For years, scientists have taken an increasing interest in the therapeutic effects of psychedelics, which are not legal under US federal law. However, despite this renewed interest, large-scale studies are still lacking.

On Wednesday, researchers took an important step to close this gap.

Her work, published in the New England Journal of Medicine, is the largest clinical study ever conducted to evaluate the effects of psilocybin, a psychoactive substance naturally found in “magic” mushrooms.

A single dose of 25 milligrams reduced symptoms of depression in people who had failed multiple conventional treatments, they showed.

An estimated 100 million people worldwide suffer from treatment-resistant depression. Some experts consider psychedelics as a possible way to help them.

Researchers tested a synthetic version of psilocybin developed by start-up Compass Pathway, which also funded the studies.

A total of 233 people in 10 countries took part in the study, in which they discontinued ongoing treatment but received psychological support.

They were divided into three groups that were randomly assigned 1 milligram, 10 milligrams, or 25 milligrams of the treatment.

Sessions, held in a dedicated room, lasted between six and eight hours, during which participants were never left alone. Some described being immersed in “a dream-like state” to remember, study co-author James Rucker said at a news conference.

One participant required a sedative during the session due to anxiety. But the observed side effects – headache, nausea, anxiety – were generally moderate and quickly resolved.

Three weeks later, patients receiving 25 mg showed significant improvement compared to lower doses in a baseline measure of depression. Almost 30 percent were in remission.

“It is the strongest evidence yet that further, larger, and longer randomized trials of psychedelics are warranted, and that psilocybin may (one day) represent a potential alternative to the antidepressants that have been prescribed for decades,” said Professor Andrew McIntosh of Psychiatry from the University of Edinburgh.

McIntosh was not involved in the study.

The Phase 2 trials were designed to determine dosing and confirm the presence of an adequate effect.

Phase 3 studies with more participants are planned to start this year and run until 2025. The startup is already in contact with the US Food and Drug Administration and regulatory authorities in Europe.

Another expert warned.

“We don’t yet know enough about the possible side effects, specifically whether some people may experience a worsening of some symptoms,” said Anthony Cleare, a professor of psychopharmacology in London, who was not involved in the study.

In the studies, three participants among those who received 25 mg exhibited suicidal behavior, compared with none in the other groups.

However, these events occurred more than 28 days after treatment, noted Guy Goodwin, a professor of psychiatry at Oxford and chief medical officer of Compass Pathways.

“Our hypothesis is that the differences are random… but we can only clarify this through further experimentation,” he said.

The question of the long-term effect also remains open, as it faded when the participants were followed up three months later. Repeated doses may be required. Two doses will be tested in future studies, Goodwin said.

Taking psilocybin leads to increases in dopamine (known to regulate mood) and another neurotransmitter that may promote brain plasticity, Rucker said.

“When the brain is in a more flexible state, it opens up what we think of as a therapeutic window of time where you can — in the context of … psychotherapy — potentially create positive changes in the minds of people,” Rucker said.

Psilocybin promotes “more communication between brain regions,” added Nadav Liam Modlin, also a co-author of the study.

Psilocybin, which is non-addictive, is also being studied for other pathologies, including post-traumatic stress, anorexia, anxiety, and addiction.

In 2020, the state of Oregon voted in favor of the therapeutic use of psilocybin. Exceptions were also granted in Canada.

But at the US federal level, psilocybin is treated as a dangerous drug in the same category as heroin.