This systematic review and meta-analysis evaluates the effectiveness of psychedelic-assisted therapy (PAT) compared to traditional antidepressants (TAD) for the treatment of major depression. The authors argue that, because the intense subjective effects of psychedelics compromise blinding, PAT results should be compared with antidepressant trials conducted under open-label conditions, in order to match the degree of unblinding across interventions.
Under this approach, the study finds that the superiority of PAT over traditional medication disappears when both treatments are administered in conditions where patients are aware of the intervention received. Likewise, the results suggest that the integrity of blinding significantly influences the reported outcomes of traditional antidepressants, but not those of PAT, pointing to a relevant methodological asymmetry between the two types of intervention.
In this context, the authors propose that part of the apparent superiority of psychedelics could be explained by a reduction in the placebo response in control groups (the “know-cebo” effect), rather than by a greater intrinsic therapeutic effect. This is a methodologically rigorous, preregistered, and comprehensive study that addresses one of the main challenges in psychedelic research: the difficulty (possibly insurmountable) of implementing conventional double-blind designs due to the nature of their subjective effects.
In this sense, the findings reinforce the need to explore alternative designs, such as pragmatic, real-world, or mechanism-focused studies, as well as to interpret the current evidence on their clinical efficacy with caution.
However, it is important to highlight a relevant limitation in the comparability of the included samples: while studies on traditional antidepressants mostly focus on patients with non-resistant depression, psychedelic trials predominantly include populations with treatment-resistant depression. This clinical heterogeneity introduces a potential bias that complicates direct comparisons between interventions, as these populations differ in prognosis and expected treatment response. Furthermore, it is difficult to compare or generalize results across different psychedelic studies due to inconsistencies in the psychotherapeutic approaches and psychological support used, as well as inefficient and inconsistent reporting of the context in which they are applied—pointing to the need for improved reporting of these aspects of the interventions.