Psychedelics in treatment-resistant depression: a comprehensive review of mechanisms, clinical evidence, and recommendations.
Cielo A Estela-fernandez, Reem Mohamed Yousif Elsheikh, Dal Bianco Beatrice, Abdullah A Alhendal, Chinonso Irene Ewe, Sebastian Y Montesinos, Jocelyn Wensel, Anushka Prakash Mishra, Asma Ahmed Yousif, Hossam Tharwat Ali
Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater June 30, 2026 Peer reviewed DOI: 10.1007/s40211-026-00584-4 via PubMed
Summary
Psychedelics show significant potential in treating treatment-resistant depression (TRD), with psilocybin, ketamine, and esketamine being the most researched. Psilocybin-assisted therapy can lead to short-term symptom improvement lasting weeks or months. Ketamine has rapid effects in reducing depressive symptoms without affecting cognitive function, while esketamine also shows meaningful improvements. Ayahuasca has demonstrated fast effects and higher remission rates. However, more rigorous studies are needed to support their use in standard treatment protocols.
Study at a glance
| Population | individuals with treatment-resistant depression |
|---|---|
| Key finding | Psychedelics have significant potential in treating treatment-resistant depression with mechanisms that may surpass traditional antidepressants. |
Abstract
Major depressive disorder (MDD) is a heterogeneous, debilitating disorder. A distinct subgroup within the MDD spectrum is identified to have treatment-resistant depression (TRD). There is an impetus to find alternative treatments for TRD to reduce disease burden and improve quality of life. Psychedelics have been used in the treatment of various psychiatric disorders since the 1950s, with potential benefits in TRD. Aiming to summarize the evidence of using psychedelics for TRD by exploring mechanisms and potential benefits, we conducted a literature search on different psychedelics with their mechanisms from clinical and preclinical evidence. Psychedelics have been examined in many preclinical studies for efficacy and mechanisms with fewer clinical studies on patients with TRD. Besides serotonergic agonism, glutamate surge and monoamine release, psychedelics promote neuroplasticity, corticolimbic function, and epigenetic changes. Psilocybin, ketamine, and esketamine are the most researched agents of psychedelics in the context of TRD. Psilocybin-assisted therapy has been shown to induce short-term improvement in symptoms that can persist for weeks and months, with some meta-analyses consolidating such findings. Ketamine, as an atypical psychedelic, in many clinical trials of intravenous, subcutaneous, and oral forms, had rapid and robust effects in reducing depressive symptoms and relapses without decreasing cognitive function. Similarly, esketamine induced early and clinically meaningful improvements in function and productivity. Ayahuasca also showed fast and sustained effects with higher remission rates and good safety. Psychedelics have significant potential in TRD with superior mechanisms over traditional antidepressants. Despite the encouraging findings of the existing studies, large, well-designed studies are needed to extend their use as part of standard recommendations.