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 physical dependence) and limited past-month cannabis use. Study 1
will examine the effects of 7 acute cannabis doses, including a 6-fold dose range of THC (5, 10, 20, 30 mg),
THC/CBD doses across a 3-fold dose range (10:10 mg; 30:30 mg 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 inhaled
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; and 4) cannabis tolerance and withdrawal.
Cannabis modulation of sleep quality during bouts of acute opioid withdrawal will also be explored. 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 inhaled cannabis in an opioid-dependent
population. These studies will provide new controlled information on potential interactions relevant to clinical
practice, prescribing, and public safety.
