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

This pre-print pre-registered meta-analysis (s=24) comparing psychedelic-assisted therapy (PAT) and open-label traditional antidepressants (tAD) for major depression found no significant difference in effectiveness between the two approaches, with both producing clinically meaningful improvements, challenging previous assumptions about PAT’s superiority when accounting for the unblinding effect present in psychedelic trials.

Abstract of ‘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. Twenty-four 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 hypotheses, 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, eight PAT trials involving 548 patients and sixteen 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 favouring open-label tAD; 95% confidence interval: −1.39 to 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.

Authors: Zachary J. Williams, Hannah Barnett & Balázs Szigeti

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

Major depressive disorder (MDD) remains one of the most prevalent and disabling psychiatric conditions worldwide. Traditional treatments include medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), collectively referred to in this study as traditional antidepressants (tADs). While widely prescribed, these treatments often produce only modest differences compared to placebo, raising concerns about their clinical effectiveness. In contrast, psychedelic-assisted therapy (PAT)—a combined approach using psychotherapy and high doses of psychedelics—has shown significantly larger treatment effects in recent trials, fuelling enthusiasm for its therapeutic potential.

However, a critical limitation in comparing these two approaches lies in the role of functional unblinding. Functional unblinding refers to the tendency of trial participants to correctly guess their treatment assignment due to noticeable effects, particularly in psychedelic trials, where 90–95% of participants are able to identify whether they received the active drug. This phenomenon can inflate reported treatment effects. Although some unblinding also occurs in tAD trials, it is far less pronounced, with correct guess rates closer to 60%. Recognising this imbalance, the authors designed this meta-analysis to compare PAT with open-label tAD trials, where participants are fully aware of the treatment they receive, thereby equalising the expectancy effects across both treatments.

Only one prior head-to-head trial between PAT and an SSRI (escitalopram) had been conducted, and while it found no difference on the primary measure, PAT outperformed the SSRI on secondary outcomes. This study aimed to expand upon that work using a systematic meta-analysis comparing the average symptom improvement (within-arm effect) of PAT and open-label tADs, in order to more fairly assess their relative efficacy under conditions where patients knew their treatment.

Methods

Pre-registration and Hypotheses

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Find this paper

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

https://doi.org/10.31234/osf.io/vhs4a_v1

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Cite this paper (APA)

Szigeti, B. (2025). ‘Equal-unblinding’ meta-analysis of psychedelic therapy vs. antidepressants for the treatment of depression. https://doi.org/10.31234/osf.io/vhs4a_v1

Study details

Compounds studied
Psilocybin Ayahuasca Mescaline LSD

Topics studied
Depression

Study characteristics
Meta-Analysis

Participants
10299 Humans

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