‘Equal-unblinding’ meta-analysis of psychedelic therapy vs. antidepressants for the treatment of depression

Importance: Psychedelic-assisted therapy (PAT) trials have high levels of functional unblinding. This effect positively biases results when PAT trials are compared against truly blinded trials. Objective: This pre-registered meta-analysis investigated the comparative efficacy of PAT and open-label traditional antidepressants (tAD; such as SSRIs and SNRIs) for the treatment of major depression. The rationale is that PAT is effectively always open-label, thus, it is only fair to compare results against open-label tAD trials, so both interventions equally benefit from effects associated with patients knowing the treatment.Data Sources: PubMed was systematically searched for trials of PAT and open-label tAD for the treatment of major depression without comorbidity in outpatient, non-psychotic adults. 24 of the initially retrieved 619 records met inclusion.Data Extraction and Synthesis: Depression scores were extracted by two independent reviewers; estimates were pooled with both Bayesian and frequentist mixed-effects models. The reporting follows the PRISMA guideline. Main Outcome(s) and Measure(s): Following pre-defined hypothesis, we compared the mean within-arm effect size from baseline to primary endpoint, i.e. the patient improvement, between PAT and open-label tAD trials on the 17-item Hamilton Depression Rating Scale. We also compared the within-arm effect size of blinded vs. open-label trials in both PAT and tAD, to assess the influence of blinding. Results: In total, 8 PAT trials involving 548 patients and 16 open-label tAD studies involving 9751 patients were included. Contrary to prior hypothesis, PAT was no more effective than open-label tAD treatment (estimated difference: 0.3 favoring open-label tAD; 95% confidence interval: [-1.39, 1.98]; p=0.730). Open-label tAD was associated with better outcomes than blinded treatment (1.3 [0.07, 2.51]; p=0.038), but the same difference was not observed in PAT (0.4 [-2.20, 3.11]; p=0.738).Conclusions and Relevance: Both tAD and PAT were associated with robust, statistically, and clinically meaningful improvements. However, PAT’s lack of superiority compared to tADs under equal-unblinding conditions highlights the influence of blinding integrity and presents a sobering viewpoint on the treatment’s potential.