Table 1_Psilocybin and ayahuasca in treatment-resistant depression: clinical evidence, methodological constraints and ethical challenges: a narrative review.docx

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.</p>Conclusion<p>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.</p>