PROJECT SUMMARY The opioid-epidemic, rooted in a chronic-relapsing disease, has had devastating consequences leading to profound national burden. Research into the enhancement of treatment options for individuals with opioid use disorder (OUD) is clearly a priority. Responding to urgent calls for non-opioid treatment, we have been evaluating the therapeutic potential of cannabidiol (CBD), a non-intoxicating cannabinoid. Our preclinical animal studies have shown that CBD decreases cue-induced heroin seeking behavior during drug abstinence, associated with incubation of craving. We have also shown that CBD was safe even in combination with a potent opioid agonist to address a potential relapse condition and that CBD decreased craving and anxiety associated with heroin cues in abstinent individuals with heroin use disorder, an effect that persisted even a week after the last CBD dose. Building on this foundation and recognizing that cannabinoids such as CBD have, to date, poor bioavailability, we propose to investigate an oral CBD powered by a novel patented technology (leveraging the kinetics of long chain fatty acid absorption) in a gelcap delivery system that improves bioavailability, reduces the incidence of gastrointestinal side effects, reduces first pass metabolism and enhances onset time. In a randomized, double-blinded, placebo-controlled study of MED-CBD, we aim to determine the pharmacokinetic and pharmacodynamic effects in OUD participants and obtain insights about the concentration range of MED- CBD that acutely reduce craving in OUD individuals (UG3 phase). Leveraging our large OUD population (~6,500) at the Addiction Institute of Mount Sinai and using ecological momentary assessment technology to monitor craving in real-time, we will study various doses MED-CBD effects on opioid abstinent individuals not maintained on medication assisted therapy as well as on those managed on opioid agonists. Subsequently, a large clinical trial based on the UG3 results will investigate the long-term (6 months) and the potential protracted effects (6 weeks) of MED-CBD administration on general and cue-induced craving, relapse, opioid medication dose as well as psychosocial functioning in OUD opiate-abstinent participants managed on opioid agonists (UH3 phase). These studies will provide concrete information necessary to develop a non-opioid, non-intoxicating FDA- approved medication to reduce craving, relapse and restore global functioning in OUD individuals.