivated initial SCRA consumption, perceived psychoactive strength drove continued use. SCRAs appear to induce more negative side-effects than cannabis. Of the SCRA + cannabis group, 27% sought medical assistance for SCRA use. Most (90%) preferred cannabis to SCRAs, citing superior safety, effects and consistency of cannabis.ConclusionsAmong clients seeking treatment for cannabis use, SCRA use was relatively common, although not a preferred substance. Hazardous substance use and poor mental health characterised SCRA consumers, highlighting the need for continued monitoring by researchers and treatment providers of SCRA consumption in populations who use substances.
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Project description:Background: Because delta-9-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, binds to cannabinoid 1 (CB1) receptors, levels of CB1 protein could serve as a potential biomarker for response to THC. To date, available techniques to characterize CB1 expression and function in vivo are limited. In this study, we developed an assay to quantify CB1 in lymphocytes to determine how it relates to cannabis use in 58 daily cannabis users compared with 47 nonusers. Furthermore, we tested whether CB1 levels are associated with mutations in a single nucleotide polymorphism known to regulate CB1 functioning (i.e., rs2023239). Methods: Total protein concentration was analyzed through the Pierce BCA Protein assay kit. CB1 protein was quantified through CNR1 enzyme-linked immunosorbent assay (ELISA) kit from MyBioSource. CB1 concentration and total protein concentration were quantified and used to calculate a ratio of CB1 to total protein. Results: Inherent levels of peripheral lymphocyte CB1 were sufficient for quantification through ELISA without protein amplification. We found a group×genotype interaction such that users with the G allele had greater CB1 concentration than users with the A/A genotype, and a trend-level difference between genotypes in nonusers. Conclusions: This study demonstrates a minimally invasive technique of CB1 quantification that holds promise for the use of CB1 protein concentration, along with rs2023239 genotype, as a potential biomarker for susceptibility to cannabis use. These results suggest a gene (rs2023239 G)×environment (cannabis use) effect on CB1 density.
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Project description:Cannabis use has not been well characterized in athletes. Studies primarily examine problematic use or its categorization by anti-doping bodies as a banned substance. Patterns of use, reasons for use, and responses to cannabis consumption have not been studied in a community-based sample of adult athletes. The Athlete PEACE Survey examined cannabis use patterns and subjective effects to cannabis in a community-based cohort of adult athletes. We used mainly social media and email blasts to recruit and SurveyGizmo to collect data. 1,161 (91.1%) of the 1,274 athletes taking the survey completed it. Current cannabis use was evaluated by asking "In the past two weeks, have you used marijuana (including THC and/or CBD)?" and cannabis type used was assessed by asking "What do you primarily use THC, CBD, or both?". Cannabis benefits and adverse effects (i.e. subjective effects) and patterns of use were reported. 302 athletes (26%) currently use cannabis of whom 301 had complete data for cluster analysis. Cluster analysis was used to determine cannabis user phenotypes and exploratory factor analysis (EFA) was used to create subjective effects factors. Associations between cannabis user phenotype clusters and the subjective effects factors were explored using multivariate analysis. Cluster analysis identified three statistically distinct cannabis user phenotypes: (1) older athletes who primarily use medical CBD, (2) mixed age athletes who use cannabis mainly recreationally with both THC and CBD use, and (3) mixed age athletes who used cannabis the longest with primary THC and CBD use. EFA showed three subjective effects factors: (1) Well-being, (2) Calm, and (3) Adverse. Mean positive subjective were higher than mean adverse subjective effects (p<0.001). The cluster using THC and CBD showed the highest mean scores for all three subjective effects factors (p<0.001). Athletes who use a combination of THC and CBD exhibited the most benefit to well-being and calm with minimal adverse effects. Our methodology can be used to develop real-world evidence to inform future use of medical cannabis products.
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