Endocannabinoid response to social stress in chronic non-medical prescription opioid users.

Rationale The ongoing global opioid crisis underscores the need to better understand the neurobiological mechanisms underlying opioid use disorder (OUD). Stress is a key risk factor for developing and maintaining OUD. While animal models report that the endocannabinoid system (ECS) plays a modulatory role in stress response, alterations of ECS stress reactivity in individuals with OUD have yet to be studied.Objectives Here, we aimed to study the response of the ECS to experimentally-induced mild psychosocial stress in individuals with non-medical prescription opioid use (NMPOU) without intravenous use.Methods We compared plasma concentrations of the two main endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) along with structurally related N-acylethalonamines (NAEs) and arachidonic acid (AA) between individuals with chronic NMPOU (n = 21) and matched opioid-naïve healthy controls (n = 29) after social exclusion using the Cyberball task. Blood samples were collected before stress induction, and 10, 20, 30, and 60 min after stress onset.Results We found a significant GROUP*TIME interaction for 2-AG, with controls showing increased 2-AG plasma levels after stress, contrasting with a blunted stress response in NMPOU. Both groups robustly differed in 2-AG levels at all time points after stress induction. No significant GROUP*TIME interactions were found for AEA, NAEs, and AA. Increased 2-AG levels were associated with greater feelings of social inclusion overall.Conclusion Results suggest dysfunctional stress response at the level of the ECS in individuals with NMPOU. Specifically 2-AG might play a critical role in stress resilience and, thus, it might be a potential pharmacotherapeutic target in the treatment of OUD.