Cannabis and Cannabinoid Research最新文献

The legalization of cannabis in several states across the United States has increased the need to better understand its effects on the body, brain, and behavior, particularly in different populations. Previous rodent studies have revealed age and sex differences in response to injected Δ⁹-tetrahydrocannabinol (THC). However, the pharmacokinetic and pharmacodynamic properties of THC administered through more translationally relevant routes of administration are less well known. Here, we addressed this gap by investigating age and sex differences in pharmacokinetics and the acute behavioral effects of vaporized cannabis e-liquid in mice. Adolescent (postnatal day [P] 35-50) and adult (≥P70) mice of both sexes received noncontingent exposure to vehicle vapor, 150 mg/mL (CAN150), or 300 mg/mL (CAN300) vaporized cannabis extract diluted in either 80% propylene glycol/20% vegetable glycerin (PG/VG) or 100% polyethylene glycol 400 (PEG). Immediately after exposure, body temperature, hot plate withdrawal latency, and locomotion were assessed. Blood was collected at 0, 30, and 60 min after vapor exposure, and plasma THC, 11-hydroxy-THC, and 11-nor-9-carboxy-THC were analyzed. THC concentrations were higher in both the plasma of vapor-exposed mice and the cannabis extract solutions when PEG was the carrier oil compared with PG/VG. Vaporized cannabis (mixed with PEG) at the highest dose tested induced hypothermic, antinociceptive, and locomotor-suppressing effects in all groups of mice. We found a dose-dependent age difference in locomotion, indicating that adolescents were less sensitive to the locomotor-suppressing effects of vaporized cannabis, which may be related to differences in circulating THC levels. Although we found no sex differences in the acute behavioral effects of vaporized cannabis, there were sex differences in plasma THC metabolites, suggesting that female mice may metabolize vaporized cannabis more slowly than male mice. Taken together, these findings add to a growing literature implementing vaporized cannabinoid delivery approaches by revealing PEG as a more effective carrier oil than PG/VG for studies involving cannabis extract.

Introduction: Hemp-derived semi-synthetic cannabinoids are marketed as legal alternatives to cannabis containing ≥0.3% Δ⁹-tetrahydrocannabinol (THC) but remain unregulated at the federal and state levels. Their growing availability underscores the urgent need to investigate patterns of use and associated health risks. Methods: Data were collected via an online survey on self-reported patterns and associations of semi-synthetic cannabinoid use, as well as related factors and effects, from a sample of U.S. adults (≥18 years old) who reported past-year cannabis use. Results: In the sample (N = 229; 55.5% male, 63.8% White, 80.3% not Hispanic/Latino), nearly half (44.5%) reported using at least one semi-synthetic cannabinoid in the past year. Patterns of use varied by cannabinoid: Δ⁷-THC (10.0%), Δ⁸-THC (21.8%), Δ¹⁰-THC (14.0%), THC-O-acetate (5.2%), THC homologue tetrahydrocannabiphorol (24.4%), and hydrogenated derivative hexahydrocannabinol (3.5%). Older individuals had lower odds of reporting past-year semi-synthetic cannabinoid use (adjusted odds ratio [aOR] = 0.96, 95% confidence interval [CI] = 0.94, 0.99, p = 0.004); factors associated with higher odds of reporting semi-synthetic cannabinoid use included reporting 101-1,000 lifetime cannabis uses (vs. <100 times; aOR = 2.55, 95% CI = 1.02, 6.38, p = 0.046), reporting 1,001-10,000 lifetime cannabis uses (vs. <100 times; aOR = 4.40, 95% CI = 1.57, 12.33, p = 0.005), and reporting non-inhaled forms of cannabis as the most frequent route of administration in the past year (vs. smoking; aOR = 2.98, 95% CI = 1.18, 7.53, p = 0.021). Adverse effects were reported across all semi-synthetic cannabinoids. Discussion: Semi-synthetic cannabinoid use was prevalent among this sample, especially among younger individuals. Despite their popularity, adverse effects underscore the need for regulation and research to address these products' safety and public health implications.

