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)

• 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
• 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

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）是一种公认​​的综合征，其特征是耐受性和戒断。 反复的大麻暴露与大脑的下调和脱敏有关 内源性大麻素（欧洲央行）系统。虽然已经测试过几种药物的CUD，但u/s的食物没有 药物管理（FDA）批准或临床接受。替换治疗，同时表现出一些希望 在减少大麻戒断综合征（CWS）时，受其精神活性效果，虐待责任和 通过有限的预防复发效应。在患有CUD的个体中，体内成像研究表明：1） 脑较低脑大麻素受体（CB1R）和2）欧洲欧洲央行脂肪酸的较低水平 酰胺水解酶（FAAH）负责降解anandamide（AEA），主内源配体 大麻素系统。因此，替代治疗的替代方法可能是增强信号传导 通过欧洲央行系统，通过慢性大麻暴露改变了欧洲央行音调。 FAAH抑制剂 增加AEA水平降低了THC依赖性动物的CW。 PF-04457845是一种口服的，长的 表演，有效和选择性法族抑制剂。在我们完成的概念证明（POC）中，双盲， 随机，安慰剂对照，住院/门诊研究相对于安慰剂，FAAH抑制剂PF-044457845 （4mg QD）施用4周减少1）大麻戒断，2）使用大麻，3）干扰 睡眠，在DSM-4大麻依赖的个体中（n = 60）。 PF-04457845非常耐受，不是 奖励/加强。 假设：PF-04457845将减少大麻使用，戒断症状和睡眠障碍，包括 N3阶段睡眠的时间，在寻求治疗的人使用大麻障碍障碍（CUD）中。 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 - 在安慰剂对照的双盲中寻求男性和女性CUD受试者（n = 260 [包括25％的损耗]） 随机，多中心，12周长（治疗8周和4周的随访）平行组研究。 创新：拟议的CUD处理基于合理和新颖的机制（即Faah 抑制作用）将恢复欧洲央行的音调，从而减少大麻使用和戒断综合征。有 很少有可用于人类使用或批准使用的FAAH抑制剂，没有可用的 商业上。拟议的研究以同样的完整POC研究的有希望的发现为基础 药物以相同的剂量。