Cycooxygenase-2 Inhibition for Cannabis Withdrawal and Relapse

描述（由申请人提供）：大量开始吸食大麻的人发展为大麻使用障碍（CUD）并主动寻求治疗，但只有一小部分人实现了持续的禁欲。迫切需要有效的CUD治疗方法。在这里，我们提出了一个概念验证，人类实验室研究，以测试一种新的和创新的药理学策略，以减少大麻戒断和促进大麻戒断慢性大麻吸烟者。在最近的临床前研究中，我们已经确定环氧合酶-2（考克斯-2）是使大脑内源性大麻素失活的关键酶，并且已经证明阻断考克斯-2活性的非甾体抗炎药（NSAIDS）可以增加中枢内源性大麻素水平和随后的CB 1受体处的内源性大麻素活性。重要的是，另一项最近的研究表明，THC给药通过CB 1激活增加脑考克斯-2表达。基于这两个最近的研究，我们提出了新的假设，慢性THC暴露上调考克斯-2的表达，这反过来又灭活内源性大麻素，导致“内源性大麻素缺乏”的状态。我们假设，这种内源性大麻素缺乏导致了持续使用大麻的负强化，阻断考克斯-2活性将使这种内源性大麻素缺乏正常化，减少戒断症状，并减少吸毒复发。本申请的主要目的是测试FDA批准的考克斯-2选择性抑制剂塞来昔布（200 mg BID）对人类实验室中大麻使用的离散特征的疗效：积极的主观效应（“良好的药物效果”，“喜欢”大麻）、戒断（情绪、睡眠、食物摄入）和复发（戒断一段时间后大麻自我给药）。参与者将是非寻求治疗的每日大麻吸烟者，他们将完成两个住院研究阶段，其中一个11天阶段测试塞来昔布，另一个11天阶段测试安慰剂维持，治疗条件在参与者中平衡。次要目的是测量作为塞来昔布治疗的函数的急性大麻给药和戒断后内源性大麻素的血浆水平，以确定塞来昔布的行为效应是否与内源性大麻素的血浆水平增加相关。我们假设塞来昔布将降低大麻戒断症状的严重程度，并将减少我们的实验室大麻复吸的措施，同时产生很少的不良事件。我们还假设，塞来昔布治疗相对于安慰剂治疗会增加血浆内源性大麻素水平，并与戒断严重程度呈负相关。如果成功，这些研究将最终引入考克斯-2抑制作为治疗CUD的新药理学策略。由于塞来昔布是FDA批准的药物，耐受性良好，因此可以很容易地将这些数据快速转化为治疗CUD。

DESCRIPTION (provided by applicant): A significant number of individuals who start smoking cannabis develop a cannabis use disorder (CUD) and seek treatment on their own initiative, yet only a small percentage achieves sustained abstinence. Efficacious treatments for CUD are critically needed. Here we propose a proof-of-concept, human laboratory study to test a novel and innovative pharmacological strategy to reduce cannabis withdrawal and facilitate cannabis abstinence in chronic cannabis smokers. In recent preclinical studies, we have identified cyclooxygenase-2 (COX-2) as a key enzyme that inactivates brain endocannabinoids, and have demonstrated that non-steroidal anti-inflammatory drugs (NSAIDS) that block COX-2 activity can increase central endocannabinoid levels and subsequent endocannabinoid activity at the CB1 receptor. Importantly, another recent study showed that THC administration increases brain COX-2 expression via CB1 activation. Based on these two recent studies, we propose the novel hypothesis that chronic THC exposure up-regulates COX-2 expression, which in turn inactivates endogenous cannabinoids, resulting in an "endocannabinoid-deficient" state. We hypothesize that this endocannabinoid deficiency contributes to the negative reinforcement driving continued cannabis use, and that blocking COX-2 activity will normalize this endocannabinoid deficiency, reduce withdrawal symptoms, and reduce relapse to drug taking. The primary objective is of this application is to test the efficacy of the FDA- approved COX-2 selective inhibitor, celecoxib (200 mg BID), on discrete features of cannabis use in the human laboratory: positive subjective effects ('good drug effect', cannabis 'liking'), withdrawal (mood, sleep, food intake), and relapse (cannabis self-administration after a period of abstinence). Participants will be non- treatment-seeking daily cannabis smokers who will complete two inpatient study phases, with one 11-day phase testing celecoxib and the other 11-day phase testing placebo maintenance, with treatment condition counter-balanced across participants. A secondary objective is to measure plasma levels of endogenous cannabinoids following acute cannabis administration and withdrawal as a function of celecoxib treatment, to determine if the behavioral effects of celecoxib are related to increased plasma levels of endogenous cannabinoids. We hypothesize that celecoxib will reduce the severity of cannabis withdrawal symptoms and will reduce our laboratory measure of cannabis relapse while producing few adverse events. We also hypothesize that plasma endocannabinoid levels will be increased by celecoxib treatment relative to placebo and will be negatively correlated with withdrawal severity. If successful, thes studies will ultimately introduce COX-2 inhibition as a novel pharmacological strategy for the treatment of CUD. Since celecoxib is an FDA- approved drug and well-tolerated, rapid translation of these data to treat CUD can be easily envisioned.