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The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine

Molecular Psychiatry volume 30, pages 4910–4927 (2025)Cite this article

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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.

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Fig. 1: Structures of NMDARs complexed with ketamine.
Fig. 2: Schematic overview of the mechanisms underlying the rapid antidepressant effects of ketamine and psilocybin.
Fig. 3: Structural models of psilocin and ketamine binding to the TM domain of TrkB receptor.
Fig. 4: Binding sites of 5-HT, psilocin, and other hallucinogenic or non-hallucinogenic compounds at the 5-HT2A receptor.

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Acknowledgements

This work was supported by a grant from the BK21 FOUR program of Graduate School, Kyung Hee University (GS-1-JO-NON-info21 20240422 to DP and GL), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00212118 to JK), and the Korean Ministry of Environment under the ’Environmental Health R&D Program’ (No. 2021003310005 to YL).

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Author notes

  1. Dongsun Park

    Present address: Institute of Integrated Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea

  2. These authors contributed equally: Dongsun Park, Gwangho Lee, Won-Gyu Lee, Bokyum Kim.

Authors and Affiliations

  1. Department of Biomedical and Pharmaceutical science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea

    Dongsun Park & Ji-Woon Kim

  2. Department of Regulatory Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea

    Gwangho Lee, Bokyum Kim & Ji-Woon Kim

  3. College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea

    Won-Gyu Lee & Ji-Woon Kim

  4. College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea

    Yoonji Lee

  5. Institute of Integrated Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea

    Ji-Woon Kim

  6. Institute of Regulatory Innovation through Science, Kyung Hee University, Seoul, Republic of Korea

    Ji-Woon Kim

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DP, GL, WGL, BK, YL, and JWK wrote the manuscript and drew the figures and Tables.

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Park, D., Lee, G., Lee, WG. et al. The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Mol Psychiatry 30, 4910–4927 (2025). https://doi.org/10.1038/s41380-025-03100-2

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