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

摘要 在美国，日益自由的大麻政策与这两个方面都有关联，即 大麻取代了酒精，从而减少了酒精的使用，并“增加”了大麻的使用 增加酒精使用量。这些相互冲突的模式可以部分解释为这样一个事实： 美国大麻中的三角洲-9-四氢大麻酚(THC；大麻中的主要精神活性大麻素)。 变化很大，合法市场上的大麻含有越来越高的THC效力。当与 酒精，大麻可能在渴望，冲动，认知方面具有协同或缓解作用 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。这一领域的有限文献产生了相互矛盾的发现；一些研究表明 THC增加了酒精的摄入量，并对酒精的主观影响有协同作用，其他人也有 结果表明，THC减少了酒精摄入量，或者对这些结果没有影响。新出现的研究还表明 酒精和大麻对消化系统、免疫系统和中枢神经系统产生相反的影响， 统称为微生物区系-肠道-脑轴(MGBA)。酒精与免疫功能障碍有关， 肠道微生物种群(微生物区系)的紊乱，以及这些MGBA的紊乱与 神经行为和UD症状(例如，渴求、控制障碍)。相反，临床前数据表明 大麻素可能会对MGBA的某些方面产生有益的影响。关于这一问题的相反发现 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，它需要更好地在人类身上表现出来。因此，这项自然主义研究的目标是 探讨合法市场大麻对急性饮酒和日常饮酒、神经行为和行为的影响 酗酒者的表型和MGBA功能。我们将招募N=61名酗酒者，合法-经常使用- 在两个7天的期间内完成每日酒精和大麻使用的日记措施(禁止- 大麻使用期和临时大麻使用期)，并进行两次实验室会议；访问A评估认知能力 功能、冲动、渴求、酒精自我给药、MGBA生物标志物和血THC水平 没有急性大麻，访问B测试了受试者自我管理后的相同结果 他们更喜欢在家里购买合法市场的大麻。这项研究使用了移动大麻类药物实验室 (IRB批准的一种方法，由我们的团队开发，用于测试合法市场上大麻的急性影响并量化 血-THC)。私人助理卡罗利博士将致力于培训目标，以拓宽她的技能集，使她能够发展 擅长1)MGBA分析，2)大麻素药理学，3)生物统计学。来指导她的研究和 在培训期间，卡罗利博士组建了一支首屈一指的导师团队，他们的专业知识涵盖了这些领域。她 将得到很好的支持，因为她发展了必要的技能和专业知识，以推出她独立的，耐心的- 面向翻译的研究计划侧重于新的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.