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: 10329999
• 负责人: Hollis C Karoly
• 金额: $ 19.18万
• 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/10329999
• 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; Cell Culture Techniques; Chemicals; Cognition; Cognitive; Communication; Conflict (Psychology); 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; Light; Link; Literature; Maintenance; Measures; Mediating; Medical; Medical Marijuana; Mentors; Mentorship; Methods; Mus; National Institute on Alcohol Abuse and Alcoholism; Neuraxis; Observational Study; Outcome; Patients; Pattern; Performance; Persons; Pharmacology; Phase; Phenotype; Physiological; Plants; Play; Policies; Proteobacteria; Rattus; Reporting; Research; Research Training; 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-brain axis; human data; immune function; innovation; liver inflammation; marijuana use; marijuana user; microbiota; microbiota-gut-brain axis; neurobehavioral; neurobehavioral test; novel; patient oriented; 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 美国越来越自由的大麻政策都与“替代者”有关 大麻代替酒精，从而减少酒精的使用和“增强”，从而可以使用大麻 增加酒精的使用。这些相互矛盾的模式可以部分解释以下事实。 美国大麻中大麻中的Delta-9-四氢大麻酚（THC；大麻中的主要精神活性大麻素） 有很大的变化，合法的市场大麻含有越来越高的THC电位。合并时 酒精，大麻可能会导致对渴望，冲动，认知的协同或缓解影响 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。该领域的有限文献引起了矛盾的发现。一些研究表明 THC增加了酒精摄入量，对酒精的主观影响具有协同作用，而其他人则具有 表明THC会降低酒精摄入量或对这些结果没有影响。新兴工作也暗示 酒精和大麻会对消化，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）的扰动，以及这些MGBA干扰已与 神经行为AUD症状（例如，渴望，控制受损）。相反，临床前数据表明 大麻素可能会对MGBA各个方面产生有益的影响。关于 大麻对饮酒的影响可能部分是由于整个大麻素的不同作用 MGBA需要更好地在人类中进行特征。那是这项自然研究的目标是 探索法律市场大麻对急性和每日饮酒的影响 饮酒者的表型和MGBA功能。我们将招募n = 61次大量饮酒，法律的常规用户 - 在两个7天期间，市场大麻完成酒精和大麻使用的日记量度（无 大麻时期和使用大麻时期）并进行了两个实验室会议；访问评估认知 功能，冲动，渴望，酒精自给自足，MGBA生物标志物和血液THC水平 缺乏急性大麻，并访问B测试在受试者自我管理之后的相同结果 在家中首选合法市场的大麻。该研究使用移动大麻素药理学实验室 （我们的团队开发了一种IRB批准的方法，用于测试合法市场大麻的急性影响并量化 血液THC）。 Karoly博士将进行培训，旨在扩大自己的技能并使她发展。 1）MGBA分析的专业知识，2）大麻素药理学和3）生物统计学。指导她的研究和 培训，Karoly博士已经组建了一支跨越这些领域的专业知识的首映式精神团队。她 随着她发展独立，患者 - 面向，翻译的研究计划的重点是新的AUD治疗和减少伤害策略。