FAAH-Inhibitor for Cannabis Dependence

描述（由申请人提供）：大麻依赖是一种公认的综合征，其特征是耐受性和戒断，目前尚无批准的治疗方法。对大麻戒断和/或依赖的几种药物进行了测试，但没有一种药物显示出一贯有效。δ -9-四氢大麻酚（THC）替代治疗虽然在减少大麻戒断综合征（CWS）方面显示出一些希望，但其精神活性作用、滥用倾向和预防复发的作用有限。替代治疗的另一种选择可能是通过内源性大麻素系统增强信号传导。大麻酰胺是脑大麻素受体（CB1R）的主要内源性配体，由脂肪酸酰胺水解酶（FAAH）降解。最近，一种FAAH抑制剂可以增加四氢大麻酚依赖动物的阿南达胺水平，从而降低CWS。与四氢大麻酚或大麻相比，faah抑制剂1)没有精神作用，2)没有回报，3)不会增加其他成瘾药物的滥用倾向，4)与耐受性无关，5)CB1-R功能的变化较少。PF-04457845是一种口服活性、长效、强效和选择性的FAAH抑制剂，不具有精神活性或认知作用，不具有提示滥用危险或停药相关戒断症状的影响，并且在建议剂量下耐受性良好。假设：PF-04457845将减弱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将减少最近戒断大麻依赖个体对大麻的渴望和复发率。方法：在这个概念验证研究中将研究FAAH抑制对大麻戒断和复发的影响。寻求大麻依赖治疗的受试者（n= 48）有明确的CWS病史，将被纳入一项随机、双盲、安慰剂对照研究。筛选期后，受试者将随机接受安慰剂或与辉瑞公司协议提供的PF-04457845 （4mg）。治疗阶段包括1周的住院治疗，以实现戒断和沉淀戒断，随后是3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抑制剂是一类新型化合物。很少有faah抑制剂可用于人类，而且没有商业上可用的。尚未对faah抑制剂用于治疗人类大麻依赖进行测试。因此，本研究具有创新性。

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.