Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Significance Psychedelic compounds, such as psilocybin, have beneficial actions in several psychiatric diseases. They also produce strong alterations of consciousness, which may be a barrier to their widespread use. We found that psilocybin has fast-acting antidepressant-like properties in mice. Using multiple assays of hedonic behavior and an antagonist of prohallucinatory 5-HT2A receptors, we further suggest that altered perception may not be necessary for its therapeutic actions. We also showed that psilocybin strengthens connections between brain cells in regions important for processing rewards and emotions. These experiments suggest that it may be possible to retain the beneficial actions of psilocybin while minimizing the alterations in consciousness, thereby accelerating its use in the clinic.