Are psychedelics better than antidepressants? New study says no

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 benefited 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, Ph.D., 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, Ph.D., of UCLA; Hannah Barnett, MSc, of Imperial College, London is also an author. The study was published 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.”