Therapeutic Potential of Classical Psychedelics and NonHallucinogenic Psychoplastogens in Psychiatric Disorders
Psychiatry and Clinical Psychopharmacology March 30, 2026 Kenji Hashimoto, Feyza Arıcıoğlu, Mesut Çetin
Classical serotonergic psychedelics—psilocybin, DMT, 5-methoxy-DMT, and LSD—can produce rapid and sometimes durable improvements in mood under supervised conditions. The review synthesizes clinical evidence for these compounds in depression and related disorders, noting challenges such as small sample sizes, expectancy effects, and limitations in maintaining blinding. Mechanistic frameworks extend beyond 5-HT2A receptor activity, involving multiple serotonergic subtypes, glutamatergic modulation, synaptic plasticity, and brain network reorganization. Preclinical and clinical evidence points to neurotrophic mechanisms, particularly BDNF-TrkB signaling, as contributors to sustained effects. Acute mystical-type experiences may enhance response but are not strictly required, suggesting plasticity-promoting mechanisms can be partially dissociated from hallucinogenic effects. Peripheral contributions, including gut-brain axis interactions, may influence treatment durability.