Cannabis and Cannabinoid Research最新文献

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.

Background: Human studies indicate a relationship between delta-9-tetrahydrocannabinol (THC) and alcohol use, yet research on their codependency remains limited. Rodent models have shown that cannabinoids can enhance the incentive salience and hedonic value of sucrose and alcohol. However, results seem to vary by the functions of THC dose and route of administration. Materials and Methods: The present study addresses these discrepancies by using a translational model of THC consumption, using lower oral doses of synthetic THC (Dronabinol). Male Long-Evans (n = 24) rats consumed a vehicle or THC-containing cookie (0.05 mg/kg or 0.5 mg/kg) before testing the palatability of rewarding and aversive substances in the taste reactivity paradigm. Results: Separate, linear, mixed-effect models revealed that THC dose-dependently increased hedonic reactions to both sucrose (0.1 M and 0.5 M) and alcohol (10% and 40% ETOH) compared with control. Comparatively, THC reduced aversion to alcohol (10% and 40%) and quinine compared with vehicle. Western blot data analyzed via one-way Analysis of Variance (ANOVA) followed by Tukey's post hoc analysis revealed that repeated oral THC consumption dose-dependently downregulated cannabinoid receptor 1 receptor expression in the dorsal hippocampus, while no significant changes were observed in the nucleus accumbens or amygdala.  Conclusions: These findings suggest that oral THC enhances the hedonic value of rewarding and aversive substances and provide insights into the neurobiological mechanisms that may contribute to the bidirectional use of cannabis and alcohol.

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.

Background: Cannabis consumption among adults, including pregnant and breastfeeding women, continues to rise. However, the long-term effects of early-life exposure to cannabinoids on brain development remain unclear. Δ9-tetrahydrocannabinol (THC) is the main psychoactive cannabinoid in cannabis and is an agonist of cannabinoid type 1 receptor, a critical component of the endocannabinoid system (ECS) that functions in normal pre- and postnatal brain development. We hypothesized that perinatal exposure to THC perturbs ECS-regulated neurodevelopment and leads to lasting cognitive effects in later life. Materials and Methods: Male and female Sprague Dawley rat pups received a single intraperitoneal injection of THC (5 mg/kg) or vehicle (sesame oil) at postnatal day 3. At postnatal weeks 6-8, animals were assessed for spatial memory and anxiety-like behavior using the Barnes maze, open field, and elevated plus maze. Following behavioral testing, brains were processed using Golgi-Cox staining to examine dendritic morphology and spine density in the frontal cortex and hippocampus. Results: THC exposure during the neonatal period induced a spatial memory deficit later in young adult female, but not male, rats. Anxiety-like behavior was not altered in either sex. THC-exposed animals of both sexes exhibited decreased spine density reductions, as well as decreases in dendritic length, branching, and complexity in cortical and hippocampal (cornu ammonis 1 [CA1], CA3, dentate gyrus) neurons. Conclusion: These findings demonstrate that a single neonatal THC exposure induces long-lasting, sex-dependent cognitive impairment and structural alterations in cortical and hippocampal neurons in rats. Our results underscore the vulnerability of the developing brain to cannabinoid exposure.

Introduction: The prevalence of prenatal cannabis use has nearly doubled in the United States. Cannabinoid 2 receptors are predominately expressed in cells of the human immune system, and delta-9 tetrahydrocannabinol (THC), the primary active component of cannabis, has been shown to suppress immune responses. Despite these findings, there is very little evidence on the impact of cannabis use on maternal immune system. Here, we evaluate the association between urine-verified cannabis use and the levels of T helper cytokines in the maternal circulation. Methods: This was an ancillary study of a prospective cohort of pregnant women who participated in the Michigan Archive for Research on Child Health study. Pregnant women (age ≥18 years) were recruited from 22 prenatal clinics in Michigan and matched on age, race, and tobacco smoking (n = 144). The urinary metabolite of delta-9 THC, 11-nor-9-carboxy-delta-9-THC (THC-COOH), was used to define cannabis use status. A bead-based assay was used for the simultaneous detection of maternal cytokines associated with cannabis use and pregnancy outcomes in previous studies. Results: Repeated-measures linear mixed models indicated that urine-verified cannabis use was associated with the suppression of maternal pro-inflammatory cytokines including interferon gamma (β = -0.5; 95% confidence interval [CI] = -0.8, -0.1) and interleukin (IL)-12 (β = -0.3; 95% CI = -0.6, -0.05), as well as the anti-inflammatory IL-4 (β = -0.7; 95% CI = -1.3, -0.2) and IL-10 (β = -0.4; 95% CI = -0.7, -0.03). Similar results were observed when heavy cannabis use was defined using the top tertile of urinary THC-COOH at each trimester. Conclusions: Urine-verified cannabis use was associated with the suppression of pro- and anti-inflammatory T helper cytokines in a cohort of pregnant women, suggesting that cannabis use can lead to modest dysregulation of the maternal immune system. Additional studies are needed to investigate the role of maternal immune responses in explaining birth outcomes linked to cannabis use.

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.