Cycooxygenase-2 Inhibition for Cannabis Withdrawal and Relapse

说明(申请人提供)：相当数量的开始吸食大麻的人患上大麻使用障碍(CUD)并主动寻求治疗，但只有一小部分人实现持续戒烟。迫切需要对CUD进行有效的治疗。在这里，我们提出了一项概念验证、人体实验室研究，以测试一种新的、创新的药理策略，以减少大麻戒断并促进慢性大麻吸烟者的戒烟。在最近的临床前研究中，我们发现环氧合酶-2(COX-2)是使脑内大麻素失活的关键酶，并证明了阻断COX-2活性的非类固醇抗炎药(NSAIDs)可以增加中枢内源性大麻素水平以及随后CB1受体上的内源性大麻素活性。重要的是，最近的另一项研究表明，THC通过激活CB1增加了大脑COX-2的表达。基于最近的这两项研究，我们提出了一个新的假设，即长期接触THC会上调COX-2的表达，进而使内源性大麻素失活，导致内源性大麻素缺乏状态。我们假设，这种内源性大麻素缺乏导致持续使用大麻的负面强化，阻断COX-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。这项应用的主要目的是测试FDA批准的COX-2选择性抑制剂塞来昔布(200 Mg Bid)在人体实验室中对大麻使用的不同特征的有效性：积极的主观效果(良好的药物效果，大麻的‘喜欢’)，戒断(情绪，睡眠，食物摄入量)和复发(戒除一段时间后的大麻自我管理)。参与者将是不寻求治疗的每日吸食大麻的人，他们将完成两个住院研究阶段，一个为期11天的阶段测试塞来昔布，另一个为期11天的阶段测试安慰剂的维持，治疗条件在参与者之间平衡。第二个目标是测量急性大麻注射和戒断后血浆内源性大麻素水平作为塞来昔布治疗的功能，以确定塞来昔布的行为影响是否与血浆内源性大麻素水平增加有关。我们假设塞来昔布将减少大麻戒断症状的严重程度，并将减少我们实验室测量的大麻复发，同时产生的不良事件很少。我们还假设，与安慰剂相比，塞来昔布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COX-2抑制作为治疗CUD的一种新的药理学策略。由于塞来昔布是FDA批准的药物，且耐受性良好，可以很容易地将这些数据快速转换为治疗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.