Behavioural, pharmacokinetic, and genetic evidence of a cannabidiol-oxycodone drug-drug interaction in mice

This study investigated the interaction between oxycodone and cannabidiol (CBD) on opioid analgesia and pharmacokinetics. We conducted in vivo behavioural studies to assess CBD's short and long-term effects on opioid analgesia and used qPCR to investigate the interaction of oxycodone and CBD at the genetic and neural level. Acute administration of CBD in male C57BL/6 J mice inhibited the metabolism of oxycodone into its less active metabolites, leading to a three-fold increase in total oxycodone exposure and a 50% increase in peak concentration. Acutely, this interaction appeared to extend the analgesic efficacy of a single oxycodone dose. In contrast, sub-chronic co-administration of CBD and oxycodone accelerated the development of tolerance to oxycodone analgesia, but not morphine. Moreover, CBD increased Oprm1 and Cnr1 mRNA expression in the periaqueductal gray in oxycodone, but not morphine-treated mice. This potential drug-drug interaction between oxycodone and CBD is possibly mediated by CYP2D6 and CYP3A4 enzymes, which are inhibited by CBD, and which are responsible for oxycodone, but not morphine metabolism. These findings suggest that CBD alters the analgesic efficacy of oxycodone and future translational studies are required to observe if this occurs at lower nutraceutical doses of CBD and in humans. The findings may have implications for chronic pain management and the simultaneous use of oxycodone and CBD.