Cannabis and Cannabinoid Research最新文献

Introduction: Ultra-endurance exercise events result in central fatigue, impacting on mental alertness and decision making. Endocannabinoids are typically elevated during endurance exercise and have been implicated in central processes such as learning and memory, but their role in central fatigue has never been studied. Materials and Methods: Twenty-four recreational male ultrarunners participated in a 100-km trail run, and 18 of them completed at least 60 km and were included in the analyses. A cognitive test battery to assess median reaction time (MRT) and median movement time during a reaction time task and median response latency during a rapid visual information processing task was completed prior to and immediately after the trail. Blood serum samples pre- and postexercise were analyzed for endocannabinoids and related lipids (anadamide: AEA; 2-arachidonoylglycerol: 2-AG; palmitoylethanolamide: PEA; oleoylethanolamide: OEA; stearoylethanolamine: SEA) via liquid chromatography-mass spectrometry. Results: Ultra-endurance exercise worsened all cognitive parameters and increased abundance of AEA, PEA, OEA, and SEA but not 2-AG. Interestingly, the exercise-induced change in MRT showed moderate, positive correlations with the change in different endocannabinoids, that is, AEA (r = 0.5164, p = 0.0338), PEA (r = 0.5466, p = 0.0251), and OEA (r = 0.5442, p = 0.0239). Conclusion: These results indicate a potential role of endocannabinoids on mental alertness following ultra-endurance exercise.

Aim: Few studies have directly compared the bioavailability of different cannabinoid formulations. Our goal was to assess the pharmacokinetic parameters and relative bioavailability of two Δ9-tetrahydrocannabinol:cannabidiol (THC:CBD) formulations: orally administered THC:CBD extract and oromucosally administered nabiximols. Methods: This pilot crossover study counterbalanced (1) 1 mL of orally administered THC:CBD extract (10 mg/mL each of THC and CBD in grapeseed oil) and (2) oromucosally administered nabiximols (four sprays of 2.7 mg THC and 2.5 mg CBD per spray, for a total dose of 10.8 mg THC and 10 mg CBD). Blood samples were obtained pre-dose and at 16 post-dose timepoints over 24 h. Pharmacokinetic parameters were calculated for THC, 11-hydroxy-tetrahydrocannabinol (11-OH-THC), and CBD. Results: Twelve occasional cannabis users (6 male, 6 female) were tested under fasting conditions. C_max for THC and CBD was significantly higher with significantly shorter half-lives for THC:CBD extract versus nabiximols. C_max for nabiximols was significantly higher in males compared with females. Under both treatment conditions, THC and CBD were undetectable by 24 h post-dose, and 11-OH-THC was markedly reduced from its peak. No serious adverse events were reported. Conclusions: Little is known about the comparative pharmacokinetics of commercially available cannabis products. This pilot study shows that the extract formulation achieved higher THC and CBD concentrations within a shorter time frame than nabiximols. These findings may have implications for clinical populations using these formulations therapeutically. Future studies should examine multiple doses in the context of therapeutic outcomes to characterize the relative clinical utility of these formulations.

Background: The relationship between cannabis and inflammation among persons with HIV (PWH) remains unclear. We examined whether the cannabis metabolite 11-nor-9-carboxy THC (THC-COOH) is associated with lower levels of plasma biomarkers of inflammation, immune activation, and microbial translocation in PWH. We hypothesized that cannabis use would be associated with lower levels of plasma inflammatory biomarkers than noncannabis use. Methods: We quantified THC-COOH in plasma, with THC-COOH levels between 5.1-69.9 μg/L and ≥70 μg/L being classified as moderate and heavy cannabis use, respectively, with noncannabis use defined as undetected THC-COOH. We measured a panel of plasma biomarkers of inflammation (interleukin [IL]-1-β, tumor necrosis factor-alpha, IL-18, IL-6, and C-reactive protein), immune activation (CD14 and CD163), and microbial translocation (iFABP2 and lipopolysaccharide binding protein [LBP]), with all biomarkers collected on the same day. We used a cross-sectional design and linear regression models to test whether cannabis use is associated with lower biomarker levels. Results: Participants were (N=107) sexual minority men with HIV (median age=32 years, IQR=28, 38), of whom 65% were virally suppressed; 36%, 44%, and 20% were classified as nonuse, moderate, and heavy cannabis, respectively. In linear regression models adjusted for viral suppression, stimulant use, and CD4 counts, heavy cannabis use was significantly associated with lower levels of log₁₀ LBP (β=-0.14, 95% confidence interval: -0.24 to -0.04; false discovery rate=0.0029; partial eta squared=0.07) than noncannabis users. No precise associations were observed for other biomarkers (all p>0.05). Conclusions: Our findings suggest that cannabis use may be associated with lower plasma LBP. Further work is needed to clarify the relationship between cannabis use and biomarkers of microbial translocation in PWH.

