Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial
Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial
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DOI：
10.1016/s2215-0366(18)30427-9
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发表时间：
2019-01-01
影响因子：
64.3
通讯作者：
Skosnik, Patrick D.
中科院分区：
文献类型：
--
作者：
D'Souza, Deepak Cyril;Cortes-Briones, Jose;Skosnik, Patrick D.
大麻是世界上使用最广泛的毒品之一。大麻使用障碍的特征是反复使用大麻，导致严重的临床和功能障碍。大麻使用障碍没有批准的药物治疗。一种方法是通过抑制脂肪酸酰胺水解酶（FAAH）来增强内源性大麻素信号传导，FAAH是降解内源性大麻素anandamide的酶。我们的目的是测试FAAH抑制剂PF-04457845在减少大麻戒断和大麻使用的男性谁是每日cannabsusers.Methods的有效性和安全性，我们做了一个双盲，安慰剂对照，平行组2A期试验在一个网站在男性18 - 55岁的大麻依赖根据DSM-IV标准（相当于DSM-5中的大麻使用障碍）。基线评估后，使用6名受试者的固定区组大小将受试者随机分配（2：1）接受PF-04457845（4 mg/天）或安慰剂，并按大麻使用的严重程度和戒烟意愿分层。参与者住院5天（最多8天）以实现禁欲和大麻戒断，之后他们出院继续作为门诊患者接受剩余3周的治疗。主要终点是住院期间大麻戒断症状的治疗相关差异，以及意向治疗人群中第4周（治疗结束）自我报告的大麻使用和尿液THC-COOH浓度。该研究在www.example.com上注册，编号为NCT 01618656。结果在2012年9月12日至2016年1月18日期间，46名男性被随机分配至PF-04457845组，24名男性被随机分配至安慰剂组。研究药物的依从性为88%，通过视频通话和药丸计数证实，并通过相应的药物和血液中的大麻素浓度证实。与安慰剂相比，PF-04457845治疗与大麻戒断症状减轻相关（治疗第1天平均症状评分11.00 [95% CI 7.78 - 15.57] vs 6.04 [4.43 - 8.24];差异4.96 [0.71 - 9.21]; p（adj）= 0.048;治疗第二天11.74 [8.28 - 16.66] vs 6.02 [4.28 - 8.47];差异5.73 [1.13 - 10.32]; p（adj）= 0.035）和住院期间的相关情绪症状。此外，PF-04457845治疗与第4周时自我报告的大麻使用减少相关（平均每天1.27个关节[95% CI 0.82 - 1.97] vs 0.40 [0.25 - 0.62];差异0.88 [0.29 - 1.46]; p = 0.0003）和尿THC-COOH浓度降低（平均值657.92 ng/mL [95% CI 381.60 - 1134.30] vs 265.55 [175.60 - 401.57];差异392.37 [17.55 - 767.18）]; p = 0.009）。PF-04457845组8例（17%）患者和安慰剂组4例（17%）患者在治疗期间停药。在4周治疗期内，PF-04457845组46例受试者中有20例（43%）和安慰剂组24例受试者中有11例（46%）发生不良事件。有没有严重的不良事件。解释PF-04457845，一种新的FAAH抑制剂，减少大麻戒断症状和大麻使用的男性，并可能代表一种有效和安全的方法来治疗大麻使用障碍。版权所有（c）2018 Elsevier Ltd.保留所有权利。
Background Cannabis is one of the most widely used drugs worldwide. Cannabis use disorder is characterised by recurrent use of cannabis that causes significant clinical and functional impairment. There are no approved pharmacological treatments for cannabis use disorder. One approach is to potentiate endocannabinoid signalling by inhibiting fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide. We aimed to test the efficacy and safety of the FAAH-inhibitor PF-04457845 in reduction of cannabis withdrawal and cannabis use in men who were daily cannabis users.Methods We did a double-blind, placebo-controlled, parallel group phase 2a trial at one site in men aged 18-55 years with cannabis dependence according to DSM-IV criteria (equivalent to cannabis use disorder in DSM-5). After baseline assessments, participants were randomly assigned (2: 1) to receive PF-04457845 (4 mg per day) or placebo using a fixed block size of six participants, stratified by severity of cannabis use and desire to quit. Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as outpatients. The primary endpoints were treatment-related differences in cannabis withdrawal symptoms during hospital admission, and week 4 (end of treatment) self-reported cannabis use and urine THC-COOH concentrations in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT01618656.Findings Between Sept 12, 2012, and Jan 18, 2016, 46 men were randomly assigned to PF-04457845 and 24 to placebo. Adherence to study medication was 88%, as confirmed by video-calling and pill count, and corroborated by corresponding drug and anandamide concentrations in blood. Relative to placebo, treatment with PF-04457845 was associated with reduced symptoms of cannabis withdrawal (first day of treatment mean symptom score 11.00 [95% CI 7.78-15.57] vs 6.04 [4.43-8.24]; difference 4.96 [0.71-9.21]; p(adj)=0.048; second day of treatment 11.74 [8.28-16.66] vs 6.02 [4.28-8.47]; difference 5.73 [1.13-10.32]; p(adj)=0.035) and related mood symptoms during the inpatient phase. Additionally, treatment with PF-04457845 was associated with lower self-reported cannabis use at 4 weeks (mean 1.27 joints per day [95% CI 0.82-1.97] vs 0.40 [0.25-0.62]; difference 0.88 [0.29-1.46]; p=0.0003) and lower urinary THC-COOH concentrations (mean 657.92 ng/mL [95% CI 381.60-1134.30] vs 265.55 [175.60-401.57]; difference 392.37 [17.55-767.18)]; p=0.009). Eight (17%) patients in the PF-04457845 group and four (17%) in the placebo group discontinued during the treatment period. During the 4-week treatment phase, 20 (43%) of 46 participants in the PF-04457845 group and 11 (46%) of 24 participants in the placebo group had an adverse event. There were no serious adverse events.Interpretation PF-04457845, a novel FAAH inhibitor, reduced cannabis withdrawal symptoms and cannabis use in men, and might represent an effective and safe approach for the treatment of cannabis use disorder. Copyright (c) 2018 Elsevier Ltd. All rights reserved.