Neurobehavioral effects of cannabidiol in youth alcohol use disorder

项目总结/摘要 饮酒在青年人中很普遍，而且存在问题，他们比成年人更有可能开始饮酒 使用，发展酒精使用障碍（AUD），并遭受持久的不良酒精相关后果。尽管 明确需要针对青少年的AUD治疗，建立心理和行为干预措施， 疗效有限，只有极少数青年实现持续戒酒或戒酒。药物疗法 在支持成人物质使用障碍治疗结果方面发挥关键作用，但迄今为止，没有药物 在青少年中的AUD值得FDA批准。开发安全有效的预防药物， 需要治疗青少年AUD，以改善治疗结果，并可能减少长期 青少年使用的后果。大麻二酚（CBD）是大麻中主要的植物大麻素之一 植物，是一个潜在的有前途的候选药物治疗青年AUD。对于年轻人来说，这尤其有吸引力 治疗选择，因为它是非中毒性的，似乎通常耐受良好，并没有表现出信号， 滥用责任CBD在中枢神经系统内有许多潜在的靶点，可以减轻症状 通过调节多巴胺能、GABA能、多巴胺能、阿片样物质能和内源性大麻素 途径。临床前研究表明，CBD影响一系列饮酒行为（例如，减少乙醇 寻求和摄入;减轻戒断症状，复发，焦虑和冲动），以及最近的临床工作 表明CBD有可能减少支持酒精和大麻共同使用的成年人的酒精摄入量。 建立急性神经代谢，神经行为和心理生理学影响的CBD在青年与 AUD将是启动更大规模试验之前药物治疗开发管道的关键第一步。 本申请的目的是通过以下方式测试CBD作为青少年AUD的潜在有效候选药物： 利用发育信息神经成像方法（磁共振波谱和功能 MRI）和基于实验室的酒精线索反应程序。为了实现这一目标，本研究将使用随机， 双盲、受试者内交叉设计。按平衡顺序，35名青年（14-24岁）， AUD标准的患者将接受600 mg CBD或安慰剂与标准餐（以调节CBD吸收 在神经影像学和行为评估范式之前3小时，间隔13天的洗脱期 期这项提议与跨NIH倡议一致，以确定神经信息的新物质使用 青春的治疗这些发现将弥合药物治疗中的一个关键的翻译缺口（“死亡之谷”） 开发青少年AUD，推进CBD严格的神经行为早期疗效测试方法。 通过这项研究建立的效果可以为更大规模的临床试验铺平道路，并最终改善 对患有AUD的年轻人的长期结果。

PROJECT SUMMARY/ABSTRACT Alcohol use is prevalent and problematic among youth, who are more likely than adults to initiate alcohol use, develop alcohol use disorder (AUD), and suffer lasting adverse alcohol-related consequences. Despite the clear need for youth-targeted AUD treatments, established psychosocial and behavioral interventions offer limited efficacy, with very few youth achieving sustained alcohol abstinence or reduction. Pharmacotherapies play a key role in bolstering substance use disorder treatment outcomes in adults, but to date, no medications for AUD in youth have merited FDA approval. The development of safe and effective adjunctive medications to treat adolescent AUD is needed to improve treatment outcomes and to potentially reduce the long-term consequences of adolescent use. Cannabidiol (CBD), one of the main phytocannabinoids in the Cannabis sativa plant, is a potentially promising candidate pharmacotherapy for youth AUD. It is particularly appealing as a youth treatment option since it is non-intoxicating, appears generally well-tolerated, and demonstrates no signal of abuse liability. CBD has many potential targets within the central nervous system that may mitigate the symptoms of AUD via modulation of the glutamatergic, GABAergic, dopaminergic, opioidergic, and endocannabinoid pathways. Preclinical work has shown that CBD affects an array of drinking behaviors (e.g., reduces ethanol seeking and intake; mitigates symptoms of withdrawal, relapse, anxiety, and impulsivity), and recent clinical work has indicated CBD's potential to reduce alcohol intake within adults who endorse alcohol and cannabis co-use. Establishing the acute neurometabolic, neurobehavioral, and psychophysiological effects of CBD in youth with AUD will be a critical first step in the pharmacotherapy development pipeline before initiating larger scale trials. The goal of this application is to test CBD as a potentially effective candidate medication for youth AUD by leveraging developmentally informed neuroimaging methods (magnetic resonance spectroscopy and functional MRI) and lab-based alcohol cue reactivity procedures. To accomplish this goal, this study will use a randomized, double-blind, within-subjects crossover design. In counterbalanced order, 35 youth (ages 14-24) who meet criteria for AUD will receive 600 mg of CBD or placebo with a standardized meal (to modulate CBD absorption rates) three hours before a neuroimaging and behavioral assessment paradigm, separated by a 13-day washout period. This proposal is consistent with the trans-NIH initiative to identify neurally-informed novel substance use treatments for youth. Findings will bridge a critical translational gap (“the valley of death”) in pharmacotherapy development for youth AUD, advancing methodology for rigorous neural-behavioral early efficacy testing of CBD. Effects established through this study could pave the way to a larger-scale clinical trial and, ultimately, improved long-term outcomes for young people suffering from AUD.