Introduction: Olivetolic acid (OLA) is a key intermediate in cannabidiol (CBD) synthesis, and cannabinoids are important neuroactive drugs. However, the catalytic activity of olivetolic acid synthase (OLS), the key enzyme involved in OLA biosynthesis, remains low and its catalytic mechanism is unclear. Materials and Methods: In this study, we conducted a scrupulous screening of the pivotal rate-limiting enzyme and analyzed its amino acid sites that are critical to enzyme activity as validated by experiments. Results: Through stringent enzyme screening, we pinpointed a highly active OLS sequence, OLS4. Then, we narrowed down three critical amino acid sites (I258, D198, E196) that significantly influence the OLS activity. Conclusions: Our findings laid the groundwork for the efficient biosynthesis of OLA, and thereby facilitate the biosynthesis of CBD.

Introduction: Animal studies suggest that adolescent exposure to Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the intoxicating constituent of cannabis, causes lasting functional alterations in brain and other organs. Those studies often neglect the impact that age- and sex-dependent differences in the distribution and metabolism of the drug might exert on its pharmacological effects. Here, we provide a comparative analysis of Δ⁹-THC pharmacokinetics in adolescent and adult female mice, which identify significant dissimilarities in distribution and metabolism of Δ⁹-THC between females of these age groups. Materials and Methods: We administered Δ⁹-THC (5 mg/kg, intraperitoneal) to adolescent (37-day old) and young adult (70-day old) female mice and quantified Δ⁹-THC and its first-pass metabolites-11-hydroxy-Δ⁹-THC (11-OH-THC) and 11-nor-9-carboxy-Δ⁹-THC (11-COOH-THC)-in plasma and brain tissue using liquid chromatography/tandem mass spectrometry. Results: Maximal plasma concentrations of Δ⁹-THC were 8 times higher in adolescent than adult female mice. Conversely, brain concentrations and brain-to-plasma ratios were 25-50% higher in adults than adolescents. Concentrations of Δ⁹-THC metabolites were higher in plasma but lower in brain of adolescent compared to adult female mice. Conclusions: The results identify multiple age-dependent differences in the pharmacokinetic properties of Δ⁹-THC in female mice, which might influence the pharmacological response to the drug.

Background: Gender and sex can influence cannabis behaviors and consequences (Cannabis Use Disorder [CUD]). Research typically examines sex and gender independently. Gender analyses often exclude transgender and gender diverse (TGD) populations. The objectives of this study were to (a) replicate less frequent cannabis use among TGD young adults compared to cisgender counterparts (b) compare severity of CUD, and (c) examine the role of sex on cannabis outcomes. Method: Online survey participants between 18 and 34 (N=1213) from the United States who reported past-week cannabis consumption provided information on cannabis practices and CUD from February to April 2022. Bivariate analyses explored gender differences across frequency (daily frequency across routes of administration [ROAs]; daily use of 2+ ROAs, use throughout the day) and CUD. Adjusted regression models provided model-estimated marginal probabilities and means to examine differences across four gender-by-sex categories (cisgender men: n=385; cisgender women: n=681; male-at-birth TGD: n=26; female-at-birth TGD: n=121). Benjamini-Hochberg adjustments (10% false discovery rate) were applied. Results: Among past-week consumers, female-at-birth TGD participants demonstrated lower probability of daily flower smoking compared to cisgender men (0.54 vs. 0.67). Cisgender men reported greater probability of daily concentrate vaping (0.55) compared to cisgender women (0.45) and female-at-birth TGD participants (0.27); they were also more likely to report daily use of 2+ ROAs (cisgender men: 0.51 vs. cisgender women: 0.39 and female at-birth TGD: 0.27). TGD participants reported greater CUD severity compared to cisgender counterparts, t(1096)=-3.69, p=0.002. Model-estimated means found lower severity among cisgender women compared to cisgender men and female-at-birth TGD participants. Stratified regression models support positive associations between daily cannabis use and CUD in both TGD in cisgender groups. Among cisgender participants, greater severity was predicted by male sex, younger age, and younger age of onset. Conclusions: The present study replicates and extends a prior finding that among past-week cannabis consumers, TGD young adults report less frequent use than cisgender counterparts. Despite this, TGD participants demonstrated greater severity of CUD. While analyses were limited by the small sample of male-at-birth TGD participants, the article highlights the importance of expanding sex- and gender-focused analyses. Future work is expanding efforts to target hard-to-reach consumers.

