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  • A new study finds synthetic psilocybin can help relieve symptoms of depression.
  • Researchers enrolled 233 people with treatment-resistant depression — defined as failing to respond to two or more courses of treatment with antidepressants.
  • An estimated 2.8 million people in the United States have treatment-resistant depression.

A single dose of a synthetic version of the psychedelic drug psilocybin, alongside psychological support, reduced symptoms in people with treatment-resistant depression, a new study found.

This randomized, double-blind clinical trial compared the impact on depression symptoms of a 25-milligram dose, 10-milligram dose, and 1-milligram dose of a synthetic version of the mind-altering component of “magic mushrooms.”

The drug was administered in the presence of trained therapists. Participants in the study also met with a therapist several times before and after the psilocybin session.

Results of the study, which were published on November 3 in The New England Journal of Medicine, showed an almost immediate decrease in depression symptoms, with the strongest benefit seen among people taking 25 milligrams of synthetic psilocybin.

“This study, which is by far the largest clinical trial on the use of psilocybin for treatment-resistant depression to date, demonstrated that a single 25-mg dose of psilocybin improved participants’ symptoms of depression in comparison to a 1-mg dose,” Dr. James Rucker, a consultant psychiatrist at King’s College London, who took part in the research, said in a news release.

“These findings are a positive step in the right direction. Our task now is to investigate psilocybin for treatment-resistant depression in larger clinical trials with more participants, comparing it both to placebo and to established treatments,” he added.

Millions with treatment-resistant depression

The clinical trial, which took place at 22 sites in the United States, Canada, and Europe, was designed to test the safety and effectiveness of different dosages of the synthetic version of psilocybin.

Researchers enrolled 233 people with treatment-resistant depression — defined as failing to respond to two or more courses of treatment with antidepressants.

An estimated 2.8 million people in the United States have treatment-resistant depression, with nearly 9 million Americans being treated medically for major depressive disorder, one study found.

People with this condition have more severe and longer-lasting depression and are at higher risk of disability, physical illness, hospitalization, and suicide, the authors of the new study wrote.

Participants in the trial were required to reduce their use of antidepressants leading up to the psilocybin session, stopping completely at least 2 weeks before their first study visit. They were also asked to not use antidepressants for three weeks after receiving psilocybin.

“However, [antidepressant treatment] could be started at any time during the trial if deemed clinically necessary by a physician investigator,” the authors wrote.

Researchers assessed the severity of participants’ depression before the psilocybin session with a psychological scale widely used by clinicians. This assessment was repeated several more times during the 12-week follow-up period.

The psilocybin session, which was supervised by two therapists, lasted between 6 and 8 hours. Participants were randomly assigned to receive one of the three dosages.

Prior to the treatment session, participants met with a therapist at least three times. They met with a therapist two times more during the next week.

“Notable” results from psilocybin

Dr. Anthony Back, an oncologist, palliative-care specialist, and professor of medicine at UW Medicine in Seattle, said psilocybin-assisted therapy in this study produced some “notable” responses. 

For example, in the 25-milligram dose group, “there was a pretty substantial benefit and it happened very quickly,” he said.

Researchers found that by 3 weeks after the psilocybin session, 37% of people who took the 25-milligram dose showed improvement. In addition, 29% were in remission at this time, the study found.

In contrast, only 19% and 18% of people in the 10-milligram and 1-milligram groups, respectively, showed improvement in their symptoms by week 3.

However, the benefits of the 25-milligram dose on depression symptoms had waned by week 12, with 20% showing an improvement in their symptoms by then. 

In addition, the difference in results between the 25-milligram and 1-milligram groups at week 12 was no longer statistically significant.

Dr. Bertha Madras, director of the Laboratory of Addiction Neurobiology at Harvard Medical School’s McLean Hospital in Belmont, Massachusetts, wrote in an accompanying editorial that the results were “both intriguing and sobering.” She did not participate in the study.

The 37% response rate seen in the 25-milligram dose group was lower than what was seen in a 2021 phase 2 clinical trial comparing psilocybin to the antidepressant escitalopram, she pointed out.

However, in that study, participants had moderate-to-severe major depressive disorder, and they received two doses of psilocybin.

Safety profile of psilocybin

Overall, Back said the results of the new study are promising and suggest the potential of psilocybin as a treatment for treatment-resistant depression.

“But it’s not the perfect treatment,” he said. “There are people who didn’t respond, and there are people for whom the depression came back.”

Future research will need to address these limitations, he said, including looking at whether more than one dose of psilocybin is needed for lasting results.

He also thinks future trials should compare psilocybin-assisted therapy to another treatment, such as a regular antidepressant. Ideally, these studies would have a longer follow-up, 6 months or more, he said.

Potential side effects

Among participants in the new study, 77% experienced side effects such as headache, nausea, and dizziness.

A small number of people in each of the dosage groups had suicidal thoughts or injured themselves during the 12-week follow-up period, researchers found.

Back said these types of serious adverse effects have been seen in all studies of treatment-resistant depression.

“What this suggests is that people with treatment-resistant depression need ongoing psychological care to watch out for [signs of suicidal thoughts and self-injury],” he said.

This is one of the reasons that he thinks psilocybin-assisted treatment should be done in the presence of trained clinicians, with ongoing psychological follow-up.

“This is not a DIY thing. Suicidality is hard to deal with,” he said. “That is my caveat for people who are thinking, ‘I’ll just get some mushrooms and try this on my own.’”

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