ABSTRACT This revised application requests 5 years of support to continue a translational research program that has made numerous important contributions to our understanding of opioid use disorder (OUD). More than 2 million Americans have OUD and the number of deaths due to opioid overdose continues to rise, in part because of the increased availability of fentanyl and its analogs that are potent, inexpensive, and easy to manufacture. This public health crisis continues despite the availability of medications that substitute for or block the abuse- related and toxic effects of opioids. New and better treatments are needed to address this crisis; ideally, an effective medication for OUD would be nonopioid with little or no abuse or dependence liability and few other adverse effects. Research proposed in this application explores the therapeutic potential of cannabidiol (CBD), a constituent of cannabis that is available increasingly due to legalization of “medical” and “recreational” cannabis by states as well as Federal approval of the CBD-containing medication Epidiolex®. Data from our pilot studies, from other preclinical laboratories, and from a recent study in humans69 suggest that CBD, while itself having no abuse liability, shows promise for treating various dimensions of OUD. Moreover, some studies suggest that mixtures of CBD and Δ9tetrahydrocannabinol (THC; Marinol®) might be more effective than CBD alone for treating OUD. The proposed research also responds to the NIH initiative to repurpose drugs already approved for use in humans by exploring the therapeutic potential of CBD, given alone and with THC, for treating different dimensions of OUD, including drug taking, relapse, and withdrawal. CBD/THC mixtures also simulate cannabis use, which will identify any detrimental effects of cannabis use by patients taking CBD for OUD. These experiments will use well-established procedures that are ongoing in our laboratory and that are highly translatable to humans. Aim 1 will tackle drug taking and relapse by determining the effects of CBD, alone or with THC, on fentanyl self-administration in a food versus drug choice procedure and on reinstatement of responding previously reinforced by fentanyl. Aim 2 will evaluate the ability of CBD, alone or with THC, to attenuate withdrawal in morphine-dependent monkeys, and Aim 3 will investigate changes in opioid toxicity by characterizing the effects of CBD on the ventilatory-depressant, antinociceptive, and cognitive effects of opioids as well as the pharmacokinetic profile of CBD alone and in combination with opioids. The persistence of the opioid crisis underscores the need to explore potential new treatments including nonopioid medications to increase options for treating OUD. In the period of just a few years, CBD has become widely available, promoted for a broad range of indications, and used extensively despite very little rigorous research that either supports or refutes its therapeutic potential. CBD is safe, has no abuse liability, and is approved by the FDA; if the proposed studies provide proof-of-principle in nonhuman primates for using CBD to treat one or more dimensions of OUD, then clinical trials in patients could begin very soon and have an immediate impact on the opioid crisis.

PROJECT NARRATIVE The opioid epidemic continues despite the availability of medications that substitute for (methadone and buprenorphine) or block (naltrexone) most of the abuse-related effects of opioids, underscoring the need for new and better treatments. We hypothesize that the nonpsychoactive cannabinoid, cannabidiol (CBD) will be effective in treating various dimensions of opioid use disorder, including drug taking, relapse, and emergence of withdrawal. These studies in nonhuman primates complement and expand significantly recent promising results with CBD in humans.