Objectives: To examine perceived risk of harm from weekly cannabis use among reproductive-aged women with disabilities. Methods: Using data from the 2021 National Survey on Drug Use and Health, we assessed perceived risk of harm associated with weekly cannabis use among women of reproductive age by disability status. Disabilities included sensory, cognitive, and those related to daily activities. Logistic regression was employed to examine correlates of risk perception associated with weekly cannabis in this subpopulation of women. Results: A significantly higher percentage of women with any disability perceived no risk associated with weekly cannabis use (37.9%) compared to those with no disabilities (26.1%). Approximately, 60.0% of women with disabilities who used cannabis in the past 12 months perceived no risk of harm from weekly cannabis use. Overall, women with disabilities and cannabis use in the past 12 months had higher adjusted odds (AOR=2.90, 95% CI=2.10-4.10) of perceiving no risk associated with weekly use of cannabis compared to women without any disability and no cannabis use. Other significant factors associated with an increased likelihood of perceiving no risk of harm from weekly use of cannabis included younger women, having higher income, being in good health, and using alcohol or tobacco. Conclusions: Perceived risk of harm associated with weekly cannabis use is particularly low among women with disabilities who use cannabis. Given current attitudes toward cannabis as a harmless drug, and the potential adverse health outcomes, it is imperative to monitor and understand women's perceptions of risk of harm from cannabis use for clinical guidance, provider and patient education, and public health programs to support evidence-based approaches in addressing its use among vulnerable populations such as those of reproductive age with disabilities.

Background: Males and females who consume cannabis can experience different mental health and cognitive problems. Neuroscientific theories of addiction postulate that dependence is underscored by neuroadaptations, but do not account for the contribution of distinct sexes. Further, there is little evidence for sex differences in the neurobiology of cannabis dependence as most neuroimaging studies have been conducted in largely male samples in which cannabis dependence, as opposed to use, is often not ascertained. Methods: We examined subregional hippocampus and amygdala volumetry in a sample of 206 people recruited from the ENIGMA Addiction Working Group. They included 59 people with cannabis dependence (17 females), 49 cannabis users without cannabis dependence (20 females), and 98 controls (33 females). Results: We found no group-by-sex effect on subregional volumetry. The left hippocampal cornu ammonis subfield 1 (CA1) volumes were lower in dependent cannabis users compared with non-dependent cannabis users (p<0.001, d=0.32) and with controls (p=0.022, d=0.18). Further, the left cornu ammonis subfield 3 (CA3) and left dentate gyrus volumes were lower in dependent versus non-dependent cannabis users but not versus controls (p=0.002, d=0.37, and p=0.002, d=0.31, respectively). All models controlled for age, intelligence quotient (IQ), alcohol and tobacco use, and intracranial volume. Amygdala volumetry was not affected by group or group-by-sex, but was smaller in females than males. Conclusions: Our findings suggest that the relationship between cannabis dependence and subregional volumetry was not moderated by sex. Specifically, dependent (rather than non-dependent) cannabis use may be associated with alterations in selected hippocampus subfields high in cannabinoid type 1 (CB1) receptors and implicated in addictive behavior. As these data are cross-sectional, it is plausible that differences predate cannabis dependence onset and contribute to the initiation of cannabis dependence. Longitudinal neuroimaging work is required to examine the time-course of the onset of subregional hippocampal alterations in cannabis dependence, and their progression as cannabis dependence exacerbates or recovers over time.