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 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.

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“This is an intriguing review with a clever approach to addressing the placebo question in psychedelic trials for depression,” says 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 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, , a selective serotonin reuptake inhibitor antidepressant – and it found no significant difference for easing depression.

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, 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 , people were given a sedative that can cause amnesia to erase their memory of the trip.

A single dose of the psychedelic drug dimethyltryptamine (DMT) had a rapid and sustained effect on depressive symptoms in a small trial.

DMT – a fast-acting and extremely potent psychedelic found in numerous plants across the world – is subject to the strictest international controls, with the United Nations considering it a substance with high abuse potential and no recognised medical use.

But a wave of observational research suggests that DMT, and other psychedelics, could help people with severe mental health conditions, particularly those .

In the latest study, at Imperial College London and his colleagues studied 34 people who had experienced moderate to severe depression for an average of 10 years, and who had unsuccessfully tried at least two conventional medicine- or psychotherapy-based treatments.

Alongside psychotherapeutic support, half of the participants were given a large, 21.5-milligram dose of DMT intravenously over 10 minutes, while the rest received a placebo infusion.

All the participants completed a depression-rating questionnaire at the start of the study. Two weeks after the infusions, the DMT group saw their depression-rating scores go down by 7.4 points more, on average, than the placebo group. This was consistently maintained for three months, and for up to six months for some of the participants.

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In another part of the study, all of the participants were free to have a dose of DMT, either as a second dose or, for the placebo group, the first, alongside therapist support. This didn’t significantly improve outcomes beyond the first dose, suggesting that one treatment is sufficient for a lasting effect.

In terms of safety, side effects were mild, with some of the participants reporting temporary anxiety, nausea and pain at the site of infusion.

“We’ve shown that a single DMT experience, lasting only around 25 minutes, can be safe, well-tolerated and associated with meaningful improvements in depression that appear to persist beyond the acute psychedelic state,” says Erritzoe. “What’s promising is how comparable these early signals look to results seen in trials of longer-acting psychedelics such as psilocybin.” A shorter psychedelic experience should reduce treatment costs, he says.

But the nature of taking a psychedelic means people can typically gauge whether or not they are in the placebo group, so the results may reflect both DMT’s effects and the participants’ expectations.

The researchers noted that the intensity of mystical-type experiences that the DMT group reported about 25 minutes after receiving the drug was linked to their degree of therapeutic improvement. “The more someone felt a sense of unity; a deeply positive emotional shift; a change in how they experienced time and space; and something so profound it was hard to put into words, the more benefit they tended to report afterwards,” says team member , also at Imperial.

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Although it is unclear exactly how psychedelics like DMT may be beneficial for treating depression, research suggests that taking them provides a temporary window of neuroplasticity, where the brain can form new connections, or that they may dampen inflammation associated with poor mental health.

– a pioneer in psychedelics research – says these results build upon in which the participants were told which drug they were taking. Yet he still stresses the importance of progressing cautiously. “While the DMT experience is briefer than psilocybin and LSD, it can be significantly more disorienting than longer-acting psychedelics and requires careful preparation, monitoring and follow-up.”

Erritzoe and his team say the results should help guide the testing of a modified form of DMT called for anxiety by Helus Pharma. In the meantime, a similar molecule, called 5-MeO-DMT, is at a more advanced testing stage for depression. For instance, in New York mean that the development of its candidate for treatment-resistant depression can be expedited, making US approval likely.