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

Psychedelic-assisted therapy (PAT) is no more effective than open-label traditional antidepressants (tADs) for major depression when both treatments are compared under similarly unblinded conditions. A meta-analysis of 8 PAT trials (548 patients) and 16 open-label tAD studies (9,751 patients) found no significant difference in patient improvement on the Hamilton Depression Rating Scale, with a slight trend favoring tADs. Open-label tADs outperformed blinded tADs, but the same blinding effect was not seen in PAT. The findings suggest that the apparent benefits of PAT may be partly due to patients knowing they are receiving an active treatment, challenging claims of its superior efficacy.

Study at a glance

Abstract

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.