Psilocybin, the psychoactive compound found in “magic” mushrooms, has shown promising antidepressant effects in both humans and rodent models. These therapeutic effects are thought to involve modulation of the medial prefrontal cortex (mPFC), a brain region implicated in depression pathology. This study presents preliminary electrophysiological evidence suggesting that psilocybin alters the excitation-to-inhibition balance in the mPFC, potentially contributing to its antidepressant properties. In vivo recordings from rodent mPFC neurons revealed divergent responses to psilocybin administration, with increased activity in GABAergic-like neurons and decreased activity in glutamatergic-like neurons. These findings support the hypothesis that psilocybin enhances inhibitory signaling within the mPFC, thereby reducing overall excitatory activity. Such a shift in network dynamics may promote greater brain flexibility and counteract rigid depressive states. Future research aims to further characterize the specific cell types involved, investigate other psychedelics with similar effects, and assess the long-term behavioral implications of psilocybin-induced neurophysiological changes.