Peripheral endocannabinoids and related lipids in individuals with chronic non-medical prescription opioid use

The ongoing opioid epidemic in North America and a significant increase of opioid use as well as opioid-related detoxification in Europe emphasize the need to gain a deeper understanding of the neurobiological mechanisms underpinning the development of opioid use disorder (OUD). Emerging evidence from both preclinical and clinical studies suggests a modulatory role of the endocannabinoid system (ECS) in stress and reward processes, which are critical for initiating and maintenance of substance use disorders. While animal models highlight a specific cross-talk between the ECS and the endogenous opioid system, human translational studies are limited. Therefore, we assessed peripheral baseline endocannabinoids levels of anandamide (AEA) and 2-arachidonoyglycerol (2-AG) along with related lipids such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and fatty acid amide hydrolase (FAAH) activity in chronic non-medical prescription opioid users (NMPOU; N=21) compared to opioid-naïve healthy controls (n=29). Moreover, we investigated whether endocannabinoids and related lipids are associated with subjective stress responses to experimentally-induced social exclusion. We found significantly elevated baseline levels of AEA, OEA, and PEA in NMPOU compared to controls, but no group differences of FAAH activity, 2-AG, or other related lipids. Among NMPOU, higher AEA levels correlated with a reduced perception of social exclusion. Robust positive correlations within N-acylethalonamines (e.g., AEA, OEA, and PEA) indicate strong metabolic associations. Together with our recent findings of elevated 2-AG levels in dependent cocaine users, our results suggest substance-specific alterations of the ECS, offering potential insights for the development of novel therapeutic interventions for these populations.