A systematic review and meta-analysis of 24 studies found that psychedelic-assisted therapy was not more effective than traditional antidepressants when compared under open-label conditions.
Researchers analyzed data from 8 psychedelic trials (249 patients) and 16 open-label antidepressant trials (7,921 patients), assessing changes in depression severity using the 17-item Hamilton Depression Rating Scale. The analysis found only a small difference in symptom improvement, favoring antidepressants but below levels considered clinically meaningful.
The study was designed to address a key methodological challenge in psychedelic research: functional unblinding. Because patients receiving psychedelics can often infer their treatment assignment due to pronounced subjective effects, trials may effectively operate as open label. The authors therefore compared psychedelic-assisted therapy with open-label antidepressant trials to better account for expectancy-related effects.
Both treatments were associated with substantial reductions in depression scores. Modeling estimates showed similar improvements for psychedelic therapy and antidepressants, with differences falling below thresholds for clinical significance.
The analysis also examined the role of blinding. Open-label antidepressant trials were associated with slightly greater improvements than blinded trials, although the effect size was small. In contrast, no meaningful difference was observed between blinded and open-label psychedelic trials, supporting the difficulty of maintaining blinding in these studies.
The authors suggested this may help explain why earlier placebo-controlled psychedelic trials appeared to show larger treatment effects than conventional antidepressant studies. In their interpretation, these differences may reflect expectancy effects related to treatment awareness as well as potentially weaker placebo responses in psychedelic trials.
Findings were consistent across sensitivity analyses, including those restricted to specific antidepressant classes and to trials outside treatment-resistant depression.
The authors said the results support more cautious interpretation of apparent advantages reported in psychedelic depression trials.
The lead author reported receiving personal fees for consulting from Roche outside the submitted work. No other disclosures were reported.
Source: JAMA Psychiatry
