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。已经测试了几种药物用于大麻戒断和/或依赖，但没有一种药物被证明是持续有效的。用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，但受到其精神活性作用，滥用倾向及其有限的复发预防作用的限制。替代治疗的替代方案可能是通过内源性大麻素系统加强信号传导。 大麻素是脑大麻素受体（CB 1 R）的主要内源性配体，可被脂肪酸酰胺水解酶（FAAH）降解。最近，一种增加大麻素水平的FAAH抑制剂被证明可以减少THC依赖性动物的CWS。与THC或大麻相比，FAAH抑制剂1）没有精神活性作用，2）没有奖励，3）不会增加其他成瘾药物的滥用倾向，4）与耐受性无关，5）CB 1-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FAAH抑制剂，无精神活性或认知效应，无提示滥用倾向或停药相关戒断症状的效应，并且在拟定剂量下耐受良好。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将降低最近戒断大麻依赖者对大麻的渴望和复发率。方法：FAAH抑制对大麻戒断和复发的影响将在这项概念验证研究中进行研究。将有明确CWS病史的寻求治疗的大麻依赖受试者（n= 48）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通过与辉瑞达成的协议提供的PF-04457845（4 mg）。治疗阶段包括1周住院治疗以实现戒断和突然戒断，随后是3周门诊治疗以评估复发预防。创新：没有已知的大麻依赖治疗方法。FAAH抑制剂是一类新型化合物。可用于人类的FAAH抑制剂非常少，并且没有一种可商购获得。FAAH抑制剂尚未被测试用于治疗人类的大麻依赖。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.