Exploring the Effects of Cannabinoids on Alcohol Consumption and the Microbiota-Gut-Brain Axis

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Summary Increasingly liberal cannabis policies in the U.S. have been associated with both “replacement”, whereby cannabis is substituted for alcohol, thus decreasing alcohol use, and “enhancement”, whereby cannabis use increases alcohol use. These conflicting patterns may be partially explained by the fact that the potency of delta-9-tetrahydrocannabinol (THC; the main psychoactive cannabinoid in cannabis) in cannabis in the U.S. varies widely, with legal-market cannabis containing increasingly higher THC potencies. When combined with alcohol, cannabis may confer either synergistic or mitigating effects on craving, impulsivity, cognitive impairment and subsequent drinking, likely depending on several factors, including cannabinoid dose and content. The limited literature in this area has generated conflicting findings; some studies have shown that THC increases alcohol intake and has synergistic effects on the subjective effects of alcohol, and others have shown that THC decreases alcohol intake or has no effects on these outcomes. Emerging work also suggests that alcohol and cannabis exert opposing effects on the digestive, immune, and central nervous systems, collectively known as the microbiota-gut-brain-axis (MGBA). Alcohol is linked to immune dysfunction and disturbances in gut microbial species (microbiota), and these MGBA disruptions have been associated with neurobehavioral AUD symptoms (e.g., craving, impaired control). Conversely, preclinical data suggest that cannabinoids may confer beneficial effects on aspects of the MGBA. The opposing findings regarding the effects of cannabis on alcohol use may be partially due to the differential actions of cannabinoids throughout the MGBA, which need to be better characterized in humans. Thus, the goal of this naturalistic study is to explore effects of legal-market cannabis on acute and daily alcohol consumption, neurobehavioral AUD phenotypes and MGBA function in heavy drinkers. We will recruit N=61 heavy drinking, regular users of legal- market cannabis to complete daily diary measures of alcohol and cannabis use during two 7-day periods (a no- cannabis period and an ad lib cannabis use period) and undergo two lab sessions; Visit A assesses cognitive function, impulsivity, craving, alcohol self-administration, MGBA biomarkers and blood-THC levels in the absence of acute cannabis, and Visit B tests the same outcomes following subjects’ self-administration of their preferred legal-market cannabis in their homes. The study uses the Mobile Cannabinoid Pharmacology Lab (an IRB-approved method developed by our team to test acute effects of legal-market cannabis and quantify blood-THC). The PI, Dr. Karoly, will pursue training aims to broaden her skillset and enable her to develop expertise in 1) MGBA analysis, 2) cannabinoid pharmacology, and 3) biostatistics. To guide her research and training, Dr. Karoly has assembled a premiere mentorship team with expertise spanning these domains. She will be well-supported as she develops the skills and expertise necessary to launch her independent, patient- oriented, translational program of research focused on novel AUD treatment and harm reduction strategies.