Summary: For years, the “psychedelic renaissance” has suggested that substances like psilocybin and LSD could revolutionize mental health care, potentially outperforming traditional SSRIs. However, a groundbreaking analysis by researchers has introduced a “sobering” reality.
The study found that when the “expectation effect” is leveled—meaning patients in both groups knew exactly what drug they were taking—psychedelic-assisted therapy was no more effective than traditional antidepressants.
Key Facts
- The Methodology Problem: Most psychedelic trials fail the “blind” test; because the drugs have such powerful subjective effects, patients almost always know if they received the psychedelic or a placebo.
- The “Level Playing Field”: To fix this, researchers compared psychedelic trials to open-label antidepressant trials (where patients also knew they were getting the active drug).
- The Result: When both treatments benefited equally from the “knowledge of treatment,” there was virtually no difference in outcome. Both groups improved by approximately 12 points on standard depression scales.
- The Expectation Boost: Previous studies made psychedelics look superior because participants who knew they received a psychedelic felt a massive psychological boost, while those who knew they got a placebo felt “let down,” making the drug’s effect seem artificially large.
- Still a Valid Option: The study does not say psychedelics are ineffective; it simply concludes they are not the “miracle cure” that significantly outperforms existing medications when compared fairly.
Source: UCSF
Psychedelic-assisted therapy may be no more effective than traditional antidepressants when patients know what drugs they are actually taking, according to a first-of-its kind analysis that compared how well each type of drug worked for major depression.
Psychedelic-assisted therapy has resisted placebo-controlled testing methods — the gold standard in clinical trial design. Due to their powerful subjective effects, nearly everyone in the trial knows whether they received a psychedelic or the placebo even if they are not told.
But in trials of antidepressants, participants may not figure out whether they have received the drug or a placebo, which makes it hard to compare them with psychedelics.
To get around this problem, researchers from UC San Francisco, UCLA, and Imperial College, London tried a different approach. They compared the results from psychedelic therapy trials to the results from so-called open-label trials of traditional antidepressants, in which the participants all knew they were getting an antidepressant. That way, both treatments benefitted equally from the positive effect of patients knowing that they were being given a drug instead of a placebo.
The findings both surprised and disappointed them: there was virtually no difference.
“Unblinding is the defining methodological problem of psychedelic trials. What I wanted to show is that even if you compare psychedelics to open-label antidepressants, psychedelics are still much better,” said Balázs Szigeti, PhD, a clinical data scientist at UCSF’s Translational Psychedelic Research Program, who led the study.
“Unfortunately, what we got is the opposite result — that they are the same, which is very surprising given the enthusiasm around psychedelics and mental health.”
Szigeti is the co-first author of the paper with Zachary J. Williams, MD, PhD, of UCLA; Hannah Barnett, MSc, of Imperial College, London is also an author. The study appeared March 18 in JAMA Psychiatry.
A sobering view
The hype around the use of psychedelics like psilocybin, or “magic mushrooms,” and LSD, to treat such conditions as depression and addiction has grown in recent years as an increasing number of studies have shown promising results, particularly for people who haven’t responded to traditional antidepressants.
The new findings don’t mean that psychedelic therapy does not work — just that it does not work better than traditional antidepressants. Patients improved substantially from both types of treatments, reducing depression scores by about 12 points on a standard scale.
Part of what has made psychedelics seem impressive in trials than antidepressants is how much more those who received the psilocybin or LSD improved than those who did not get it.
But the researchers concluded that this was the result of the lack of blinding in psychedelic trials: those who got the drug improved more because they knew they had gotten it, while those who received a placebo did worse because they knew they did not. Whereas in trials of traditional antidepressants, the difference between the groups was much smaller, making it seem like the drugs weren’t that effective.
When this ‘knowing the treatment’ factor leveled out, the seeming advantage of psychedelics disappeared.
“Psychedelics may still be a valuable treatment option,” Szigeti said. “But if we want to understand their true benefits, we have to compare them fairly — and when we do that, the advantage over standard antidepressants is much smaller than many people, including myself, expected.”
Funding: None.
Disclosures: Williams received consulting fees from Roche. The other authors did not declare any conflicts.
Key Questions Answered:
A: No, they definitely work! Both the psychedelics and the traditional antidepressants reduced depression scores significantly. The real news is that they seem to work about the same. The “hype” made it seem like psychedelics were 10 times better than SSRIs, but this study suggests that was mostly due to the excitement of the patients knowing they were getting a “cool” new treatment.
A: Because psychedelic trials have a “blinding” crisis. In a normal drug trial, you aren’t supposed to know if you got the drug or a sugar pill. With psychedelics, you definitely know. This creates a massive placebo-like boost. By comparing them to “open-label” antidepressants (where people also knew what they were getting), scientists finally got an “apples-to-apples” comparison.
A: For some, traditional antidepressants don’t work or have side effects they can’t tolerate. Psychedelic therapy is also usually a “one-or-two-dose” experience paired with therapy, rather than a daily pill. So, while they might be equal in effectiveness, the experience and protocol are still very different options for patients.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this psychopharmacology research news
Author: Victoria Colliver
Source: UCSF
Contact: Victoria Colliver – UCSF
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis” by Zachary J. Williams, Hannah Barnett, and Balázs Szigeti. JAMA Psychiatry
DOI:10.1001/jamapsychiatry.2025.4809
Abstract
Treatment of Depression Under Equal Unblinding Conditions: A Systematic Review and Meta-Analysis
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.
