Cannabinoids and the Microbiota-Gut-Brain Axis: Emerging Effects of Cannabidiol and Potential Applications to Alcohol Use Disorders.

The endocannabinoid system (ECS) has emerged in recent years as a potential treatment target for alcohol use disorders (AUD). In particular, the nonpsychoactive cannabinoid cannabidiol (CBD) has shown preclinical promise in ameliorating numerous clinical symptoms of AUD. There are several proposed mechanism(s) through which cannabinoids (and CBD in particular) may confer beneficial effects in the context of AUD. First, CBD may directly impact specific brain mechanisms underlying AUD to influence alcohol consumption and the clinical features of AUD. Second, CBD may influence AUD symptoms through its actions across the digestive, immune, and central nervous systems, collectively known as the microbiota-gut-brain axis (MGBA). Notably, emerging work suggests that alcohol and cannabinoids exert opposing effects on the MGBA. Alcohol is linked to immune dysfunction (e.g., chronic systemic inflammation in the brain and periphery) as well as disturbances in gut microbial species (microbiota) and increased intestinal permeability. These MGBA disruptions have been associated with AUD symptoms such as craving and impaired cognitive control. Conversely, existing preclinical data suggest that cannabinoids may confer beneficial effects on the gastrointestinal and immune system, such as reducing intestinal permeability, regulating gut bacteria, and reducing inflammation. Thus, cannabinoids may exert AUD harm-reduction effects, at least in part, through their beneficial actions across the MGBA. This review will provide a brief introduction to the ECS and the MGBA, discuss the effects of cannabinoids (particularly CBD) and alcohol in the brain, gut, and immune system (i.e., across the MGBA), and put forth a theoretical framework to inform future research questions.

Investigating the Relationships Between Alcohol Consumption, Cannabis Use, and Circulating Cytokines: A Preliminary Analysis.

BACKGROUND: In recent years, human and animal studies have converged to support altered inflammatory signaling as a molecular mechanism underlying the pathophysiology of alcohol use disorders (AUDs). Alcohol binds to receptors on immune cells, triggering signaling pathways that produce pro-inflammatory cytokines. Chronic inflammation is associated with tissue damage, which may contribute to negative effects of AUD. Conversely, cannabis is associated with decreased inflammatory signaling, and animal studies suggest that cannabinoids may impact alcohol-induced inflammation. Thus, the impact of cannabis on inflammation in AUDs in humans warrants examination. METHODS: We explored the relationship between self-reported alcohol and cannabis use and circulating levels of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-8, and IL-1ß in the blood. Among 66 regular drinkers (mean age = 30.08), we examined circulating cytokines and administered questionnaires assessing alcohol consumption and days of cannabis use over the past 90 days. We examined whether alcohol consumption, cannabis use, and gender were associated with changes in circulating cytokines, and whether there was a significant interaction between alcohol and cannabis use predicting blood levels of circulating cytokines. RESULTS: A positive association between alcohol and IL-6 emerged. We also observed a negative association between cannabis and IL-1ß. Follow-up moderation analyses indicated a cannabis by alcohol interaction predicting circulating IL-6, such that cannabis nonusers showed a stronger relationship between alcohol and IL-6 compared to cannabis users. CONCLUSIONS: These preliminary findings suggest that cannabinoid compounds may serve to mitigate inflammation associated with alcohol use. In addition, the present results provide data to inform future investigations, with the goal of ultimately leveraging knowledge of the role of inflammation in AUDs to develop more effective treatments focused on novel immune targets.

Cannabinoid Exposure and Subjective Effects of THC and CBD in Edible Cannabis Products.

Background: The popularity of edible cannabis products continues to grow in states with legal cannabis access, but few studies have investigated the acute effects of these commercially available products. The present study sought to explore the effects of three commercially available edible products with different levels of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Methods: A sample of regular cannabis users (N=99) were evaluated. Fifty participants completed the study procedures in-person, whereas 49 participants completed the study procedures remotely via Zoom. Subjective effects and plasma cannabinoid levels (in-person participants only) were assessed before and 2 h after participants self-administered one of three products ad libitum: a THC-dominant edible product, a CBD-dominant edible product, or a THC+CBD edible product. Results: At the 2-h post-use assessment, among in-person participants, plasma THC and CBD levels were robustly correlated with self-reported milligrams of THC and CBD consumed, respectively. Across all three conditions, in-person and remote participants experienced (1) an increase in subjective intoxication and elation, (2) a decrease in tension, and (3) no change in paranoia from pre-use to post-use. At post-use, participants who used a CBD product reported less intoxication relative to participants who used a THC+CBD or THC-only product. Participants who used a THC+CBD product reported consuming less THC-and displayed lower plasma THC levels (in-person participants)-relative to participants who used a THC-only product, despite reporting similar levels of positive (intoxication, elation, liking) and psychotomimetic (paranoia, tension) effects. Psychotomimetic effects were very low among both in-person and remote participants across all three conditions, and there were no post-use differences across conditions. Conclusions: Findings suggest that experienced users who consumed a THC+CBD product reported similar levels of positive and psychotomimetic effects relative to those who consumed a THC-only product, despite consuming less THC and displaying lower plasma THC concentrations. Given the potential harms associated with acute cannabis reward and long-term THC exposure, further research is needed to establish whether edible cannabis products with CBD pose less risk to users. Future studies should examine whether these effects generalize to samples of infrequent users, who may have less experience with edible cannabis use. ClinicalTrials.gov ID: NCT03522103.

