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.
New treatments for cannabis use disorder (CUD) are critically needed. This human laboratory study follows up on compelling new preclinical findings showing that the COX-2 inhibitor, celecoxib, increases endogenous cannabinoid levels, which could mitigate cannabis withdrawal symptoms and thereby reduce rates of cannabis relapse. Since celecoxib is an FDA-approved drug and well-tolerated, rapid translation of these data to treat CUD can be easily envisioned.