Bridging ancient substances and modern psychiatry: the role of classic psychedelics in depression treatment.
Neuroscience January 22, 2026 Guilherme Lodetti, Gislaine Zilli Réus, Eduardo Pacheco Rico
Fewer than half of patients with major depressive disorder achieve remission with standard pharmacotherapy, and many cannot tolerate it. This narrative review examines classic psychedelics as an alternative treatment. These substances primarily bind to 5-HT2A receptors, increasing connectivity between sensory and motor brain networks. They generate long-term behavioral responses comparable to traditional antidepressants. Clinical and experimental studies show that classic psychedelics alleviate depressive symptoms. The mood improvement is thought to stem from effects on neuroplasticity, including neurogenesis and related signaling pathways.