High dose of psilocybin induces acute behavioral changes without inducing conditioned place preference in Sprague-Dawley rats.

Background: In recent years, there has been a resurgence of scientific interest in psychedelics, including psilocybin, for their potential in treating neuropsychiatric disorders. However, the reward-related effects of psilocybin and its impact on behavior remain underexplored.

Aims: We aimed to evaluate the potential rewarding effects of high doses of psilocybin and its effects on rat behavior.

Methods: Sprague-Dawley rats were exposed to the conditioned place preference (CPP) paradigm. Over an 8-day period, rats were administered either psilocybin (10 mg/kg, i.p.) or vehicle (0.9% saline, i.p.) on odd conditioning days, while receiving vehicle (0.9% saline, i.p.) on even conditioning days. The potential rewarding effect induced by psilocybin was assessed 48 hours after the last psilocybin injection. Behavioral assessments, including head twitch, body shaking, grooming, body licking, defecation pellets, and rearing, were conducted during the CPP exposure.

Results: Psilocybin did not induce CPP in rats, highlighting its lack of reinforcing effects under these conditions. However, this regimen of administration led to modifications in the behavioral profile during CPP test by increasing head twitching, wet-wet-dog shaking, and defecation pellets and decreasing grooming, body licking, and rearing compared to the vehicle group. Importantly, 48 hours after the final psilocybin injection, no behavioral differences were observed between psilocybin and vehicle groups.

Conclusion: Psilocybin at this regimen (10 mg/kg, every other day) does not induce CPP, but induces changes in behavior, which disappear 48 hours after the last injection. More research is needed to better evaluate the addiction liability of psychedelics using different paradigms, doses, and protocols.