Psychedelic Therapy Matches Efficacy of Antidepressants in MDD, With Balázs Szigeti, PhD

New findings suggest the perceived advantage of psychedelic-assisted therapy (PAT) for depression may reflect trial design rather than superior efficacy.

“Psychedelics have generated a lot of hype… When are trying to incorporate how to analyze this issue of functional unblinding into the trials, I would say there is enough good stuff left about psychedelics that is worth looking into, but maybe the efficacy and the promise have been oversold by those early research that did not pay attention to these methodological issues,” said investigator Balázs Szigeti, PhD, from the Translational Psychedelic Research Program at University of California San Francisco (UCSF), in an interview with HCPLive.

In a recent meta-analysis, Szigeti and colleagues found no statistically significant difference in symptom improvement between PAT and open-label traditional antidepressants (TADs) when accounting for functional unblinding, a known challenge in psychedelic trials. The analysis included 24 studies and compared within-arm changes in depression severity.

In an interview with HCPLive, lead investigator Balázs Szigeti, PhD, emphasized that clinicians often focus on between-group differences, assessing how much better a treatment performs than placebo, rather than the total magnitude of symptom improvement experienced by patients.

“That is only half of the story. That just tells you how much better [the treatment] is than the placebo,” Szigeti said. “You really need to know where that baseline [is]... to really interpret this study.”

The analysis found that PAT and open-label antidepressants produced nearly identical reductions in depression scores, with an estimated difference of just 0.3 points on the Hamilton Depression Rating Scale (HAM-D) (95% confidence interval [CI], −1.39 to 1.98; P =.73). These results challenge earlier narratives suggesting psychedelics may offer substantially greater efficacy than standard pharmacotherapy.

A key factor underlying this discrepancy is functional unblinding. Due to the pronounced subjective effects of psychedelics, patients in these trials can often correctly guess their treatment assignment. Szigeti noted that correct guess rates reach approximately 90–95% in psychedelic studies, compared with about 60% in antidepressant trials.

This phenomenon, referred to as the “know-cebo” effect, may be particularly pronounced in psychedelic trials, where participants often enter with high expectations of a transformative experience. When those expectations are not met, outcomes in the control arm may fall well below typical placebo responses seen in antidepressant studies.

“Psychedelics are a very exciting new treatment option,” he said. “A lot of people would like to get it, and they sign up for these trials…it's a lot of paperwork and a lot of effort to participate in these trials. You have to fill out all of the questionnaires, go to the hospital several times, and you also have preparatory psychotherapy. In this psychotherapy, we are typically telling the patients that you know you're going to have this likely life, transformative, mind-expanding experience, a spiritual transformation…we're really building it up in these preparatory therapy sessions. And then, for the unlucky patients, they show up for dosing, they take the capsule, and then nothing happens. Of course, they are disappointed. I know I would be disappointed.”

Szigeti cautioned against interpreting these findings as evidence that psychedelics are ineffective.

“What we show is not that psychedelics are not effective. We are just showing that they are not more effective than open-label antidepressants,” he said. “What this means in practice is that it just seems that the magnitude of the improvement that can be achieved with these 2 treatment modalities [is] the same.”

Szigeti has no reported disclosures.

References

Williams ZJ, Barnett H, Szigeti B. Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis. JAMA Psychiatry. Published online March 18, 2026. doi:10.1001/jamapsychiatry.2025.4809