Purpose of Review <p>This review considers the complexity of literature on the potential opioid-sparing properties of cannabinoids. As public debate and opinion intensifies around the role of cannabinoids in human health, we distill findings of seminal studies on opioid and cannabinoid co-use and identify areas for future exploration.</p> Recent Findings <p>Cannabinoid and opioid systems involve common neural circuitry in areas of the brain associated with reward-processing and motivation. These findings, drawn from animal studies, illustrate preclinical evidence of analgesic synergy in two main ways, by demonstrating that (1) cannabinoid agonists augment the analgesic effects of opioids in animal models, and (2) cannabinoids extend the duration of analgesia afforded by opioids. Though preclinical evidence for cannabinoids and opioid analgesic synergy is growing, findings amongst clinical studies are much more limited and variable. Furthermore, from an opioid use disorder standpoint, preclinical and clinical studies of cannabis use on opioid craving and opioid misuse have also yielded mixed and inconclusive results.</p> Summary <p>Opioid overdose deaths have catalyzed an intense focus on strategies to reduce opioid use, particularly in the medical setting where many opioids continue to have a significant therapeutic role. As a growing body of research delves into opioid-sparing approaches, these efforts also mirror burgeoning public interest in cannabis as a potential therapeutic. The strength and reproducibility of evidence for opioid-sparing cannabinoids is heterogenous, though our understanding of the neurobiology of this potential phenomenon is expanding. Nonetheless, further research is needed, as current evidence lags behind public policy, opinion and commercial interest in cannabis as an adjunctive therapy for opioid use disorder and pain.</p>