Background: HYPER-H21-4 trial, a randomized, placebo-controlled, crossover trial, showed that chronic cannabidiol (CBD) supplementation reduces blood pressure (BP) in patients with primary hypertension. Given the association between the endocannabinoid (EC) system and hypertension, we aimed to determine whether changes in circulating ECs, signaling molecules of the EC system, could explain CBD-mediated cardiovascular effects. Methods: For this purpose, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured in 66 patients with hypertension. Patients were assigned to receive CBD for 5 weeks (225-300 mg/day for the first 2.5 weeks, increasing to 375-450 mg/day for the subsequent 2.5 weeks), followed by 5 weeks of placebo, or 5 weeks of placebo followed by 5 weeks of CBD. Results: Administration of the CBD formulation for 5 weeks resulted in a significant increase in plasma AEA levels, whereas no such increase was observed during the placebo period (Placebo: 37.0 ± 18.0 ng/mL vs. 38.9 ± 20.8 ng/mL, CBD: 36.7 ± 18.0 ng/mL vs. 47.9 ± 24.6 ng/mL, F = 3.592, p = 0.042; Δ_CBDAEA 11.1 ± 3.7 ng/mL, p = 0.025). Change in AEA levels following CBD administration (Δ_CBDAEA) did not correlate with change in systolic BP following CBD administration (Δ_CBDSBP) (r = -0.106, p = 0.428). Multivariate analysis showed that body mass index, current antihypertensive treatment, and fasting plasma glucose at baseline emerged as significant predictors of AEA increase, while BP reduction did not demonstrate a significant association. No significant association was found between chronic CBD administration and 2-AG plasma concentrations (placebo: 28.8 ± 4.3 ng/mL vs. 38.9 ± 20.8 ng/mL; CBD: 36.7 ± 18.0 ng/mL vs. 47.9 ± 24.6 ng/mL; F = 0.513, p = 0.478). Conclusions: Collectively, these findings suggest that although chronic CBD administration appears to increase AEA, but not 2-AG plasma levels, this study provides no conclusive evidence that such alterations explain CBD-mediated BP reduction.

Introduction: Prenatal alcohol exposure (PAE) is a leading cause of birth defects and developmental impairments, resulting in a spectrum of disorders ranging from mild to severe, which are termed fetal alcohol spectrum disorders (FASD). Globally, there is a high prevalence of FASD, and currently, there is no known available cure. PAE most severely impacts the developing brain, causing long-term structural and functional impairments. Cerebral blood circulation plays a critical role in neuronal and overall brain development. Previous studies have shown that PAE leads to a decrease in fetal brain blood flow velocity via fetal cerebral artery dilation, but the specific targets underlying this effect remain largely unknown. Methods and Results: A previous study indicated that a mixture of cannabinoid blockers ablated alcohol-induced vasodilation, but the exact mechanism(s) involved have not been fully elucidated. Here, we investigated the concentration-dependent effects of alcohol on fetal cerebral arteries (anterior, middle, posterior, and basilar) in baboons (Papio sp.) using toxicologically relevant alcohol concentrations. We observed effects best described by polynomial fittings in both male and female fetuses, with low alcohol concentrations (5-30 mM) causing vasodilation. However, the alcohol concentrations that caused maximal dilation varied among cerebral arteries. Quantitative PCR analysis confirmed the presence of cannabinoid receptor 1 (CB1 receptor) but not cannabinoid receptor 2 (CB2 receptor) transcripts in fetal cerebral arteries. Probing of ex vivo pressurized cerebral arteries with a selective CB1 receptor antagonist (AM251) before alcohol exposure at the maximal vasodilating concentration resulted in decreased alcohol effect in the basilar arteries of female fetuses and in the middle cerebral arteries of male fetuses. In addition, liquid chromatography-mass spectrometry revealed no significant changes in endocannabinoid levels (anandamide and 2-arachydoniylglycerol). Our findings suggest that alcohol may activate CB1 receptors independently of endocannabinoid production to trigger vasodilation. Conclusions: In summary, alcohol induces fetal cerebral artery dilation via the CB1 receptor, with regional and sex-specific differences. Our work provides new insights into the role of the fetal cerebrovascular CB1 receptor in the effect of PAE on cerebral circulation.

