Acute psilocybin robustly improves cognitive flexibility in male and female rats, enhancing their ability to switch between previously learned strategies in response to uncued environmental changes. Psilocybin did not affect Pavlovian reversal learning, indicating its cognitive effects are selective to strategy switching. The serotonin 5HT2A receptor antagonist ketanserin blocked psilocybin's effect on set-shifting, while a 5HT2C-selective antagonist did not; ketanserin alone also improved set-shifting performance, suggesting a complex pharmacological relationship. The psychedelic DOI impaired cognitive flexibility in the same task, showing this effect does not generalize to all serotonergic psychedelics. These findings provide a behavioral model for investigating psilocybin's neuronal effects relevant to its clinical outcomes.
Psilocybin, MDMA, and ketamine show promise for rapidly treating mood and related psychiatric disorders. Clinical data for psilocybin and MDMA, with positive outcomes for depression, anxiety, PTSD, and substance use disorders, have always involved clinician-assisted intervention. Even ketamine's first successful psychiatric use for depression combined it with psychotherapy, and emerging evidence indicates that the subjective experience during ketamine treatment predicts clinical outcome. This review examines how the context and process of drug administration have been integral to published work, stresses the need for trials comparing drug alone versus drug with psychological support, and suggests future animal models that consider context, experience, and expectancy in drug effects.