Psilocybin and ayahuasca in treatment-resistant depression: clinical evidence, methodological constraints and ethical challenges: a narrative review

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.