EFFICACY AND SAFETY OF PSILOCYBIN IN TREATMENT-RESISTANT DEPRESSION: A REVIEW
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6573Keywords:
Psilocybin, Treatment-Resistant Depression, Psychedelic-Assisted Therapy, Neuroplasticity, Rapid-Acting Antidepressants, Serotonin 5-HT2A ReceptorAbstract
Major depressive disorder (MDD) is one of the leading causes of disability worldwide. A substantial proportion of patients fail to achieve remission through standard monoaminergic therapies, meeting the clinical criteria for treatment-resistant depression (TRD). TRD is associated with significant clinical morbidity and a profound economic burden on healthcare systems. This review evaluates the clinical efficacy, safety profile, and neurobiological mechanisms of psilocybin, a serotonergic psychedelic, as a targeted intervention for TRD. Current neurobiological evidence indicates that psilocybin, upon conversion to its active metabolite psilocin, acts primarily as a 5-HT2A receptor agonist. This mechanism promotes rapid structural neuroplasticity and modulates the aberrant functional connectivity characteristic of severe depression. Recent randomized clinical trials demonstrate that psilocybin, when administered in controlled settings with psychological support, produces rapid and clinically significant reductions in depressive symptoms. Comparative data indicate that its therapeutic efficacy is at least comparable to standard first-line treatments, such as SSRIs, while frequently offering a faster onset of action. Regarding safety, psilocybin is generally well-tolerated in clinical environments; adverse events are typically mild to moderate and transient. However, the strict requirement for concurrent psychological support and rigorous psychiatric screening highlights a clinical complexity distinct from traditional pharmacotherapies. Overall, current evidence indicates that psilocybin is a promising intervention for TRD with a manageable safety profile in controlled settings. Nevertheless, large-scale, long-term randomized trials are required to determine the durability of its effects and to establish standardized treatment protocols.
References
Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M. J., Erritzoe, D., Kaelen, M., Bloomfield, M. A. P., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Pilling, S., Curran, V. H., & Nutt, D. J. (2016). Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study. The Lancet Psychiatry, 3(7), 619–627. https://doi.org/10.1016/S2215-0366(16)30065-7
Carhart-Harris, R. L., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D., & Nutt, D. J. (2021). Trial of psilocybin versus escitalopram for depression. The New England Journal of Medicine, 384(15), 1402–1411. https://doi.org/10.1056/NEJMoa2032994
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H. (2016). Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants. Nature Medicine, 22(3), 238–249. https://doi.org/10.1038/nm.4050
Gautam, S., Jain, A., Gautam, M., Vohra, A. K., & Gautam, A. (2017). Clinical practice guidelines for the management of depression. Indian Journal of Psychiatry, 59(Suppl 1), S34–S50. https://doi.org/10.4103/0019-5545.196973
Goodwin, G. M., Aaronson, S. T., Alvarez, O., Arden, P. C., Baker, A., Bennett, J. C., Bird, C., Blom, R. E., Brennan, C., Brusch, D., Campbell, I. G., Carhart-Harris, R. L., Cattell, J., Daniel, A., DeBattista, C., Erritzoe, D., Feifel, D., Fischer, S., & Malievskaia, E. (2022). Single-dose psilocybin for a treatment-resistant episode of major depression. The New England Journal of Medicine, 387(18), 1637–1648. https://doi.org/10.1056/NEJMoa2206443
McIntyre, R. S., Alsuwaidan, M., Baune, B. T., Berk, M., Demyttenaere, K., Goldberg, J. F., Gorwood, P., Ho, R., Kasper, S., Kennedy, S. H., Ly-Uson, J., Mansur, R. B., McAllister-Williams, R. H., Murrough, J. W., Nemeroff, C. B., Nierenberg, A. A., Rosenblat, J. D., Sanacora, G., Schatzberg, A. F., ... Maj, M. (2023). Treatment-resistant depression: Definition, prevalence, detection, management, and investigational interventions. World Psychiatry, 22(3), 394–412. https://doi.org/10.1002/wps.21120
Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264–355. https://doi.org/10.1124/pr.115.011478
Raison, C. L., Sanacora, G., Woolley, J., Heinzerling, K. G., Dunlop, B. W., Brown, R. T., Kakar, R. S., Hassman, M., Trivedi, M. H., Robison, R. A., Gukasyan, N., Nayak, S. M., Hu, X., & Usona Institute Study Group. (2023). Single-dose psilocybin treatment for major depressive disorder: A randomized clinical trial. JAMA, 330(9), 843–853. https://doi.org/10.1001/jama.2023.14530
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., McGrath, P. J., Rosenbaum, J. F., Sackeim, H. A., Kupfer, D. J., Luther, J., & Fava, M. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. The American Journal of Psychiatry, 163(11), 1905–1917. https://doi.org/10.1176/ajp.2006.163.11.1905
Sussman, M., O'Sullivan, A. K., Shah, A., Olfson, M., & Menzin, J. (2019). Economic burden of treatment-resistant depression on the U.S. health care system. Journal of Managed Care & Specialty Pharmacy, 25(7), 823–835. https://doi.org/10.18553/jmcp.2019.25.7.823
Vollenweider, F. X., & Preller, K. H. (2020). Psychedelic drugs: Neurobiology and potential for treatment of psychiatric disorders. Nature Reviews Neuroscience, 21(11), 611–624. https://doi.org/10.1038/s41583-020-0367-2
World Health Organization. (2023). Depressive disorder (depression). https://www.who.int/news-room/fact-sheets/detail/depression
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Copyright (c) 2026 Mateusz Gawin, Emilia Koziara, Mateusz Gadzina, Julia Gawlak, Maciej Krzesimir Kuświk, Zofia Tarnawska, Karolina Figiel, Wojciech Sontag, Mateusz Zawisza, Aleksandra Golec
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