Psychedelics may be no better than antidepressants for depression

Psychedelics may be no more effective than traditional antidepressants for treating depression. Drugs like psilocybin, LSD and DMT have shown huge promise recently in treating various mental health conditions, but an ongoing issue in such research is that people can often gauge whether they have received these drugs or a placebo, based on the former’s hallucinogenic effects. When this is accounted for, it seems that psychedelics can be effective for depression, but no more so than antidepressants are.

“Our results do not disprove the exciting results about psychedelic treatments,” says Balázs Szigeti at the University of California, San Francisco (UCSF). “We also show that psychedelics are effective at treating depression; it is just that they are not more effective than open-label [unblinded] traditional antidepressants, which feels underwhelming given the attention [on psychedelics].”

Hallucinogens have shown promise for treating 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, when someone’s medical symptoms are lessened through the power of suggestion and expectation. But in psychedelic research, people are often able to perceive whether they are in the dosing group.

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

The team found that the traditional antidepressants seemed to outperform PAT by just 0.3 points on a 52-point depression-rating scale, which is neither statistically nor clinically significant.

Psychedelics have generally outperformed a placebo by 7.3 points in previous trials, versus about 2.4 points when antidepressants are pitted against a placebo. But the researchers argue that much of this advantage may stem from participants being able to gauge whether they have received a psychedelic. “Ours and other studies provide emerging evidence that unblinding suppresses the placebo response,” says Szigeti.

“This is an intriguing review with a clever approach to addressing the placebo question in psychedelic trials for depression,” says Matthew Johnson at John Hopkins University in Maryland, who was involved in some of the studies the team reviewed. Some researchers have a “a religious-like zeal to show psychedelics are effective, rather than a principled approach of trying to really test hypotheses”, he says.

But Rayyan Zafar at Imperial College London says psychedelics need to be compared head-to-head against antidepressants, not just placebos, to understand their effects: “The jury is still out scientifically.” Only one trial has done so, testing psilocybin against escitalopram, a selective serotonin reuptake inhibitor antidepressant – and it found no significant difference for easing depression.

Robin Carhart-Harris, also at UCSF – who was involved in the escitalopram trial – has a common criticism of the methodology behind the latest study: that comparing multiple trials with different designs, including varying sample sizes and inclusion criteria, doesn’t generally yield a conclusive result. “It’s proposed as comparing apples with apples, when really it’s more like comparing apples with oranges,” he says.

Last September, a study looking at LSD for treating anxiety sought to decrease the likelihood of unblinding by giving lower doses of the drug to the control group, so they induced hallucinogenic effects without necessarily impacting mental health. And in a psilocybin trial, people were given a sedative that can cause amnesia to erase their memory of the trip.