Psilocybin's psychoactivity is primarily attributed to agonism at 5-HT2A receptors, but it also binds to 5-HT2C and 5-HT1A receptors and indirectly modulates the dopaminergic system. In an animal model, psilocin (psilocybin's active metabolite) induced broadband desynchronization and disconnection in EEG, decreasing mean absolute power across 1–25 Hz and reducing global functional connectivity, particularly fronto-temporal connections. Antagonists of 5-HT1A, 5-HT2A, and 5-HT2C receptors, as well as antipsychotics haloperidol (D2 antagonist) and clozapine (mixed D2/5-HT antagonist), normalized power decreases in 1–25 Hz, but only clozapine affected 25–40 Hz decreases. The 5-HT2A antagonist reversed psilocin-induced connectivity decreases, while other drugs had no effect, indicating that multiple serotonergic and dopaminergic mechanisms contribute to these neurophysiological changes.
Psilocin, the active compound in magic mushrooms, promotes the formation of new synapses in rat brain cells, an effect comparable to ketamine and lithium. In laboratory experiments on rat cortical cultures, psilocin increased the number of synaptic puncta and boosted expression of the immediate early gene Arc after acute treatment. Lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) did not produce significant synaptogenic effects. Fluoxetine, a common antidepressant, had no effect on synapse formation but upregulated other immediate early genes. These findings add evidence that psilocin may be a promising therapeutic agent for psychiatric conditions.
Psychedelics can produce rapid and lasting antidepressant effects, likely through neuroplasticity, though the precise molecular mechanisms are not yet understood.