The FDA has approved psilocybin, the psychoactive compound in magic mushrooms, as a breakthrough therapy for depression, but its detailed mechanism remains unknown. Serotonergic psychedelics like psilocybin and LSD produce hallucinatory effects by stimulating the serotonin 5-HT2A receptor. In mice, 5-HT2A agonists such as DOI and psilocin (the active metabolite of psilocybin) reduced immobility time in the forced-swim test, an effect absent when the 5-HT2A gene was knocked down in the lateral septum. Activating Gq signaling in 5-HT2A-positive neurons in the lateral septum produced antidepressant and anxiolytic effects. Most 5-HT2A-positive cells in the lateral septum are GABAergic inhibitory neurons, suggesting their activation underlies the antidepressant effect.
Psilocin, the active metabolite of psilocybin, produces antidepressant effects in mice by activating serotonin 5-HT2A receptors on GABAergic neurons in the lateral septum that project to the dorsomedial hypothalamic nucleus. Selectively inhibiting this pathway eliminated the antidepressant-like effect in forced-swim and social defeat stress tests, while activating it induced antidepressant-like effects. Microinjection of bicuculline, a GABAA receptor antagonist, into the dorsomedial hypothalamic nucleus diminished psilocin's antidepressant effect. These findings suggest that this specific neural network underlies the antidepressant action of serotonergic psychedelics, separate from their hallucinatory effects mediated by the visual cortex.