Neurobehavioral effects of cannabidiol in youth alcohol use disorder

项目概要/摘要 酗酒在青少年中很普遍，也存在问题，他们比成年人更有可能开始酗酒 酒精使用障碍 (AUD)，并遭受与酒精相关的持久不良后果。尽管 明确需要针对青少年的 AUD 治疗、已建立的社会心理和行为干预措施 效果有限，很少有年轻人能够持续戒酒或减少饮酒。药物治疗 在增强成人物质使用障碍的治疗效果方面发挥着关键作用，但迄今为止，还没有药物 青少年澳元的治疗值得 FDA 批准。开发安全有效的辅助药物 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)，大麻中的主要植物大麻素之一 植物，是一种潜在有前途的青少年 AUD 候选药物疗法。作为年轻人来说尤其有吸引力 治疗选择，因为它是非中毒的，通常耐受性良好，并且没有表现出任何信号 滥用责任。 CBD 在中枢神经系统内有许多潜在的目标，可以减轻症状 通过调节谷氨酸能、GABA能、多巴胺能、阿片能和内源性大麻素来减少 AUD 途径。临床前工作表明 CBD 会影响一系列饮酒行为（例如，减少乙醇摄入量） 寻求和摄取；减轻戒断、复发、焦虑和冲动的症状）以及最近的临床工作 表明 CBD 有可能减少支持酒精和大麻同时使用的成年人的酒精摄入量。 确定 CBD 对青少年的急性神经代谢、神经行为和心理生理影响 在开始更大规模的试验之前，AUD 将是药物治疗开发管道中关键的第一步。 该应用程序的目标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： 利用发育信息神经影像方法（磁共振波谱和功能 MRI）和基于实验室的酒精提示反应程序。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。按照平衡顺序，35 名青少年（14-24 岁）相遇 AUD 的标准将在标准化膳食中接受 600 毫克 CBD 或安慰剂（以调节 CBD 吸收） 率）在神经影像学和行为评估范例之前三小时，中间间隔 13 天的冲洗 期间。该提案与跨 NIH 识别神经信息新型物质使用的倡议一致 针对青少年的治疗。研究结果将弥合药物治疗中关键的转化差距（“死亡之谷”） 青年 AUD 的发展，推进 CBD 严格神经行为早期功效测试的方法。 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 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.