Introduction: Epidemiological data indicate that regular users of cannabis products may be protected from type 2 diabetes, although the mechanism is not understood. Observations from animal studies suggest that the cannabinoid, cannabidiol (CBD) may protect/improve glucose tolerance; an effect that may be partially mediated by favorable modifications to the gut microbiome. The aims of the current pilot project were to gain initial insight into the influence of short-term CBD ingestion on oral glucose tolerance, the gut microbiome, and inflammation in sedentary adults with overweight or obesity and free from diabetes. Materials and Methods: Using a randomized, double-blind, repeated measures, parallel design, oral glucose tolerance was determined in 16 adults (6 males, 10 females) prior to and following 4 weeks of daily ingestion of either placebo or CBD (30 mg every 12 h). Fecal samples were collected at baseline and post-intervention. Results: Compared with placebo, CBD did not influence glucose tolerance (Matsuda Index: placebo-pre 7.6 [5.5], placebo-post 10.1 [5.5], vs. CBD-pre 11.7 [7.9], and hCBD-post 10.1 [10.2]; median [interquartile range]; p > 0.05). Characteristics of the gut microbiome or inflammation were not appreciably modified by CBD or placebo. Discussion: Short-term daily ingestion of low-dose CBD did not appear to favorably modify glucose tolerance in sedentary adults with overweight or obesity. It is possible that CBD may not account for the previously reported protection from type 2 diabetes bestowed to regular users of cannabis products.

Introduction: The endocannabinoid system regulates numerous physiological functions, including the stress response, and is frequently implicated in stress-related disorders. Understanding how this system is altered during stress is therefore critical for both diagnostic and therapeutic applications. The primary ligands of the endocannabinoid system, N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG), are measurable in circulation and are commonly used to assess endocannabinoid function under various conditions in humans. More recently, endocannabinoids have also been detected in saliva; however, the physiological relevance of their salivary responses remains poorly understood. The present study, therefore, aims to compare stress-induced changes in endocannabinoid and related molecule levels in saliva and plasma, with the goal of advancing understanding of stress-related alterations in salivary endocannabinoids. Methods: The Maastricht Acute Stress Test was used to induce acute stress in 59 participants, with plasma and saliva samples collected at baseline, immediately after stress, and 25-min post-stress. Stress-induced changes in AEA, 2-AG, N-palmitoylethanolamine, N-oleoylethanolamine, arachidonic acid, cortisol, cortisone, and dehydroepiandrosterone sulfate (DHEA-S) were measured using liquid chromatography-tandem mass spectrometry. Norepinephrine was also analyzed in plasma using an enzyme-linked immunosorbent assay. Changes over time and associations among these analytes in response to stress were then examined. Results: Salivary endocannabinoid concentrations were independently stress-responsive of those in plasma, suggesting they reflect distinct physiological functions. Although changes in salivary endocannabinoid concentrations were not associated with changes in plasma norepinephrine, post-stress changes in salivary 2-AG correlated with changes in DHEA-S and subjective stress ratings. Conclusions: The findings from this study provide new evidence that salivary endocannabinoids offer a novel approach to examining the endocannabinoid system during the stress response and may reflect its crosstalk with other physiological systems.

