ReviewFrontiers in psychiatry2026
Psilocybin and ayahuasca in treatment-resistant depression: clinical evidence, methodological constraints and ethical challenges: a narrative review.
Review in Frontiers in psychiatry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
0 citing papers in PubMed.
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Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Background: Treatment-resistant depression (TRD) is a major clinical challenge, with many patients failing to respond to conventional antidepressants. Psychedelic compounds such as psilocybin and ayahuasca have recently gained attention as potential rapid-acting therapies. Beyond their neurobiological effects, methodological, ethical, and real-world applicability concerns are critical for understanding their clinical utility. Methods: We conducted a narrative review of literature on psilocybin and ayahuasca in adult patients with TRD, focusing on safety, efficacy, and study design characteristics. PubMed and PsycINFO databases were searched from inception to August 2025. Studies were assessed for clinical outcomes, side effect profiles, and methodological and ethical limitations, including participant selection, blinding, and informed consent procedures. Results: Both psilocybin and ayahuasca demonstrate rapid reductions in depressive symptoms, with psilocybin showing more robust evidence for sustained effects. However, clinical trials are predominantly conducted in highly controlled environments with stringent inclusion and exclusion criteria, systematically excluding patients with comorbidities, high suicide risk, or polypharmacy. Challenges in maintaining blinding, high participant expectations, small sample sizes, and reliance on adjunct psychotherapy further limit the interpretation and generalizability of findings. Ethical considerations, including informed consent for intense psychedelic experiences and the potential for enduring personality or cognitive changes, remain under-addressed. Consequently, current evidence primarily reflects outcomes in clinically stable and selected subpopulations, rather than real-world TRD patients. Conclusion: Psychedelic-assisted therapies hold significant potential for TRD, but their current evidence base is constrained by methodological and ethical limitations. Future research should prioritize large, representative trials, standardized protocols, and robust safeguards to ensure both scientific validity and patient safety. Unlike previous reviews that primarily synthesized efficacy outcomes across different psychedelic compounds, the present narrative review specifically compares psilocybin and ayahuasca within the framework of treatment-resistant depression while integrating methodological, ethical and real-world implementation issues. This perspective aims at complementing the existing evidence by highlighting factors that may influence future clinical translation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.