Combination of THC and CBD as a Novel Treatment for Co-Occurring Opioid Addiction and Chronic Pain - PROJECT SUMMARY/ABSTRACT This application aims to examine the combined analgesic and anti-craving effects of delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) in individuals with co-occurring opioid use disorder (OUD) and chronic pain undergoing opioid agonist therapy. Chronic pain affects up to 60% of people with OUD, leading to greater morbidity and mortality. Yet, pain is overlooked in OUD treatment due to the lack of effective therapies addressing both conditions. Hence, there is an urgent need for novel therapeutic approaches. THC has been shown to mitigate pain, while CBD reduces cue-induced opioid craving. Some evidence also suggests that CBD may counterbalance THC’s undesired effects. However, the combined effects of THC and CBD on individuals with co-occurring OUD and chronic pain remain unknown. Studying this population is crucial, as the co-occurrence of pain and OUD causes unique neuroadaptations, clinical trajectories, and poorer outcomes. To close this critical knowledge gap, we propose a human laboratory study to characterize the combined therapeutic effects of THC and CBD among people with co-occurring OUD and chronic pain who are undergoing opioid agonist therapy. The study will investigate the combined effects of THC and CBD on two important triggers of non-medical opioid use: pain sensitivity and cue-induced opioid craving, assessed using multimodal quantitative sensory testing (QST) and a well-validated visual probe task that involves the presentation participant-matched opioid cues (i.e., heroin paraphernalia), respectively. Three groups of 40 participants will be randomized to single doses of oral THC (5 mg, 10 mg) and CBD (400 mg, 800 mg, 1200 mg), across four test sessions separated by three days each. The study will have 3x4 design, with THC dose as a between-subject factor and CBD dose as a within-subject factor. Participants will meet DSM-5 criteria for OUD, have chronic non-cancer low back pain for ≥ 3 months, and will be receiving stable doses of methadone (40-120 mg/day). This study will have a significant impact for this under-researched population, by determining the combined effects of THC/CBD for relieving pain sensitivity and cue-induced opioid craving, two key treatment targets (Aim 1); and determining the abuse potential and cognitive/psychomotor effects of combined THC/CBD, administered with opioid agonist maintenance (Aim 2). This study will also investigate if sex influences the responses to THC/CBD; the combined effects of effects of THC/CBD on central sensitization; and potential drug interactions, indexed by plasma opioid, THC, and CBD levels (Exploratory Aims). This application will advance the understanding of THC/CBD combinations as non-opioid therapeutics, supporting new drug applications for co-occurring OUD and chronic pain. Finally, our model for assessing both OUD and pain treatment targets will establish a benchmark to evaluate novel therapies, addressing NIH's priorities and informing patients, healthcare professionals, and policy stakeholders amidst the opioid crisis.
