Differential effects of psilocybin derivatives on fentanyl-induced conditioned place preference in male and female mice

Background: Fentanyl is the leading cause of fatal overdoses worldwide, and repeated use may lead to substance use disorder (SUD). In SUD, drug-associated contexts can trigger reward-related behavior even in the absence of the drug. Psychedelic compounds may weaken context-drug associations, reducing reward-related behavior to fentanyl. Aims: We evaluated the effects of the psychedelic psilocin and its derivatives, 4-MeO-MiPT and 4-HO-MiPT, on fentanyl-induced conditioned place preference (CPP) in male and female C57BL/6J mice. Methods: Mice were conditioned to distinct fentanyl and saline control contexts, then assessed for fentanyl place preference before and after treatment with one of the test compounds. Anxiety-related side effects of each compound were evaluated using an elevated plus maze (EPM) model. Results: Psilocin reduced fentanyl CPP exclusively in females, 4-MeO-MiPT in both sexes, and 4-HO-MiPT had no effect. None of the compounds significantly altered anxiety-like behaviors in EPM. Conclusion: These findings support further preclinical investigations of the sex-dependent effects of psilocin and 4-MeO-MiPT on fentanyl reward behavior.