The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine.
Dongsun Park, Gwangho Lee, Won-Gyu Lee, Bokyum Kim, Yoonji Lee, Ji-Woon Kim
Molecular Psychiatry July 7, 2025 DOI: 10.1038/s41380-025-03100-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Neuroplasticity Esketamine Ketamine Psilocybin |
| Keywords | Depression treatment Antidepressant therapy Mood disorder treatment Rapid-acting depression relief Mental health solutions Neural connections Brain remodeling Psychedelic medicine Ketamine treatment Psilocybin therapy Novel antidepressants Rapid-acting compounds Brain research Neurobiology Neural mechanisms Therapeutic mechanisms |
| Citations | 7 |
| Key findings | Ketamine and psilocybin enhance synaptic plasticity through distinct initial mechanisms but converge on BDNF-TrkB signaling to produce rapid and sustained antidepressant effects. |
Abstract
Major depressive disorder is a debilitating condition, with many patients unresponsive to conventional monoaminergic antidepressants. Rapid-acting antidepressants such as ketamine and psilocybin offer promising alternatives, relieving symptoms within hours. Ketamine, an NMDA receptor antagonist, and psilocybin, a serotonergic psychedelic primarily targeting 5-HT2A receptors, both enhance synaptic plasticity in mood-regulating circuits through distinct mechanisms. This review synthesizes recent clinical and preclinical findings on ketamine and psilocybin, emphasizing their molecular targets, circuit-level effects, and converging downstream pathways. A key shared mechanism involves BDNF-TrkB signaling, which promotes spinogenesis and synaptogenesis critical for sustained antidepressant efficacy. We also discuss 5-HT2A receptor biased agonism as a potential strategy to dissociate psilocybin's therapeutic effects from its hallucinogenic actions. By comparing their mechanistic profiles, we identify both overlapping and distinct features that may inform the development of next-generation rapid-acting antidepressants. Understanding how serotonergic, glutamatergic, and neurotrophic systems converge may guide the development of fast-acting, durable, and non-hallucinogenic antidepressants.
Comparable studies
Other narrative reviews on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| The pharmacology of psilocybin | 2002 | Review | |
| Serotonin research: contributions to understanding psychoses | 2008 | Review | |
| Psychedelics, Meditation, and Self-Consciousness | 2018 | Review | |
| The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act | 2018 | Review |
Citations in the library
Cited by 6
- Psilocybin improves novel object recognition in a rat model of Fragile X Syndrome through the modulation of the BDNF/TrkB signaling pathway Neuropsychopharmacology February 13, 2026
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring. Neuropsychopharmacology February 1, 2026
- Psilocybin-assisted therapy for major depressive disorder: Perspective from meta-analysis. Journal of Affective Disorders August 1, 2026
- Naturally Derived Psilocybin for Therapeutic Use: A Six-Criterion Framework for Evidence, Safety, and Benefit–Risk Considerations in Policy and Clinical Development Biomolecules July 3, 2026
- Psilocybin restores behavioral and neuroplastic deficits induced by chronic stress in rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 20, 2026
and 1 more in the library
Cites 109
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
and 104 more in the library