Advancing Varenicline as a Treatment for Cannabis Use Disorder

摘要 大麻是美国最常用的非法药物。虽然大麻的使用很普遍， 关于大麻素的基础科学研究已经很发达，药物开发的进展， 大麻使用障碍（CUD）的影响有限。伐尼克兰，一种选择性烟碱nACH受体部分激动剂 α4β2亚型和α7亚型的完全激动剂，可以说是最有效的药物治疗， 促进戒烟，并且还显示出治疗酒精使用障碍的前景。Varenicline 可能通过多种机制改善大麻使用的结果，包括与中脑边缘系统的相互作用 多巴胺系统，增强认知功能，恢复抑制控制。然而，迄今为止， 伐尼克兰尚未在寻求专门治疗CUD的个体中进行评估。在此UG 3/UH 3 应用，我们建议快速而彻底地评估伐尼克兰对CUD的效用，以潜在地促进 通过FDA的药物开发审批渠道。在UG 3组件中，我们将执行 一项为期6周的安慰剂对照的概念验证临床试验，研究伐尼克兰治疗CUD， 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价 阐明伐尼克兰作为治疗CUD的药效学。如果UG 3组件的里程碑 UH 3项目将是一项具有充分把握度的12周临床试验，并进行随访，以充分评估 伐尼克兰在该人群中的疗效。

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.