Are the Acute Effects of THC Different in Aging Adults?

In recent years of expanding legalization, older adults have reported the largest increase in cannabis use of any age group. While its use has been studied extensively in young adults, little is known about the effects of THC in older adults and whether the risks of cannabis might be different, particularly concerning intoxication and cognition. The current study investigated whether age is associated with the deleterious effects of THC on cognitive performance and other behavioral measures before and after ad libitum self-administration of three different types of cannabis flower (THC dominant, THC + CBD, and CBD dominant). Age groups consisted of young adults (ages 21-25) and older adults (ages 55-70). Controlling for pre-use scores on all measures, the THC dominant chemovar produced a greater deleterious effect in younger adults compared with older adults in tests of learning and processing speed, whereas there were no differences between old and young in the effects of the other chemovars. In addition, the young group reported greater cannabis craving than the older group after using the THC chemovar. Consistent with some reports in the preclinical literature, the findings suggest that older adults may be less sensitive to the effects of THC on cognitive and affective measures.

Investigating Relationships Between Alcohol and Cannabis Use in an Online Survey of Cannabis Users: A Focus on Cannabinoid Content and Cannabis for Medical Purposes.

Cannabis is commonly used among people who drink alcohol, but findings are mixed regarding the direction of this relationship. The type of cannabis used [high-cannabidiol (CBD) vs. high-delta-9tetrahydrocannabinol (THC)] and motives for use (i.e., whether cannabis is used to treat a medical condition) may influence the relationship between cannabis and drinking. Specifically, CBD has shown preclinical promise in reducing alcohol consumption, and medical cannabis users report using cannabis to reduce drinking. This study leverages survey data from cannabis users who drink alcohol (N = 533). Respondents were categorized as using cannabis to treat (CTT) a medical condition or as individuals whose cannabis use is not intended to treat (NCTT) a medical condition and grouped based on the THC/CBD ratio of the flower or edible cannabis they typically use (e.g., "High-THC/CBD," "Medium-THC/CBD" and "Low-THC/CBD"). The CTT group (n = 412) reported drinking significantly less frequently than the NCTT group (n = 121). Cannabinoid content of flower cannabis was associated with alcohol consumed on cannabis-use days, such that individuals in the High-THC/CBD group drink more on cannabis-use days compared to the Medium-THC/CBD group. Cannabinoid content of edible cannabis was associated with drinks per drinking occasion, such that the High-THC/CBD group consumed the most drinks and the Low-THC/CBD group consumed the fewest. For both edible and flower groupings, higher-THC/CBD cannabis was associated with more frequent co-use than lower-THC/CBD cannabis. Results suggest that whether someone uses cannabis to treat a medical condition may impact their drinking frequency, and the cannabinoid content in flower and edible cannabis impacts alcohol consumption.

Exploring cannabis concentrates on the legal market: User profiles, product strength, and health-related outcomes.

BACKGROUND: Concentrated cannabis products are increasingly available and used, particularly in states with legal cannabis, but little is known about the profiles and characteristics of concentrate users. We aimed to characterize user profiles of cannabis users living in states with legal medical or recreational cannabis who reported using concentrates to those who do not use concentrates. METHODS: An anonymous online survey was advertised in California, Colorado, Nevada, Oregon, and Washington. We compared respondents who endorsed frequent concentrate use (FC; N = 67) (i.e. 4 days/week) with cannabis users who never use concentrates (NC; N = 64), and with those who smoke/vaporize cannabis flower frequently but never or very rarely use concentrates (FF; N = 60), on measures related to cannabis use patterns and cannabinoid product strength, other substance use, and occupational functioning and health. RESULTS: FC endorsed more symptoms of cannabis use disorder as compared to non-concentrate users (p < 0.05), but were similar to FF and NC on other health and occupational outcomes. FC also differed from FF and NC in that they tended to use cannabis that was higher in THC (p < 0.0005), even when using non-concentrated forms of cannabis (p < 0.005). Over half of FC users reported typically using concentrates of at least 80% THC, and 21% endorsed use of (non-concentrated) dry cannabis flower containing at least 30% THC. CONCLUSIONS: Concentrate users endorsed higher symptoms of cannabis use disorder and use higher strength cannabis even when using non-concentrated forms. Frequent use of concentrates may be associated with additional risks over and above frequent use of flower forms.