A new study finds psychedelic-assisted therapy may offer no measurable advantage over traditional antidepressants when patients in both groups know what they’re taking.
You’ve probably heard the pitch: psilocybin — the active compound in “magic” mushrooms — is going to revolutionize mental health treatment. Maybe you’ve read about the retreats, the micro-dosing protocols, the clinical trials producing results that made traditional antidepressants look almost quaint by comparison. Studies have shown promising results, particularly for people who haven’t responded to traditional antidepressants. But a new study published this week in JAMA Psychiatry is complicating that narrative in a way that’s worth paying close attention to — especially if you’ve been considering psychedelic-assisted therapy as an alternative to conventional treatment.
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. The research comes from a collaboration across UC San Francisco, UCLA, and Imperial College London — institutions known for their work in the psychedelic research space.
The testing problem
Here’s where it gets really interesting. 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. In other words, if you take psilocybin, you know you took psilocybin. 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.
This is a real scientific problem, and it’s one the research community has been wrestling with. The lead researcher on the new study, Balázs Szigeti, PhD, a clinical data scientist at UCSF’s Translational Psychedelic Research Program, designed the analysis specifically to address it. Researchers 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 results were not what Szigeti was hoping for. “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.”
What the data actually showed
Both treatments worked — patients improved substantially from both types of treatments, reducing depression scores by about 12 points on a standard scale. That’s meaningful clinical improvement. The question is whether psychedelics produced any advantage beyond what a traditional antidepressant could offer under the same conditions.
Part of what has made psychedelics seem more 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.
In other words, the expectation of getting a powerful, transformative drug — the knowing — may have been doing a significant portion of the work. When this “knowing the treatment” factor leveled out, the seeming advantage of psychedelics disappeared.
Szigeti is careful not to dismiss psychedelics altogether, and that nuance matters. “Psychedelics may still be a valuable treatment option,” he 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.”
The study, co-authored with Zachary J. Williams, MD, PhD, of UCLA, and Hannah Barnett, MSc, of Imperial College London, doesn’t close the door on psychedelic-assisted therapy. It does, however, call for a more rigorous and honest accounting of what these treatments are actually delivering — and for whom. For anyone navigating serious depression, that distinction is worth knowing before booking a session or abandoning their current prescription. And if you are considering psychedelic therapy, be sure and speak with your primary care physician about it.
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