By Victoria Colliver
With an innovative approach, scientists are trying to get around the problem of participant expectations in tests of psychedelics.
A new study is dampening some of the hype surrounding psychedelic therapy. It found that drugs like LSD and psilocybin are only as good as — but no better than — antidepressants when it comes to treating major depression.
Previous studies have suggested that psychedelics may be more powerful than standard antidepressants for conditions like depression. But the new analysis concluded that much of psychedelics’ apparent advantage in those earlier trials may be explained by how the studies were designed.
“Psychedelics may still be a valuable treatment option,” said Balázs Szigeti, PhD, a clinical data scientist at UCSF’s Translational Psychedelic Research Program and the co-first author of the paper, which appeared March 18 in JAMA Psychiatry. “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.”
Balázs Szigeti, PhD
The study focuses on a long-standing challenge in psychedelic research: blinding. In standard drug trials, the study is blinded, meaning neither patients nor researchers know who receives the active treatment and who gets a placebo. This helps control for expectations, since people can feel better even if they receive the inactive placebo treatment. Researchers then measure effectiveness by comparing how much each group improves.
Psychedelic studies are hard to blind. These drugs cause strong effects, so participants can usually tell whether they received the drug or a placebo. In contrast, people in antidepressant trials are often less sure which treatment they got.
In psychedelic studies, placebo groups often improve less, partly because participants may realize they did not receive the drug. In antidepressant trials, placebo groups tend to improve more, possibly because more placebo recipients believe they received the active therapy. This difference can make psychedelics appear more effective.
To deal with this issue, researchers created a comparison that put both treatments on more equal terms. They compared results from eight psychedelic therapy trials with 18 trials in which participants knew they had received an active, traditional antidepressant. This made both treatments more equally affected by patients’ expectations.
When the researchers accounted for these factors, the advantage of psychedelics disappeared. On average, participants in both types of studies improved by about 12 points on a standard measure of depression symptoms.
“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,” Szigeti said. “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.”
Authors: Co-first author Zachary J. Williams, MD, PhD, of UCLA, and Hannah Barnett, MSc, of Imperial College, London.
Funding: None.
Disclosures: Williams received consulting fees from Roche. The other authors did not declare any conflicts.
Read the paper
- JAMA Psychiatry: Psychedelic Therapy vs Antidepressants for the Treatment of Depression Under Equal Unblinding ConditionsA Systematic Review and Meta-Analysis
About UCSF Psychiatry and Behavioral Sciences
The UCSF Department of Psychiatry and Behavioral Sciences and the Langley Porter Psychiatric Institute are among the nation's foremost resources in the fields of child, adolescent, adult, and geriatric mental health. Together they constitute one of the largest departments in the UCSF School of Medicine and the UCSF Weill Institute for Neurosciences, with a focus on providing unparalleled patient care, conducting impactful research, training the next generation of behavioral health leaders, and advancing diversity, health equity, and community across the field.
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The UCSF Weill Institute for Neurosciences, established by the extraordinary generosity of Joan and Sanford I. "Sandy" Weill, brings together world-class researchers with top-ranked physicians to solve some of the most complex challenges in the human brain.
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The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF’s primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area.
