Psychedelics may not be any better for depression than antidepressants

Psychedelics may not be any more effective in treating depression than traditional antidepressants. Drugs such as psilocybin, LSD, and DMT have recently shown great promise in treating a variety of mental health conditions, but a persistent problem in this research is that people can often judge whether they have received these drugs or a placebo based on the hallucinogenic effects of the former. When this is taken into account, it seems that psychedelics may be effective for depression, but no more so than antidepressants.

“Our results do not refute the exciting results about psychedelic treatments,” he says Balázs Szigeti at the University of California, San Francisco (UCSF). “We’ve also shown that psychedelics are effective in treating depression; it’s just that they’re no more effective than open [unblinded] traditional anti-depressants that feel insufficient in terms of attention [on psychedelics].”

Hallucinogens have shown promise in the treatment of depression, anxiety, and obsessive-compulsive disorder. The gold standard for drug development is usually to test a treatment against a placebo. This overcomes the placebo effect, where one’s health symptoms are alleviated by the power of suggestion and expectation. But in psychedelic research, people are often able to sense whether they are in the dosing group.

To counter this, Szigeti and his colleagues reviewed 24 studies, eight of which looked at psychedelic-assisted therapy (PAT)—a combination treatment of psychotherapy and psychedelics. The remaining 16 were open trials for traditional antidepressants. This means that both researchers and participants knew what treatment was being administered, eliminating “blinding”, which is also considered the gold standard in most studies.

The team found that traditional antidepressants appeared to outperform PAT by just 0.3 points on a 52-point depression rating scale, which was not statistically or clinically significant.

Psychedelics generally outperformed placebos by 7.3 points in previous studies, compared to about 2.4 points when antidepressants are pitted against placebo. However, the researchers say that much of this benefit may stem from the fact that participants were able to judge whether they had received the psychedelic. “Our and other studies provide new evidence that unblinding suppresses the placebo response,” says Szigeti.

“This is an interesting review with a clever approach to addressing the placebo issue in psychedelic depression trials,” he says Matthew Johnson at John Hopkins University in Maryland, who participated in some of the studies the team investigated. Some researchers have “a religious zeal to show that psychedelics work, rather than a principled approach of trying to actually test hypotheses,” he says.

But Rayyan Zafar at Imperial College London says that psychedelics need to be compared directly with antidepressants, not just placebos, to understand their effects: “The jury is still out scientifically.” He only made one attempt to do so, testing psilocybin against escitaloprama selective serotonin reuptake inhibitor—and found no significant difference in the alleviation of depression.

Robin Carhart-Harrisalso at UCSF — which participated in the escitalopram study — has a common criticism of the latter study’s methodology: that comparing multiple studies with different designs, including different sample sizes and inclusion criteria, generally does not yield a conclusive result. “It’s designed as an apples-to-apples comparison, although it’s more like an apples-to-oranges comparison,” he says.

Last September, a study looking at LSD for the treatment of anxiety sought to reduce the chance of going blind by giving a control group lower doses of the drug so it produced hallucinogenic effects without necessarily affecting mental health. AND in the psilocybin testpeople were given a sedative that can cause amnesia to erase their memory of the trip.

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