The largest clinical study ever conducted on psilocybin, the psychedelic compound found in “magic mushrooms”, will begin by the end of December.
It is the first time that a hallucinogen clinical trial has reached Phase 3, one of the last steps required before an investigational drug can go to the Food and Drug Administration for eventual regulatory approval.
The research will examine whether the drug can effectively treat depression when other therapies have failed.
COMPASS Pathways, a UK-based pharmaceutical company that focuses on psilocybin research, is leading the study. It is expected to include more than 900 people in 14 countries, including the United States, and is expected to finish by mid-2025, said Dr. Steve Levine, COMPASS Senior Vice President of Patient Access.
Levine said the company is building on previous research showing the drug’s safety and efficacy. “This gives us a lot of hope that potentially within a few years we could take this through regulatory approval and hopefully to patients who really need it.”
There are more obstacles. Most psychedelics, including psilocybin, are federally illegal in the United States. Nobody knows for sure how it might work to treat depression. And previous research has shown that less than a third of psilocybin-treated patients actually improved – and even then the benefits wore off after just a few weeks.
But is that enough to make a significant difference?
‘A population difficult to heal’
Of the 8.9 million people in the United States who take medications to treat depression, a 2021 study estimated that just under a third, or 2.8 million, are not helped by medication, a condition known as resistant depression. treatment.
Previous research from COMPASS Pathways, a Phase 2 clinical trial, was published Wednesday in the New England Journal of Medicine. The study included 233 participants with moderate to severe treatment-resistant depression. All had tried up to four antidepressants prior to enrollment, without success.
“These are people who are not only severely depressed, but also very frustrated, because they have tried so many different things,” said Stewart Shankman, a clinical psychologist at Northwestern Medicine in Chicago who was not involved in the new research.
Psilocybin seemed to work for some participants, at least in the short term.
Three weeks after taking a 25-milligram dose of the drug, 29 percent of participants reported improvements in their depression, the researchers found. By three months, this had dropped to 20 percent – statistically indistinguishable from participants who had taken a lower dose – 10 milligrams or 1 milligram – of the drug.
Dr. Sandeep Nayak, assistant professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, noted that while most of the people in the study did not get better from psilocybin, the study showed a benefit in a group of people. ” that have not done well with existing treatments and therefore will be much more difficult to treat. “
Nayak was also not involved in the COMPASS study, but conducts research on psilocybin for other mental health conditions.
Despite the relatively low percentage of respondents, Levine said he was thrilled with the results. “This is a difficult population to care for,” he said. “If we look at other existing data to give us some hints on how we would expect any type of intervention to work in this population, we would expect much, much lower numbers.”
Dr. Steve Zalcman, head of the section for the development of biological interventions and adult pathophysiology at the National Institute of Mental Health, called the new research “admirable,” but will require much broader and longer-term follow-up. .
“For a lifelong crippling illness like major depressive disorder, a three-week improvement is good, but it’s hard to build a story,” said Zalcman, who was not involved in the new research.
Psychedelics plus therapy
Treatment with a psychedelic drug like psilocybin is not as simple as giving a patient a pill and sending him home.
In COMPASS Pathway studies, participants first participate in three therapy sessions with a licensed physician.
On the day of treatment, participants are given psilocybin in pill form, then lie down in a room with two therapists. They wear eye masks and listen to a “carefully curated playlist designed to map the trajectory of the psychedelic experience,” a COMPASS Pathways representative said in an email.
Participants stay in that room for up to eight hours, with therapists nearby as needed. For safety reasons, the FDA requires psilocybin clinical trials to have two people with participants during each session.
Zalcman, of the National Institute of Mental Health, said that because the study included speech therapy, it’s impossible to “untangle” the two. That is, is it the drug that helps, or is it the combination of the two therapies? Previous research has found that the therapeutic component plays an important role.
In the phase 2 study, most participants, regardless of the dosage received, experienced side effects, usually within 24 hours of treatment. The most frequent complaints were headache, nausea, dizziness and fatigue.
But the study also found a potentially troubling problem. Of the 79 people in the group who received the highest dose of psilocybin, two individuals reported suicidal thoughts during the three weeks following treatment. Two other people in the 10-milligram group had similar experiences.
Three months after treatment, three people in the 25-milligram group exhibited suicidal behavior. The company said none of the behaviors resulted in suicide attempts and that the three participants had a history of suicidal ideation.
Zalcman said the number of people who had suicidal ideation in the study was so small that it’s hard to interpret its meaning, if nothing else.
These participants, Levine noted, did not respond to psilocybin treatment.
It’s this lack of initial response that could play a role in suicidal behavior, Nayak said. He said that in his experience of him, patients with treatment-resistant depression have high hopes for experimental treatments like psilocybin, and when it doesn’t work, “not only are they depressed, they are also demoralized.”
All adverse events will be investigated in the next Phase 3 study. The project will comprise three parts. The 25-milligram dose will be directly compared to a placebo (possibly niacin, a B vitamin that causes a flushing sensation). Another will mirror the Phase 2 protocol, comparing doses of 1, 10, and 25 milligrams, but will give a second dose three weeks later.
The goal, Levine said, is to see if that second dose would improve response rates.
The study is also expected to include long-term monitoring to see how long the effects, if any, can last. Levine declined to say how long that part of the process would last.
Another confounding problem with psilocybin’s potential is that no one really knows how it works. There is evidence that the drug interacts with the serotonin receptors in the brain. If so, researchers may be able to isolate the active ingredient and turn it into a pill that doesn’t cause hallucinations.
But another school of thought suggests that the euphoria produced by psilocybin travel may somehow help a person explore their feelings and experiences with depression that they otherwise might not.
“Is the drug alone enough? Or do you need the mystical experience?” Zalcman asked.
Despite the lack of understanding of its potentially therapeutic mechanism, psilocybin is also being studied for other difficult-to-treat conditions.
NYU Langone Health researchers are looking into psilocybin to treat alcoholism. Johns Hopkins Medicine, Nayak said, is studying whether hallucinogen can help people quit smoking, as well as anorexia nervosa, chronic Lyme disease, and Alzheimer’s. He is preparing for upcoming studies on the drug’s potential for obsessive-compulsive disorder and opioid use disorder.
COMPASS Pathways is also investigating whether psilocybin can treat post-traumatic stress syndrome.
“Our ability to successfully and sustainably treat these disorders is embarrassingly low,” said Zalcman. “It is not unreasonable that people have the aspiration to try to find treatments that work for these very serious and disabling ailments.”
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