Major depressive disorder remains a leading cause of disability worldwide, and current antidepressants are limited by delayed onset and incomplete response. Building on advances driven by ketamine research, renewed interest has focused on classical serotonergic psychedelics-particularly psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-DMT, and lysergic acid diethylamide (LSD)-which, under supervised conditions, can produce rapid and sometimes durable improvements in mood. This review synthesizes contemporary clinical evidence for classical psychedelics in depression and related disorders and evaluates key translational challenges, including small sample sizes, expectancy effects, and limitations in maintaining blinding in randomized controlled trials. We further evaluate mechanistic frameworks that move beyond an exclusively 5-HT2A receptor-centric framework. Classical psychedelics engage multiple serotonergic receptor subtypes and convergent intracellular signaling pathways that modulate glutamatergic neurotransmission, promote synaptic plasticity, and reorganize large-scale brain networks. Converging preclinical and clinical evidence implicates neurotrophic mechanisms-particularly brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling-as contributors to sustained therapeutic effects. Although acute mystical-type experiences may enhance clinical response, emerging evidence suggests they are not strictly required, raising the possibility that plasticity-promoting mechanisms can be partially dissociated from hallucinogenic effects. We also consider peripheral contributions, including gut-brain axis interactions, that may influence treatment durability. Finally, we discuss safety considerations and future directions, emphasizing the need for rigorously designed trials of next-generation non-hallucinogenic psychoplastogens to improve safety, scalability, and long-term tolerability.
