The therapeutic efficacy of psilocybin in major depressive disorder: A review of recent clinical and mechanistic evidence
Zenodo (CERN European Organization for Nuclear Research) January 26, 2026 Fernando Mora López, Johynny Solís Solís, Ekaterina Daniela Hernández Baker et al.
Psilocybin, acting as a 5-HT2A receptor agonist, alters brain connectivity in networks involved in self-referential processing and emotional regulation, accompanied by neuroplastic changes such as enhanced synaptogenesis and functional reorganization. Neuroimaging shows reduced amygdala activity and modifications in default mode and executive networks. Clinical evidence indicates substantial reductions in depressive symptoms, with meta-analyses reporting large effect sizes and durable benefits lasting from weeks to a year. Randomized controlled trials show rapid onset and higher remission rates than conventional treatments, even in treatment-resistant depression. Adverse events are mild, transient, and predictable, though methodological limitations like small samples and high heterogeneity call for larger Phase III trials.