Psilocybin Does Not Induce Conditioned Place Preference, but Modifies Behavioral Patterns in Sprague-Dawley Rats

Abstract Background Recent years have seen renewed scientific interest in psychedelics, including psilocybin, for their potential in treating neuropsychiatric disorders. However, the reward-related properties and behavioral impacts of a high dose of psilocybin remain insufficiently explored. Aims 70%) indicated that head-twitching, dog-shaking, and defecation were more strongly associated with psilocybin, while grooming, body licking, and rearing were more characteristic of the vehicle group. For behavioral assessment, RM two-way ANOVA showed that on CT1, the psilocybin-treated group exhibited higher scores on head-twitching (p0.0001), dog-shaking (p0.05), and defecation (p0.01), but lower scores on grooming (p0.05), body licking (p0.01), and rearing (p0.01) compared to the vehicle group. These differences were even more pronounced on CT7 for head-twitching, dog-shaking, grooming, and body licking (p0.0001), but not for rearing or defecation. Importantly, on the post-conditioning day (48 hours after the last psilocybin injection), the unpaired Student’s t-test revealed no behavioral differences. Discussion but decreased grooming, rearing and body licking behaviors, which could reflect anxiolytic/anti-repetitive effects. No long-term behavioral changes were found, aligning with evidence that psychedelics do not cause physical dependence or withdrawal symptoms. These findings support the safety profile of psilocybin and its therapeutic potential, even if more studying assessing reward (i.e. self administration) should be conducted.