Importance Psychedelic-assisted therapy (PAT) trials have high levels of functional unblinding, which biases results when comparing PAT with blinded interventions. Because PAT is effectively always open label, treatment results should be compared with those of open-label traditional antidepressants (TADs), so potential benefits associated with patients knowing their treatment is equal between the interventions. Objective To investigate the comparative effectiveness of PAT vs open-label traditional antidepressants (TADs; such as selective serotonin and norepinephrine reuptake inhibitors) for the treatment of major depression. Data Sources PubMed was systematically searched in March 2024 for trials of PAT and open-label TADs for the treatment of major depression without comorbidity in adults without psychosis in the outpatient setting. Extraction was supplemented with data from a review and meta-analysis of antidepressant drugs to assess the open-label vs blinded TAD difference. Data Extraction and Synthesis Depression scores were extracted by 2 independent reviewers; estimates were pooled with both bayesian and frequentist mixed-effects models. Reporting follows the PRISMA guideline. Main Outcomes and Measure Following predefined hypotheses, the mean within-arm effect from baseline to primary end point (ie, patient improvement between PAT and open-label TAD trials on the 17-item Hamilton Depression Rating Scale) was compared. To assess the potential role of blinding, the within-arm effect of blinded vs open-label trials in both PAT and TADs was also compared. Results Of the initially retrieved PubMed 619 records, 24 met inclusion criteria. Contrary to the first of 3 hypotheses, PAT (8 trials; 249 patients) was no more effective than open-label TAD treatment (16 open-label TAD trials; 7921 patients), with an estimated difference of 0.3 favoring open-label TADs (95% CI, −1.39 to 1.98; P = .73). Open-label TADs were associated with better outcomes than blinded treatment (144 blinded TAD trials; 31 792 patients), with an estimated difference of 1.3 (95% CI, 0.07-2.51; P = .04;), but the same difference was not observed for PAT (0.67; 95% CI, −3.08 to 1.73; P = .58). Conclusions and Relevance In trials of depression, PAT was not more effective than open-label TADs. Blinding made a difference for TADs, but not for PAT, confirming that PAT trials are effectively always open label. These results argue against highly optimistic narratives surrounding PAT and highlight the importance of blinding integrity.