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

脂肪酸酰胺水解酶 (FAAH) 抑制剂治疗大麻使用障碍 (CUD)

基本信息

批准号：
9460794
负责人：
DEEPAK Cyril D'SOUZA
金额：
$ 318.49万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9460794
关键词：
Abstinence Adherence Admission activity Agreement Alcohols Anger Animals Back Brain CNR1 gene Cannabinoids Cannabis Chemicals Chronic Clinical Cocaine Cognitive DSM-IV Data Dependence Desire for food Dose Double-Blind Method Down-Regulation Endocannabinoids Enzymes FAAH inhibitor Female Goals Heroin Human Individual Inpatients Laboratories Legal Ligands Marijuana Dependence Measures Medical Mental Depression Moods Opioid Oral Outpatients Patient Self-Report Pharmaceutical Preparations Pharmacological Treatment Phase Placebo Control Placebos Polysomnography Questionnaires Randomized Relapse Safety Signal Transduction Sleep Sleep Architecture Sleep disturbances Stage III Sleep Substance Withdrawal Syndrome Suggestion Syndrome System Testing Tetrahydrocannabinol Time Toxicology United States United States Food and Drug Administration Urine Visual Waxes Weight Withdrawal Withdrawal Symptom analog anandamide base cannabinoid receptor cannabis withdrawal craving desensitization disorder later incidence prevention efficacy testing endogenous cannabinoid system experience fatty acid amide hydrolase follow-up imaging study in vivo imaging innovation male marijuana use marijuana use disorder novel pre-clinical public health relevance safety testing synthetic cannabinoid

项目摘要

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.

抽象的大麻使用障碍（CUD）是一种众所周知的综合征，其特征是耐受和戒断。反复接触大麻与大脑的下调和脱敏有关内源性大麻素（ECB）系统。虽然已经对多种药物进行了 CUD 测试，但美国食品和药物管理局没有对这些药物进行过测试。药物管理局 (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，受到其精神作用、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，体内成像研究表明：1) 较低的大脑大麻素受体 (CB1R) 和 2) 较低水平的 eCB 代谢酶脂肪酸酰胺水解酶 (FAAH) 负责降解主要的内源配体 anandamide (AEA) 大麻素系统。因此，替代治疗的另一种选择可能是增强信号传导通过 eCB 系统恢复因长期接触大麻而改变的 eCB 音调。 FAAH抑制剂增加 AEA 水平可减少 THC 依赖动物的 CWS。 PF-04457845 是一种口服活性、长效有效的、有效的、选择性的 FAAH 抑制剂。在我们完成的双盲概念验证 (POC) 中，与安慰剂 FAAH 抑制剂 PF-04457845 相关的随机、安慰剂对照、住院/门诊研究（4 毫克每日一次）服用 4 周可减少 1) 大麻戒断，2) 大麻使用，以及 3) 精神障碍 DSM-4 大麻依赖个体 (n=60) 的睡眠情况。 PF-04457845 的耐受性非常好，并且没有奖励/强化。假设：PF-04457845 将减少大麻使用、戒断症状和睡眠障碍，包括患有大麻使用障碍（CUD）寻求治疗的个体处于 N3 阶段睡眠的时间。方法：将在治疗中研究 PF-04457845（4 mg QD）对大麻使用的功效和安全性 - 在安慰剂对照、双盲、随机、多中心、为期 12 周（8 周治疗和 4 周随访）平行组研究。创新：拟议的 CUD 治疗方法基于一种合理且新颖的机制（即 FAAH 抑制），这将恢复 eCB 基调，从而减少大麻使用和戒断综合症。有可用于或批准用于人类的 FAAH 抑制剂非常少，而且目前还没有可用的商业上。拟议的研究建立在已完成的 POC 研究的有希望的结果之上，该研究具有相同的结果相同剂量的药物。