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Psilocybin and Psychotherapy Relieve Treatment-Resistant Depression in Largest Clinical Trial to Date

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The largest study to date testing the ability of the psychedelic compound psilocybin to treat a psychiatric disorder has shown that the mushroom-derived drug, delivered in combination with integrative psychotherapy sessions, significantly reduced participants’ depression as compared to a placebo after three weeks.

The trial, conducted by an international team across 12 locations, has published its results in the New England Journal of Medicine.

The psychedelic revival

Psychedelics, once reviled as medically worthless and societally destructive, have made a comeback into acceptance within the psychiatric community. Promising early results in small trials suggested that drugs including psilocybin and MDMA could treat a host of psychiatric disorders such as post-traumatic stress disorder and addiction.

The latest and largest psychedelic study was funded by the private drug developer Compass Pathways. The Phase IIb clinical trial used Compass’s psilocybin formulation COMP360. The study has been eagerly awaited by the community since promising topline results were announced last year.

Now, the full data is here.

Largest study to date

The trial assessed the ability of a single dose of psilocybin to ameliorate treatment-resistant depression (TRD), a particularly stubborn form of the disorder that affects roughly a third of patients. TRD is defined as depression that does not respond to multiple rounds of antidepressant intervention. Patients often report extremely high scores, indicating more severe illness, on depression rating scales, such as the Montgomery–Åsberg Depression Rating Scale (MADRS). In Compass’s trial, led by chief medical officer Dr. Guy Goodwin, also an emeritus professor of psychiatry at the University of Oxford, 233 participants had their MADRS score assessed one day prior to a psychedelic therapy session, where they were randomly assigned to receive a dose of either 25 mg, 10 mg or 1 mg psilocybin.

This design was chosen to allow an analysis of the relationship between the strength of a psychedelic dose and the resulting clinical benefit. The participants had three therapy sessions with a trained practitioner prior to the dosing day, and then two additional sessions afterward to discuss their experience, a process called integration.

The team’s primary outcome was the reduction in participants’ MADRS scores three weeks after dosing. They also measured their score at follow-up points up until the 12-week mark. Secondary analyses included the clinical response (defined as a ≥ 50% decrease from baseline in the MADRS total score) at week 3, remission (a total MADRS score of less than 10; participants started on average at a score above 30, indicating severe depression) at week 3 and sustained benefit at 12 weeks.

Fuzzy findings

The team’s primary outcome was positive – while patients given 1 mg, a dose so low as to be considered a control, saw their MADRS scores fall by 5.4 points, those given the highest 25 mg dose saw falls of 12.0 points, a significant difference. At the same time point, 37% of the 25 mg group showed a response to treatment and 29% were classed as being in remission. The improvements were seen very quickly, in marked comparison to the slower pace of change that classical antidepressants produce.

"We saw positive results in a particularly difficult-to-treat group of patients, and the highest dose of COMP360 psilocybin had the greatest impact on people’s depression. This suggests that COMP360 psilocybin has a true pharmacological effect, a finding that is critical for it to be recognized as a new treatment option in the future,” said Goodwin in a press release.

However, beyond these initial findings, the team’s results get fuzzier. To avoid the risk of Type 1 errors, Compass stated that their analysis would have a “hierarchical” analysis pattern. This involves a sequential analysis, beginning with the primary measure and then moving through other tests. When an analysis produces an insignificant result, all subsequent analysis is halted and presumed to also be statistically insignificant.

What is a Type 1 error?

A false positive, or Type 1 error, is the result of a failure of specificity in an experimental design or test. For example, a test that identifies every healthy person as being negative for a particular illness is very specific. But another test that incorrectly identifies 30% of healthy people as being ill would be deemed to be less specific, having a higher false positive rate. These errors are the incorrect rejection of a true null hypothesis.

The second comparison the team made was between the 10 mg and 1 mg groups, where no difference was found, ending further significance analysis as per the hierarchical design. This meant that the team was unable to make much of any of their secondary outcomes, only to say that they roughly “supported” the primary outcome. They did note that at the 12-week mark, the highest 25 mg dose was no longer statistically different from the 1 mg dose, casting some doubts on the treatment’s effectiveness over longer periods, a key component of successful mental health interventions. “The effects did start to wear off by three months, and we need to know how best to prevent the depression returning. This might involve adding in other treatments, such as psychological therapies, or repeating the psilocybin treatment periodically,” said Professor Anthony Cleare of King’s College London, who was not involved in the research.

Skeptical editorial

An accompanying editorial written by Bertha K. Madras, a professor of psychobiology at Harvard Medical School, was skeptical about the efficacy levels achieved in the study, comparing the response rates unfavorably with other antidepressants and the values achieved in a previous, smaller trial that assessed psilocybin against the serotonin selective reuptake inhibitor (SSRI) escitalopram.

However, that smaller trial did not involve patients with the harder-to-treat TRD form of depression, and used two separate doses of the psychedelic, raising the possibility that better results would have been attained in a comparable population with repeated doses. Cleare said, “Given that patients had not responded to between two and four other treatments, it is a very encouraging finding that nearly 4 in 10 showed a clear response to a single dose of psilocybin.”

“The findings were positive, but not what I could call ‘spectacular’,” said Ravi Das, an associate professor at University College London. Das identified the 12-week data, at which point only 20% of the high-dose group were still responding to treatment versus 10% in the control, as evidence that expectations should be tempered.

Safety concerns

The other finding in the trial that came under scrutiny was the safety data produced. While regular SSRI antidepressants are not without their own side effects, there was a noticeable dose-response relationship for side effects present in the new study’s data. In all groups, a majority of patients experienced adverse events: 84% of the 25 mg group, 75% of the 10 mg group and 72% of the 1 mg group. Three instances of suicidal behavior in the 25 mg group were a particular cause for concern. Dr. Natalie Gukasyan, an assistant professor at Johns Hopkins University, suggested this could be an effect of lowered expectations after the treatment, as each of the three participants who showed suicidal behavior did not respond to the 25 mg treatment.

Psychedelic trials remain at an early stage – Compass will take this trial forward to a full phase 3 study imminently – but more and more data is accumulating that suggests a benefit may arise from these psychedelic compounds, even if the size and duration of that benefit remain frustratingly unclear.  

Reference: Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine. 2022;387(18):1637-1648. doi:10.1056/NEJMoa2206443