Cannabis Modulation of Outcomes Related to Opioid Use Disorder: Opioid Withdrawal, Opioid Abuse Potential and Opioid Safety

Abstract Opioids and cannabinoids are the two most widely used and misused drug classes. Worldwide, an estimated 53 million people misuse opioids. In the US, 2.6 million individuals meet criteria for opioid use disorder and nearly 47,000 people died in 2019 due to opioid overdose. At the same time, global cannabis (i.e., marijuana) use is also at record high levels - in 2018, 43.5 million individuals in the US reported past-year cannabis use. Despite high rates of both licit and illicit use of these drug classes, there are no controlled data on the effects of cannabis in one of the most high-risk groups – individuals with opioid use disorder. Thus, the current project aims to explore how both acute (Study 1) and repeated (Study 2) cannabis administration impacts 1) opioid abuse potential, 2) opioid withdrawal severity, and 3) opioid safety/physiological effects. Two independent inpatient studies will be conducted during this 4-year project and each will utilize a randomized, within-subject, double-blind, placebo-controlled design and will enroll samples of participants with moderate to severe opioid use disorder (with current opioid physical dependence) and limited past-month cannabis use. Study 1 will examine the effects of 7 acute cannabis doses, including concentrations that are commonly used for medical and recreational purposes (i.e., high potency THC, combinations of THC+CBD), and matched placebo on outcomes related to 1) opioid abuse liability (i.e., ratings of high, drug liking) during an acute opioid challenge, 2) withdrawal severity (during acute instances of opioid withdrawal), and 3) safety/physiological effects (e.g., respiratory drive) of the drug conditions and combinations. Study 2 will explore the effects of repeated smoked cannabis (3 times/day for 6.5 consecutive days), across three randomized dosing blocks (two active cannabis doses, matched placebo), to determine how a repeated cannabis dosing model impacts outcomes related to 1) opioid abuse potential (i.e., ratings of high, drug liking) assessed during an acute opioid challenge; 2) withdrawal severity (measured during acute instances of opioid withdrawal), 3) safety/physiological effects (e.g., respiratory drive) of the drug conditions and combinations; 4) cannabis withdrawal will also be assessed during wash-out phases between each cannabis dosing block. Cannabis modulation of sleep quality during bouts of acute opioid withdrawal will also be explored in both studies. Both studies will employ a full complement of pharmacodynamic outcomes, including subjective and observer-rated measures, as well as a full battery of physiological and psychomotor outcomes related to safety and impairment to fully assess the potential risk/benefit profile of cannabis in OUD. Overall, these timely and innovative studies will provide the first empirical data on the effects of smoked cannabis in an opioid- dependent population. These studies will provide new controlled information on potential interactions relevant to clinical practice, prescribing, and public safety.