Severe depression eased by single dose of synthetic ‘magic mushroom’

A single dose of a synthetic version of the mind-altering component of magic mushrooms, psilocybin, improved depression in people with a treatment-resistant form of the disease, a new study found.

Cultivated Mushrooms.

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The randomized, double-blind clinical trial, which authors called “the largest of its kind,” compared results of a 25-milligram dose to a 10-milligram and 1-milligram dose of a synthetic psilocybin, COMP360, that was administered in the presence of trained therapists.

Results of the study, published Wednesday in The New England Journal of Medicine, found “an immediate, fast, rapid-acting, sustained response to 25 milligrams (of COMP360),” said study coauthor Dr. Guy Goodwin, a professor emeritus of psychiatry at the University of Oxford in the United Kingdom.

“This drug can be extracted from magic mushrooms, but that is not the way our compound is generated. It’s synthesized in a purely chemical process to produce a crystalline form,” said Goodwin, who is the chief medical officer of COMPASS Pathways, the company that manufactures COMP360 and conducted the study.

Experts in the field found the study findings promising.

“They clearly found a dose effect and clinically meaningful improvement in just three weeks,” said Dr. Matthew Johnson, a professor in psychedelics and consciousness at Johns Hopkins Medicine in Baltimore. He was not involved in the new study.

“If you were in the 25-milligram group, you were nearly three times as likely to respond than if you were in the 1-milligram group,” said Johnson, who coauthored safety guidelines for psychedelic research in 2008.

The rapid response to treatment was notable as well.

“The maximum effect (was) seen the day after receiving the treatment. This contrasts with standard antidepressants, which take several weeks to reach maximum effect,” said Dr. Anthony Cleare, a professor of psychopharmacology and affective disorders at King’s College London, in a statement. He was not involved in the study.

However, there are a number of issues that need further study before this drug would be available for clinical use, experts said.

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“The effects did start to wear off by three months, and we need to know how best to prevent the depression returning,” Cleare said, adding that not enough is yet known about potential side effects.

“While the safety profile seems encouraging overall, great care is obviously needed when using psychoactive substances such as psilocybin. Larger studies are on the way that we hope will help answer these issues,” he said.

Benefits faded

The clinical trial occurred at 22 sites in the United States, Canada, the UK and seven countries in Europe. The study was designed to test the safety of different dosages of the proprietary version of psilocybin.

The 233 study participants had treatment-resistant depression, which can only be diagnosed after a person fails to respond to two courses of antidepressants. Of the 9 million people in the US with medically treated depression, 3 million patients are resistant to treatment, studies have estimated. Globally, some 100 million people have treatment-resistant depression, Goodwin said.

People with the condition are at a high risk of physical illness, disability, hospitalization and suicide, the study said.

A laboratory researcher removes a psilocybin mushroom from a container.

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Any study participants on antidepressants were required to wean themselves from those medications prior to the start of the trial. Psychedelic treatment doesn’t work on people who are actively taking antidepressants — the receptors where psychedelics attach in the brain are already flooded with serotonin from their current mood-altering drugs.

“Participants were requested to remain off antidepressant treatment during the first 3 weeks after the trial-drug administration; however, these medications could be started at any time during the trial if deemed clinically necessary by a physician investigator,” the study said.

Depression severity for each person was assessed the day before treatment using a psychological scale widely used by clinicians. Counselors trained to offer psychological support were present during the psychedelic trips, which lasted between six and eight hours. Participants were also given two more therapy sessions in the first week, the study said.

Depression levels were documented the day after the “trip” and another five times over a 12-week period. About 37% of people who took the 25-milligram dose showed improvement. In fact, 29% were considered to be in remission at week three, the study found.

By week 12, however, the positive impact on depressive symptoms had waned and no longer reached a level of statistical significance, the study found.

“The incidence of sustained response at week 12 was 20% in the 25-mg group, 5% in the 10-mg group, and 10% in the 1-mg group,” wrote psychobiologist Dr. Bertha Madras, director of the laboratory of addiction neurobiology at Harvard Medical School’s McLean Hospital in Belmont, Massachusetts, in an accompanying editorial. She did not participate in the study.

closeup of marijuana joint and buds on a checkerboard table with a shallow depth of field

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“This is not a spectacular response rate for a psychiatric treatment … and we would only expect this to worsen over a longer follow-up period,” said Dr. Ravi Das, an associate professor of educational psychology research methods and statistics at University College London via email. He who was not involved with the study.

In addition, “there were an uneven number of severely depressed patients in each group; with significantly fewer severely depressed people in the apparent ‘effective’ (25mg) dose group,” Das said in a statement. “This does not appear to be acknowledged in the paper.”

Safety profile

Headache, nausea, fatigue and dizziness plagued 77% of the study participants and occurred at all dosage levels, which experts say is a typical response on the day of psilocybin administration.

A small number of people in all three dosage groups experienced suicidal thoughts or injured themselves over the 12-week follow-up period, the study found. Within the first three weeks alone, two people in the 25-milligram group thought about suicide and two intentionally injured themselves. Two people in the 10-milligram group were suicidal, one self-injured and one was hospitalized for severe depression, the study reported.

Those behaviors are “common in treatment-resistant depression studies — most cases occurred more than a week after the COMP360 psilocybin session,” the company said.

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“Remember that this is in people who were assessed not to be at significant risk of suicide when they entered the trial. The numbers were fairly small, but this is something that will need to be taken carefully into account in any later-stage trials,” said Kevin McConway, professor emeritus of applied statistics at The Open University, a British public research university.

The study results are promising, but many questions remain and it’s unknown if this drug would be successful for different types of depression, said McConway, who was not involved in the study.

“They can’t tell us how effective this psilocybin plus therapy treatment is in comparison with other existing drug or non-drug treatments for depression,” said McConway, noting that as a next step for follow-up trials.