The Classical Psychedelic Psilocybin Mitigates Oxycodone Withdrawal

Abstract ID 93521 Poster Board 320 Opioid use disorder (OUD) is a major health issue in the United States, with more than 100,000 opioid overdose deaths yearly. Treatments for OUD currently exist, but their efficacy is limited due to misuse potential, undesirable side effects, and low levels of compliance. Cross-sectional studies suggest that lifetime psilocybin use, a classical psychedelic drug, is associated with lower odds of OUD. Therefore, the current study sought to characterize the effects of psilocybin on different aspects of oxycodone, a widely used prescription opioid drug, withdrawal in mouse models. We evaluated the effect of psilocybin on oxycodone spontaneous withdrawal in mice. This study used 7-9 week-old C57BL/6J male and female mice who were surgically implanted with osmotic minipumps containing oxycodone (60 mg/kg/day) or saline for 7 days. Each treatment group was further injected with either saline or psilocybin (1 mg/kg ip) 2 hours following removal of minipumps. The next day, mice were evaluated for somatic signs of withdrawal and 7 days later for mechanical hypersensitivity. A separate cohort was also tested to determine the effect of psilocybin on oxycodone antinociceptive properties in the tail-withdrawal test. An additional cohort of serotonin (5-HT) 2A receptor knockout (KO) mice were tested in the same paradigm to determine the necessity of the 5-HT2A receptor, a receptor thought to be responsible for the "hallucinogenic" effects of psychedelics. Oxycodone male but not female mice that received psilocybin showed significantly less somatic signs of withdrawal. However, in both sexes, psilocybin reduced oxycodone withdrawal-induced mechanical hypersensitivity while not altering the antinociceptive effects of oxycodone. In addition, the reduction of somatic withdrawal signs by psilocybin was lost in the 5-HT2A KO male mice, however the reduction in withdrawal induced mechanical hypersensitivity remained in the KO mice of both sexes, implicating both 5-HT2A dependent and non-dependent reductions in withdrawal by psilocybin, respectively. Psilocybin shows promising potential for the treatment of opioid withdrawal. Future studies will determine the effect of psilocybin on the reinforcing properties of oxycodone in animals. Suoported by NIH P30 DA033934