Changes in peripheral endocannabinoid levels in substance use disorders: a review of clinical evidence

The endocannabinoid (eCB) system is a key modulator of stress and reward and is impacted by alcohol and drug use. Recently, the eCB system has been highlighted as a potential novel target in the treatment of substance use disorders (SUDs). Understanding how chronic substance use impacts the function of the eCB system can provide a mechanistic rationale for targeting this system in the treatment of SUDs. A comprehensive review of studies assessing concentrations of eCB ligands N-arachidonoyl ethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) in individuals with a SUD diagnosis was performed using all EBSCO databases, PubMed, and Google Scholar. Methods and results related to eCB concentrations, diagnosis, and other factors (e.g. treatment status) were extracted from papers written in English and published in peer-reviewed journals before May 22, 2024. Fifteen studies were reviewed; three in alcohol use disorder (AUD), three in cannabis use disorder (CUD), four in cocaine use disorder, one in opioid use disorder (OUD) and four across SUDs. Generally, AEA concentrations were usually, but not always, increased in AUD, CUD, OUD, and cocaine use disorder. 2-AG concentrations were measured less often but were increased in CUD and decreased in cocaine use disorder. Studies generally support the hypothesis that chronic substance use can impact eCB levels, most often with increased AEA and decreased (or not quantified) 2-AG concentrations, though results were often conflicting. Variability in methodology and study design may limit generalizability across studies.