FAAH-Inhibitor for Cannabis Dependence

说明(申请人提供)：大麻依赖是一种公认的综合症，其特征是耐受和戒断，目前还没有得到批准的治疗方法。已经对几种药物进行了大麻戒断和/或依赖测试，但没有一种药物被证明始终有效。德尔塔-9-四氢大麻酚(THC)替代治疗在减少大麻戒断综合征(CWS)方面显示出一些希望，但其精神效应、滥用倾向和有限的复发预防作用限制了替代治疗，替代治疗的一种选择可能是通过内源性大麻素系统增强信号传递。阿南达胺是脑大麻素受体(CB1R)的主要内源性配体，被脂肪酸酰胺水解酶(FAAH)降解。最近，一种FAAH抑制剂被证明可以降低THC依赖动物的CWS，它可以增加ANANDAME水平。与THC或大麻相比，FAAH-抑制剂1)没有精神作用，2)没有回报，3)不增加其他成瘾药物的滥用倾向，4)与耐受性无关，5)CB1-R功能变化较小。PF-04457845是一种口服活性、长效、有效和选择性的FAAH抑制剂，不具有精神或认知影响，不具有滥用倾向或与戒断相关的戒断症状的影响，在建议剂量下耐受性良好。假设：PF-04457845将减轻与大麻戒断综合征相关的主观、行为、多导睡眠图、认知和内分泌变化。此外，PF-04457845将减少对大麻的渴望和最近戒除大麻依赖者的复发率。方法：在这项概念验证研究中，将研究FAAH抑制对大麻戒断和复发的影响。寻求治疗的有明确CWS病史的大麻依赖受试者(n=48)将被纳入一项随机、双盲、安慰剂对照研究。在筛查期后，受试者将被随机接受安慰剂或PF-04457845(4毫克)，这是与辉瑞公司达成的协议提供的。治疗阶段包括住院一周以实现戒除和迅速戒断，然后是为期三周的门诊阶段以评估复发预防。创新：目前还没有已知的治疗大麻依赖的方法。FAAH抑制剂是一类新的化合物。可用于人类的FAAH抑制剂很少，而且没有商业化的。FAAH抑制剂还没有被测试用于治疗人类的大麻依赖。因此，本研究具有创新性。 与公共卫生相关：FDA没有批准的大麻依赖治疗方法。这项拟议研究的目标是测试一种药物的安全性和有效性，这种药物可以增加大脑自身的大麻样化学信使，减少大麻戒断综合症，防止复发。

DESCRIPTION (provided by applicant): Cannabis dependence is a well-recognized syndrome characterized by tolerance and withdrawal for which there are no approved treatments. Several medications have been tested for cannabis withdrawal and/or dependence, but none have been shown to be consistently effective. Substitution treatment with delta-9- tetrahydrocannabinol (THC), while showing some promise in reducing cannabis withdrawal syndrome (CWS), is limited by its psychoactive effects, abuse liability, and by its limited relapse prevention effects An alternative to substitution treatment may be to potentiate the signaling through the endogenous cannabinoid system. Anandamide, a principal endogenous ligand of brain cannabinoid receptors (CB1R) is degraded by the enzyme fatty acid amide hydrolase (FAAH). Recently, a FAAH inhibitor which increases anandamide levels was shown to reduce CWS in THC-dependent animals. Compared to THC or cannabis, FAAH-inhibitors 1) do not have psychoactive effects, 2) are not rewarding, 3) do not increase the abuse liability of other addictive drugs, 4) are not associated with tolerance and 5) produce fewer changes in CB1-R function. PF-04457845 is an orally active, long-acting, potent and selective FAAH inhibitor that does not have psychoactive or cognitive effects, does not have effects suggestive of abuse liability or discontinuation-related withdrawal symptoms and is well-tolerated at the proposed dose. Hypotheses: PF-04457845 will attenuate the subjective, behavioral, polysomnographic, cognitive and endocrine changes associated with cannabis withdrawal syndrome. Furthermore, PF-04457845 will reduce cravings for cannabis and relapse rates in recently abstinent cannabis dependent individuals. Approach: The effects of FAAH inhibition on cannabis withdrawal and relapse will be studied in this proof-of- concept study. Treatment seeking cannabis-dependent subjects (n= 48) with a clear history of CWS will be included in a randomized, double-blind, placebo-controlled study. After a screening period, subjects will be randomized to receive placebo or PF-04457845 (4 mg) provided through an agreement with Pfizer. The treatment phase consists of a 1-week inpatient stay to achieve abstinence and precipitate withdrawal, followed by a 3-week outpatient phase to assess relapse prevention. Innovation: There are no known treatments for cannabis dependence. FAAH inhibitors are a novel class of compounds. There are very few FAAH-inhibitors that are available for use in humans, and none are available commercially. FAAH-inhibitors have not been tested for the treatment of cannabis dependence in humans. Therefore, the proposed study is innovative. PUBLIC HEALTH RELEVANCE: There are no FDA approved treatments for cannabis dependence. The goal of the proposed study is to test the safety and efficacy of a drug that increases the brain's own cannabis-like chemical messenger in reducing cannabis withdrawal syndrome and preventing relapse.