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

总结 美国越来越自由的大麻政策与“替代”有关， 大麻替代酒精，从而减少酒精的使用，以及“增强”， 增加酒精使用。这些相互冲突的模式可以部分地解释为， 美国大麻中的δ-9-四氢大麻酚（THC;大麻中主要的精神活性大麻素） 不同的是，合法市场上的大麻含有越来越高的THC效力。当结合 酒精、大麻可能会对渴望、冲动、认知能力、 损害和随后的饮酒，可能取决于几个因素，包括大麻素剂量和 内容这一领域的文献有限，产生了相互矛盾的结果;一些研究表明， 四氢大麻酚增加酒精摄入量，对酒精的主观影响有协同作用，其他物质则有 表明THC减少酒精摄入量或对这些结果没有影响。新的研究还表明， 酒精和大麻对消化、免疫和中枢神经系统产生相反的影响， 统称为微生物群-肠-脑-轴（MGBA）。酒精与免疫功能障碍有关， 肠道微生物物种（微生物群）的干扰，这些MGBA中断与 神经行为AUD症状（例如，控制力受损）。相反，临床前数据表明， 大麻素可以对MGBA的各个方面产生有益的影响。关于《公约》的相反结论 大麻对酒精使用的影响可能部分是由于大麻素在整个过程中的不同作用 MGBA，需要在人类中更好地表征。因此，这项自然主义研究的目标是 探索合法市场大麻对急性和日常饮酒，神经行为AUD的影响 表型和MGBA功能。我们将招募N=61名重度饮酒，经常使用法律的- 在两个7天的时间内，销售大麻，以完成酒精和大麻使用的每日日记措施（一个没有， 大麻使用期和随意大麻使用期），并进行两次实验室检查;访视A评估认知功能 功能，冲动，渴望，酒精自我管理，MGBA生物标志物和血液THC水平 不存在急性大麻，访视B在受试者自我施用其 更喜欢在家里合法销售大麻这项研究使用了移动的大麻素药理学实验室 (an IRB批准的方法由我们的团队开发，用于测试合法市场大麻的急性效应并量化 血液-THC）。PI，Karoly博士，将继续接受培训，旨在扩大她的技能，使她能够发展 在1）MGBA分析，2）大麻素药理学和3）生物统计学方面的专业知识。指导她的研究， 培训，Karoly博士已经组建了一个首屈一指的导师团队与专业知识跨越这些领域。她 将得到很好的支持，因为她发展的技能和必要的专业知识，推出她的独立，耐心- 导向的，转化的研究计划，重点是新的AUD治疗和减少伤害的策略。

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.