Advancing Varenicline as a Treatment for Cannabis Use Disorder

摘要 大麻是美国最常用的非法药物。尽管大麻的使用很普遍，而且 大麻类物质基础科学研究发达，药物开发进展 大麻使用障碍(CUD)一直受到限制。选择性烟碱型NACh受体部分激动剂varenicline α4β2亚型和α7亚型的完全激动剂，可以说是治疗 促进戒烟，并在治疗酒精使用障碍方面显示出希望。伐尼克兰 可通过多种机制改善大麻的使用结果，包括与中脑边缘的相互作用 多巴胺系统、认知功能的增强和抑制控制的恢复。然而，到目前为止， 尚未对专门寻求CUD治疗的患者进行评估。在此UG3/UH3中 ，我们建议快速而彻底地评估varenicline对CUD潜在进展的效用 Varenicline通过FDA的药物开发审批流程。在UG3组件中，我们将进行 Varenicline治疗CUD的为期六周的安慰剂对照概念验证临床试验，配对治疗前后 大麻线索反应性和抑制控制中涉及的认知功能和神经回路的评估 目的：阐明伐伦尼克林治疗慢性阻塞性肺疾病的药效学。如果UG3组件的里程碑 UH3项目将是一项动力充足的为期12周的临床试验，并进行跟踪以全面评估 伐伦克林在这一人群中的疗效。

ABSTRACT Cannabis is the most commonly used illicit drug in the United States. Although cannabis use is widespread and basic science research on cannabinoids is well-developed, advancements in medication development for cannabis use disorder (CUD) have been limited. Varenicline, a selective nicotinic nACH receptor partial agonist of the α4β2 subtype and a full agonist of the α7 subtype, is arguably the most effective pharmacotherapy for promoting tobacco abstinence, and has also shown promise for the treatment of alcohol use disorder. Varenicline may improve cannabis use outcomes through multiple mechanisms, including interaction with the mesolimbic dopamine system, enhancement of cognitive functioning, and restoration of inhibitory control. To date, however, varenicline has not been evaluated in individuals specifically seeking treatment for CUD. In this UG3/UH3 application, we propose to rapidly yet thoroughly assess the utility of varenicline for CUD to potentially advance varenicline through the FDA's drug development approval pipeline. In the UG3 component, we will conduct a six-week, placebo-controlled proof-of-concept clinical trial of varenicline for CUD, paired with pre- and post- evaluations of cognitive functioning and neural circuitry involved in cannabis cue reactivity and inhibitory control to elucidate the pharmacodynamics of varenicline as a treatment for CUD. If milestones of the UG3 component are met, the UH3 project will be an adequately powered 12-week clinical trial with follow-up to fully assess the efficacy of varenicline in this population.