Fatty Acid Amide Hydrolase (FAAH) Inhibitor Treatment of Cannabis Use Disorder (CUD)

摘要 大麻使用障碍(CUD)是一种公认的以耐受和戒断为特征的综合征。 反复接触大麻与大脑的调节下调和脱敏有关 内源性大麻(ECB)系统。虽然有几种药物已经被检测出CUD，但没有一种是U/S食品和 美国药品监督管理局(FDA)批准或临床接受。替代治疗，同时显示出一些希望 在减少大麻戒断综合症(CWS)方面，受到其精神活性影响、滥用倾向和 由于其预防复发的效果有限。在患有CUD的个体中，活体成像研究表明：1) 更低的大脑大麻素受体(CB1R)和2)更低水平的欧洲央行代谢酶脂肪酸 酰胺水解酶(FAAH)，负责降解内源性主要配体--山梨酰胺(AEA) 大麻素系统的。因此，替代治疗的一种替代方法可能是增强信号转导 通过欧洲央行系统，恢复随着长期大麻暴露而改变的欧洲央行基调。FAAH抑制剂 增加AEA水平可减少THC依赖动物的CWS。PF-04457845是一种口服有效、长期有效的 有效的、有效的和选择性的FAAH抑制剂。在我们完整的概念证明(POC)中，双盲， 与安慰剂相关的随机、安慰剂对照的住院/门诊研究，FAAH抑制剂PF-04457845 (4 mg，qd)连续4周减少1)大麻戒断，2)大麻使用，以及3)干扰 睡眠，DSM-4大麻依赖者(n=60)。PF-04457845的耐受性很好，而不是 奖励/强化。 假设：PF-04457845将减少大麻使用、戒断症状和睡眠障碍，包括 在患有大麻使用障碍(CUD)的寻求治疗个人中，处于N3阶段睡眠的时间。 方法：将研究PF-04457845(4mgqd)对大麻使用的有效性和安全性。 采用安慰剂对照、双盲、 随机、多中心、为期12周(治疗8周、随访4周)的平行分组研究。 创新：建议的CUD治疗是基于一种合理而新颖的机制(即FAAH) 抑制)，这将恢复欧洲央行的语气，从而减少大麻使用和戒断综合症。确实有 很少有FAAH抑制剂可用于或被批准用于人类，而且没有可用的 在商业上。拟议的研究建立在完成的POC研究结果的基础上，该研究具有相同的 相同剂量的药物。

ABSTRACT Cannabis use disorder (CUD) is a well-recognized syndrome characterized by tolerance and withdrawal. Repeated cannabis exposure is associated with downregulation and desensitization of the brain endocannabinoid (eCB) system. While several medications have been tested for CUD, none are U/S Food and Drug Administration (FDA) approved or clinically accepted. Substitution treatment while showing some promise in reducing the cannabis withdrawal syndrome (CWS), is limited by its psychoactive effects, abuse liability, and by its limited relapse prevention effects. In individuals with CUD, in vivo imaging studies have demonstrated: 1) lower brain cannabinoid receptors (CB1R) and 2) lower levels of the eCB-metabolizing enzyme fatty acid amide hydrolase (FAAH) which is responsible for degrading anandamide (AEA), a principal endogenous ligand of the cannabinoid system. Thus, an alternative to substitution treatment may be to potentiate signaling through the eCB system to restore eCB tone that is altered with chronic cannabis exposure. FAAH inhibitors which increase AEA levels reduce CWS in THC-dependent animals. PF-04457845 is an orally active, long- acting, potent, and selective FAAH inhibitor. In our completed proof of concept (POC), double-blind, randomized, placebo-controlled, inpatient/outpatient study relative to placebo, the FAAH inhibitor PF-04457845 (4mg QD) administered for 4 weeks reduced 1) cannabis withdrawal, 2) cannabis use, and 3) disturbances in sleep, in DSM-4 cannabis dependent individuals (n=60). PF-04457845 was very well-tolerated and was not rewarding/reinforcing. Hypotheses: PF-04457845 will reduce cannabis use, withdrawal symptoms, and sleep disturbances including time in Stage N3 sleep, in treatment-seeking individuals with a cannabis use disorder (CUD). Approach: The efficacy and safety of PF-04457845 (4 mg QD) on cannabis use will be studied in treatment- seeking male and female CUD subjects (n= 260 [including 25% attrition]) in a placebo-controlled, double-blind, randomized, multicenter, 12-week long (8 weeks of treatment & 4 weeks follow up) parallel-group study. Innovation: The proposed treatment for CUD is based on a plausible and novel mechanism (i.e., FAAH inhibition) that will restore eCB tone, thereby reducing cannabis use and the withdrawal syndrome. There are very few FAAH-inhibitors that are available or approved for use in humans, and none are available commercially. The proposed study builds on the promising findings of a completed POC study with the same drug at the same dose.