New York State Psychiatric Institute, New York, New York, USA.
Columbia University Irving Medical Center, New York, New York, USA.
Addict Biol. 2022 Jul;27(4):e13183. doi: 10.1111/adb.13183.
Attenuating enzymatic degradation of endocannabinoids (eCBs) by fatty acid amide hydrolase (FAAH) reduces cannabis withdrawal symptoms in preclinical and clinical studies. In mice, blocking cyclooxygenase-2 (COX-2) activity increases central eCB levels by inhibiting fatty acid degradation. This placebo-controlled study examined the effects of the FDA-approved COX-2 selective inhibitor, celecoxib, on cannabis withdrawal, 'relapse', and circulating eCBs in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (12M, 3F) completed a crossover study comprising two 11-day study phases (separated by >14 days for medication clearance). In each phase, the effects of daily BID placebo (0 mg) or celecoxib (200 mg) on cannabis (5.3% THC) intoxication, withdrawal symptoms (4 days of inactive cannabis self-administration) and 'relapse' (3 days of active cannabis self-administration following abstinence) were assessed. Outcome measures included mood, cannabis self-administration, sleep, food intake, cognitive performance, tobacco cigarette use and circulating eCBs and related lipids. Under placebo maintenance, cannabis abstinence produced characteristic withdrawal symptoms (negative mood, anorexia and dreaming) relative to cannabis administration and was associated with increased OEA (a substrate of FAAH) and oleic acid (metabolite of OEA), with no change in eCB levels. Compared to placebo, celecoxib improved subjective (but not objective) measures of sleep and did not affect mood or plasma levels of eCBs or associated lipids and increased cannabis craving. The overall absence of effects on cannabis withdrawal symptoms, self-administration or circulating eCBs relative to placebo, combined with an increase in cannabis craving, suggests celecoxib does not show promise as a potential pharmacotherapy for CUD.
通过脂肪酰胺水解酶 (FAAH) 来减弱内源性大麻素 (eCBs) 的酶促降解，可减少临床前和临床研究中的大麻戒断症状。在小鼠中，通过抑制脂肪酸降解来阻断环氧化酶-2 (COX-2) 活性，可增加中枢 eCB 水平。这项安慰剂对照研究，在人类大麻使用障碍的实验室模型中，检查了 FDA 批准的 COX-2 选择性抑制剂塞来昔布对大麻戒断、“复吸”和循环 eCB 的影响。每日，未接受治疗的大麻吸烟者 (12M，3F) 完成了一项交叉研究，包括两个 11 天的研究阶段 (用 >14 天清除药物)。在每个阶段，评估了每日两次 BID 安慰剂 (0mg) 或塞来昔布 (200mg) 对大麻 (5.3%THC) 中毒、戒断症状 (4 天不主动吸食大麻) 和“复吸” (3 天停止吸食大麻后的主动吸食大麻) 的影响。结果包括情绪、大麻自我给药、睡眠、食物摄入、认知表现、吸烟和循环 eCB 及其相关脂质。在安慰剂维持下，与吸食大麻相比，大麻戒断产生了特征性的戒断症状 (负面情绪、厌食和做梦)，并与 OEA( FAAH 的底物)和油酸 (OEA 的代谢物) 的增加有关，而 eCB 水平没有变化。与安慰剂相比，塞来昔布改善了睡眠的主观 (但不是客观) 测量，对情绪或血浆中 eCB 或相关脂质水平没有影响，并增加了大麻的渴望。与安慰剂相比，塞来昔布对大麻戒断症状、自我给药或循环 eCB 没有显示出明显的影响，同时增加了大麻的渴望，这表明塞来昔布作为一种潜在的 CUD 药物治疗方法并没有希望。
