Balázs Szigeti, PhD, from the Translational Psychedelic Research Program at University of California San Francisco (UCSF)

Balázs Szigeti, PhD

 Psychedelics Expand Options, Not Efficacy, in Depression Care, With Balázs Szigeti, PhD

As interest in psychedelic-assisted therapy (PAT) continues to grow, new data suggest its role in 

 treatment may be more complementary than transformative.

, Balázs Szigeti, PhD, from the Translational Psychedelic Research Program at the University of California, San Francisco (UCSF), discussed how clinicians should interpret recent findings showing no significant difference in core depressive symptom improvement between PAT and traditional antidepressants under comparable unblinding conditions.

Rather than positioning PAT as a replacement for existing therapies, Szigeti framed it as an additional tool in the treatment armamentarium. Differences in adverse event profiles, treatment logistics, and patient preferences will likely shape its clinical role.

“It's just one more tool that the clinician can use to treat their patients,” he said.

In the meta-analysis of 24 studies, PAT and open-label antidepressants brought comparable reductions in depression scores, with an estimated difference of 0.3 points on the Hamilton Depression Rating Scale (HAM-D) (95% confidence interval [CI], −1.39 to 1.98; 

 =.73). These findings challenge earlier beliefs that psychedelics may provide substantially greater efficacy than standard antidepressants, which had fueled enthusiasm in the psychiatry field.

According to Szigeti, the study also adds methodological clarity to a debate increasingly shaped by concerns over trial design, particularly functional unblinding. Earlier trials on MDMA-assisted therapy for PTSD largely overlooked this issue, but scrutiny intensified following the US Food & Drug Administration (FDA) decision. Szigeti noted that his team’s meta-analytic approach offers a way to address these biases without relying on elusive “active placebo” controls.

Beyond symptom reduction, Szigeti highlighted the need to expand how treatment success is measured. Functional outcomes, such as quality of life, daily functioning, and overall well-being, remain underrepresented in antidepressant trials.

“Psychedelic studies started to collect such data because, from anecdotal evidence, there are indications that psychedelics improve in those domains as well,” Szigeti said. “The issue is that, because they are not there with the traditional antidepressant trial[s], we just have no basis of comparison.”

Szigeti identified the gap between clinical trials and real-world use as a critical challenge. Antidepressant studies often assess outcomes at 8 weeks, despite long-term use in practice. He expects this disconnect to be even more pronounced with psychedelics, given the added psychotherapy component.

“It always struck me as something weird that we are putting millions and billions of dollars into clinical research, but very often how these medicines are used in real life has nothing to do with how we have tested them in clinical research,” Szigeti said. “The real question is how the efficacy is going to look once it is practiced in real life, not in the highly constrained clinical research environment.”

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. 

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Findings suggest psychedelics match antidepressants for symptom relief, with future research needed on real-world use and functional outcomes.

Psychedelics Expand Options, Not Efficacy, in Depression Care, With Balázs Szigeti, PhD

Psychedelics vs Antidepressants: New Study Challenges the Hype

New findings suggest the perceived advantage of psychedelic-assisted therapy (PAT) for 

 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 

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.

, 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; 

 =.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.”

Meta-analysis shows psychedelic-assisted therapy offers similar symptom improvement to open-label antidepressants under equal unblinding conditions.


Balázs Szigeti, PhD

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