Impact of cyclooxygenase‐2 inhibition on cannabis withdrawal and circulating endocannabinoids in daily cannabis smokers

Abstract

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.

Sex differences in endocannabinoid tone in a pilot study of cannabis use disorder and acute cannabis abstinence

“…[13][14][15] More recently, work has emerged suggesting that the eCB system may also undergo changes during acute cannabis abstinence in individuals with CUD. [16][17][18] This is consistent with the known role of the eCB system in reward, 19 sleep 20 and feeding, 21 all of which are disrupted in cannabis withdrawal. 3 Normalizing eCB signalling during early abstinence might serve as a viable pharmacotherapeutic strategy to reduce cannabis withdrawal symptoms and subsequently prevent relapse in people with CUD.…”

“…While we cannot definitively attribute this difference to race, it is consistent with previously described racial differences in peripheral 2‐AG 44 and highlights the importance of considering individual factors when conducting research related to the eCB system. Similarly, both eCB and eCB congener levels and subjective outcomes may have been impacted by differences in individual adherence to abstinence procedures, which were laxer than those previously described in the literature (i.e., inpatient observation) 16–18 . Indeed, it is possible that missing saliva drug test videos in this study corresponded with instances of use, which may have impacted results.…”

“…In addition to the canonical eCB system are eCB congeners that share synthetic and degradative pathways with AEA (i.e., the other N ‐acylethanolamines [NAEs]: palmitoylethanolamide [PEA], stearoylethanolamide [SEA], linoleylethanolamide [LEA], oleoylethanolamine [OEA], docosatetraenylethanolamide [DEA]), and their associated enzymes and receptor subtypes that comprise an “endocannabinoidome.” 10 The endocannabinoidome shows evidence of reactivity to acute cannabis use 11,12 and dysregulation during heavy use 13–15 . More recently, work has emerged suggesting that the eCB system may also undergo changes during acute cannabis abstinence in individuals with CUD 16–18 . This is consistent with the known role of the eCB system in reward, 19 sleep 20 and feeding, 21 all of which are disrupted in cannabis withdrawal 3 …”

“…Similarly, both eCB and eCB congener levels and subjective outcomes may have been impacted by differences in individual adherence to abstinence procedures, which were laxer than those previously described in the literature (i.e., inpatient observation). [16][17][18] Indeed, it is possible that missing saliva drug test videos in this study corresponded with instances of use, which may have impacted results.…”

“…However, work evaluating eCB tone during early abstinence and the efficacy of eCB-modulating pharmacotherapeutics beyond direct CB1R agonism has been limited almost entirely to male subjects. 2,[16][17][18] Likewise, despite known sex differences in the eCB system [22][23][24][25] and in the presentation of cannabis withdrawal, 4,5,26 sex differences in eCB tone in individuals with CUD during use and withdrawal have not been evaluated.…”