Introduction: In epidemiological studies, people who use cannabis have a lower prevalence of obesity. Furthermore, the endocannabinoid system is recognized as a potential target for obesity treatment and partial agonism of the cannabinoid type-1 (CB₁) receptor may reduce body weight. We thus hypothesized that 12 weeks of pharmacotherapy with the partial CB₁ receptor agonist nabilone would reduce body weight, relative to placebo, in adults with obesity. Methods: We conducted a randomized, double-blind, placebo-controlled pilot clinical trial that investigated the feasibility, tolerability, and efficacy of 12 weeks of treatment with nabilone compared with placebo in adults with obesity. Otherwise healthy adults aged 25-45 years with obesity were randomized in a 1:1:1 ratio to one of three parallel treatment arms: high-dose nabilone (6 mg/day), low-dose nabilone (2 mg/day), or placebo. Safety and feasibility outcomes included adverse events (AEs), number of dropouts, and medication adherence per treatment arm. Efficacy outcomes included body weight, body mass index (BMI), and waist circumference. Secondary outcomes included gut microbiome changes, blood biomarkers (e.g., glucose and insulin levels), and mood. Results: Overall, 18 participants were randomized and 15 participants received at least one dose of drug (4 high-dose arm, 5 low-dose arm, 6 placebo). The trial was terminated early due to poor tolerability of the medication (e.g., all four participants allocated to high-dose nabilone withdrew due to AEs). Only eight participants completed per protocol (four in the low-dose arm and four in the placebo arm). Using data from completers only (n = 8), we saw a significant treatment effect on body weight (p < 0.001) and BMI (p < 0.001) that appeared to be driven by greater decreases in the low-dose arm (n = 4) relative to placebo (n = 4). Based on the Bray-Curtis dissimilarity, the low-dose arm showed a greater change in the overall fecal microbiome composition compared with the placebo arm (p < 0.05). Discussion: This pilot trial found poor tolerability of nabilone pharmacotherapy (especially at 6 mg/day) for adults with obesity who had not used any cannabinoid drugs for 6 months prior to enrolment. Preliminary results suggest a possible impact of nabilone on the gut microbiome.

Introduction: Taxane-induced peripheral neuropathy (TIPN) is experienced by most patients with breast cancer, and there is no efficacious treatment. In pre-clinical studies, co-administration of two constituents of cannabis, Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduces TIPN. Materials and Methods: The goal of this 8-week, double-blind, randomized pilot study, conducted from 2019 to 2021, was to test the feasibility and tolerability of oral cannabis (100 mg CBD: 5 mg THC, TID) relative to placebo on pain resulting from TIPN. Participants with painful TIPN completed daily questionnaires online about their pain, sleep, and medication use, and weekly questionnaires on neuropathy. Results: All participants (12 women; 51 ± 6 years) randomized to placebo (n = 6) or active (n = 6) cannabis capsules completed the trial. Participants in both medication groups requested dose reductions (mean ± SEM capsules/day: placebo: 2.4 ± 0.4; active: 2.0 ± 0.4). In a preliminary evaluation of efficacy, measures of pain, pain interference, sleep, and functional well-being significantly improved over time (p < 0.03), but participants receiving cannabis had significantly higher ratings of neuropathy at each week (p < 0.035) and lower ratings of functional well-being in the last 3 weeks of treatment compared with participants receiving placebo (p < 0.02). Similarly, cannabis significantly worsened ratings of sleep and pain interference relative to placebo (p < 0.05). Discussion: This study demonstrates that: (1) double-blind, placebo-controlled testing of cannabis capsules in this dose range is feasible and well tolerated in women with TIPN and (2) ratings of pain, neuropathy, and well-being significantly improved over 8 weeks, but cannabis significantly worsened several endpoints relative to placebo. These findings highlight the necessity of placebo control when assessing the therapeutic utility of cannabis. Although there was no signal of efficacy herein, a fully powered study testing a range of cannabis doses for TIPN is warranted, given its impact on most patients with breast cancer, promising pre-clinical data, and the widespread use of cannabis among patients with cancer.