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

探索大麻素对酒精消耗和微生物群-肠-脑轴的影响

• 批准号: 10548156
• 负责人: Hollis C Karoly
• 金额: $ 18.99万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548156
• 关键词: Acute; Agonist; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Animals; Applications Grants; Area; Attenuated; Bacteria; Bifidobacterium; Biological; Biological Markers; Biometry; Blood; Brain; Brain region; CNR1 gene; Cannabinoids; Cannabis; Cannabis policy; Cannabis retail; Cell Culture Techniques; Central Nervous System; Chemicals; Cognition; Cognitive; Communication; Consumption; Data; Data Set; Dependence; Dose; Drug usage; Ethanol; Etiology; Future; Goals; Harm Reduction; Heavy Drinking; Home; Human; Immune; Immune System Diseases; Immune system; Impaired cognition; Impairment; Impulsivity; Individual; Inflammation; Inflammatory; Institutional Review Boards; Intestinal permeability; Legal; Link; Literature; Maintenance; Marketing; Measures; Mediating; Medical; Medical Marijuana; Mentors; Mentorship; Methods; Mus; National Institute on Alcohol Abuse and Alcoholism; Observational Study; Outcome; Patients; Pattern; Performance; Persons; Pharmacology; Phase; Phenotype; Physiological; Plants; Proteobacteria; Rattus; Recreation; Reporting; Research; Risk; Rodent; Role; Sampling; Self Administration; Signal Transduction; Smoke; Strategic Planning; Symptoms; System; Testing; Tetrahydrocannabinol; Time; Training; United States National Institutes of Health; Visit; Work; alcohol craving; alcohol effect; alcohol exposure; alcohol use disorder; career; cognitive function; craving; cytokine; design; diaries; drinking; endogenous cannabinoid system; gut microbes; gut microbiota; gut-brain axis; human data; immune function; innovation; liver inflammation; marijuana use; marijuana user; microbiota; microbiota-gut-brain axis; neurobehavioral; neurobehavioral test; novel; patient oriented; pharmacologic; pre-clinical; recruit; sample collection; skills; translational research program; zonulin

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.

概括 美国日益自由的大麻政策与“替代”联系在一起，因此 大麻代替了酒精，从而减少了酒精的使用，而“增强”，因此大麻的使用 这些相互矛盾的模式可能部分是由于酒精的效力而增加的。 美国大麻中的 delta-9-四氢大麻酚（THC；大麻中主要的精神活性大麻素） 差异很大，合法市场上的大麻与 THC 的含量越来越高。 酒精、大麻可能对渴望、冲动、认知产生协同或减轻作用 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 该领域的有限文献得出了相互矛盾的结论； THC 会增加酒精摄入量，并对酒精的主观影响产生协同作用，其他研究也发现 研究表明，THC 可以减少酒精摄入量或对这些结果没有影响。 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， 统称为微生物群-肠-脑轴（MGBA），酒精与免疫功能障碍有关。 肠道微生物种类（微生物群）的紊乱，这些 MGBA 破坏与 临床前数据表明，神经行为 AUD 症状（例如渴望、控制力受损）。 大麻素可能对 MGBA 的各个方面产生有益的影响。 大麻对饮酒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 探讨合法市场大麻对急性和日常饮酒量、神经行为 AUD 的影响 重度饮酒者的表型和 MGBA 功能 我们将招募 N = 61 名重度饮酒的经常使用者。 销售大麻，以完成两个 7 天期间酒精和大麻使用的每日日记测量（无 大麻期和随意使用大麻期）并进行两次实验室会议评估认知能力； 功能、冲动、渴望、自我饮酒、MGBA 生物标志物和血液 THC 水平 没有急性大麻，并且访问 B 在受试者自行服用大麻后测试了相同的结果 该研究使用移动大麻药理学实验室。 （我们团队开发的IRB批准的方法，用于测试合法市场大麻的急性影响并量化 PI，Karoly 博士，将进行培训，以扩大她的技能，使她能够发展。 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和研究。 通过培训，Karoly 博士组建了一支具有跨这些领域专业知识的一流导师团队。 当她发展必要的技能和专业知识以开展独立、耐心的工作时，她将得到大力支持。 面向转化的研究计划，重点关注新型 AUD 治疗和减少伤害策略。