• Posted November 3, 2022

Single Dose of Psychedelic Curbs Depression, But Study Raises Concerns

A single psychedelic trip with psilocybin -- the mind-altering component of magic mushrooms -- appears to lift the fog of major depression in some hard-to-treat patients, a new clinical trial reports.

A 25-milligram dose of a synthetic psilocybin compound called COMP360 caused a "rapid and durable response" in more than a third of patients suffering from treatment-resistant depression, said Dr. Steve Levine, senior vice president of patient access for the London-based pharmaceutical company COMPASS Pathways. It focuses on psilocybin research and created the COMP360 synthetic compound and funded the clinical trial.

The results occurred in a phase 2 trial aimed at finding the most effective dose of COMP360, according to a report published Nov. 3 in the New England Journal of Medicine.

However, there was one caveat: While side effects were minimal, four patients (out of 79) who took the highest dose either reported having suicidal thoughts or intentionally harming themselves in the weeks that followed.

The psilocybin compound will now proceed to a full-fledged clinical trial that promises to be the largest ever conducted for a psychedelic compound, Levine said.

The trial testing its effectiveness is expected to include more than 900 people in 14 countries, including the United States, Levine said. It's expected to conclude in mid-2025.

These early findings show that psilocybin could well provide an alternative to standard treatments for major depression that doesn't respond to antidepressants, said Dr. Brian Barnett, a psychiatrist who runs the Cleveland Clinic's program for treatment-resistant depression.

"In this patient population, we don't see a lot of treatments that are very successful outside of things such as electroconvulsive therapy [ECT] and ketamine," said Barnett, who was not part of the study. "The results here look to be on par with those treatments."

About a third of the 8.9 million U.S. people taking antidepressants don't really respond to the usual drugs, a 2021 study in the Journal of Clinical Psychiatry estimated.

"We really have made a decision to focus on an area of big, big unmet need, which is when people have difficult-to-treat depression," Levine said. "And that's who we enroll in these trials."

The latest clinical trial results came from a study involving 233 people from 10 countries, including Canada and the United States, who received either a 25 mg, 10 mg or 1 mg dose of COMP360, the NEJM report said.

All of the patients had difficult-to-treat depression, and were in the middle of a depressive episode that had not been alleviated with treatment using at least two and as many as four different antidepressants, Levine said.

No therapy occurred during their psychedelic trip, which for heavy doses lasted between six to eight hours, Levine said.

Instead, each patient simply sat in a calm, quiet room, wearing eyeshades and listening to music, letting the drug work on their minds. Two therapists stayed with them the entire time, for support.

In the week following their treatment, the patients attended "integration" therapy sessions, in which they discussed what they experienced with the therapists who had sat with them during the treatment.

The results from the 10 mg and 1 mg doses were negligible, but about 37% of people who got the heavy 25 mg dose had significantly lower levels of depressive symptoms three weeks out from treatment.

In fact, about 29% had symptom scores so low that their depression appeared to be in remission, results show.

The effect of the trip waned over time, however. Just 20% of the 25-mg group still had lower depressive symptoms at the three-month mark.

But that is on par with other treatments used in depression patients who aren't responding to antidepressant drugs, Barnett said.

Those patients might need "ECT once a month, potentially for the rest of their life. In the case of ketamine, some patients need ketamine weekly or twice a month or monthly, possibly the rest of their life as well," Barnett said.

"It looks like it's helpful for patients who have failed antidepressants, because that's really going to be one of the primary questions for insurance coverage if this is approved," he added. "A treatment this intensive, it's going to be expensive. And so obviously, insurers are going to require that patients fail in antidepressants before they would consider covering it."

Most of the side effects were "things like headache, nausea and dizziness, things that you might naturally expect with the administration of a psychedelic substance," Levine said.

Suicidal behavior or thoughts are a concern. Three weeks out from the psychedelic session, two patients in the heavy dose group reported suicidal thoughts and two had intentionally harmed themselves.

In their report, the researchers noted that "suicidality demands clinical vigilance in future trials of psilocybin for depression."

Whether psychedelics induce suicidal thoughts in some vulnerable people has always been a big question, Barnett noted. The numbers are small, he added, but a signal is there.

"The big question is: Was this directly related to the psilocybin or was it this phenomenon we often see in clinical trials of patients with treatment-resistant depression, where they're very invested in being in the trial because they think this is finally going to be the thing that works," Barnett said. "With psychedelics there's a lot of hype by the media, and so a lot of patients have what's called a disappointment reaction afterwards. I am wondering if that's what happened here."

So how might psilocybin affect the brain in a way that would treat depression?

Researchers suspect that the drug affects receptors in the brain that lead to neurochemical and psychological changes that let people see things in a different way.

"People under the influence of psilocybin, they're able to look at themselves, look at the narrative that they've developed about their life and their identity in different ways," Barnett said. "And it does seem that the psilocybin allows new flexibility in the way that we think about our lives and the stories of our lives."

COMPASS Pathways plans to follow up with two clinical trials, Levine said.

One trial will test a single 25 mg dose directly against a placebo. The other will retest the three different doses, but this time patients will undergo two trips, one administered three weeks after the first.

More information

Brown University has more information about psilocybin.

SOURCES: Steve Levine, MD, senior vice president, patient access COMPASS Pathways, London; Brian Barnett, MD, psychiatrist, Cleveland Clinic; New England Journal of Medicine, Nov. 3, 2022