Serotonergic psychedelics have shown promise in clinical trials for treating an array of mental health disorders, including depression, anxiety, and post-traumatic stress disorder. Despite these findings, our understanding of how these drugs mechanistically exert their therapeutic effects remains incomplete. While researchers have regularly employed rodent preclinical models to assess such mechanisms, many of these findings arise from stress-naïve animals. Given that prior environmental stress is a critical component for the mental health disorders being studied in clinical trials of psychedelics, understanding the performance of these drugs in animals previously exposed to acute or chronic stress is of strong translational relevance. In this study, we examined the effects of psilocybin in male mice that were stress-naïve, as well as in those that underwent either single-prolonged stress (SPS) or chronic restraint stress (CRS). The effects of these treatments on corticosterone release, extinction of freezing behavior, and recall of extinction in Pavlovian fear conditioning were examined for each group. We observed that psilocybin challenge transiently increased serum corticosterone in stress-naïve mice relative to saline; however, this effect was not observed in SPS and CRS animals. Interestingly, psilocybin treatment enhanced fear extinction and promoted extinction recall 24 h later not only in stress-naïve animals but also in stressed animals. These findings indicate psilocybin's ability to acutely enhance fear extinction and promote enhanced extinction recall across animals with diverse environmental stress experiences prior to exposure.
