Negative cognitive biases—where mood colors learning and memory—are a core feature of major depressive disorder, and reversing them may be key to how rapid-acting antidepressants work. In rats, a single dose of ketamine, scopolamine, or psilocybin selectively weakened a negative affective bias induced in an associative learning task. Low doses of ketamine and psilocybin, but not high doses, reversed the valence of the bias 24 hours later. Only psilocybin produced a lasting positive bias that depended on new learning. Ketamine's relearning effects required protein synthesis in the medial prefrontal cortex and could be altered by cue reactivation, pointing to experience-dependent neural plasticity as a shared mechanism for both the rapid and sustained effects of these drugs.
In a mouse model of autism spectrum disorder (ASD) created by prenatal exposure to valproic acid, the acute response to the serotonergic psychedelic psilocybin was reduced compared to controls. However, psilocybin treatment reversed the social behavior deficits that are characteristic of the ASD model. These findings suggest that psilocybin may have therapeutic potential for improving social interaction in ASD.