Synthetic Psilocybin Shows Promise in Phase 2 Trial For Treatment-Resistant Depression

Synthetic psilocybin has shown rapid and sustained effectiveness against the symptoms of treatment-resistant depression (TRD) in a new Phase 2b clinical trial from COMPASS Pathways, a mental health care innovations company.

The trial, which included results from 233 patients across 10 countries in North America and Europe, is the largest ever randomized, controlled, double-blind psilocybin therapy study ever completed. The purpose of the trial was to examine the safety and effectiveness of COMPASS Pathway’s synthetic psilocybin drug, COMP360, at three different doses.

It was found that nearly one-third of patients receiving a high dose were in remission from TRD when assessed three weeks after the treatment session. Nearly one-quarter of those who received the highest dose still showed a sustained response 12 weeks after treatment.

“No one is untouched by the mental health crisis – everyone has a story. We urgently need options for people who are not helped by existing therapies,” COMPASS Pathways’ CEO and co-founder George Goldsmith said in a statement. “We set out to explore the safety and efficacy of COMP360 psilocybin therapy in treatment-resistant depression, through a rigorous and large-scale trial, and to find an appropriate dose to take to the next stage. I am delighted that we have succeeded in doing this.”

Largest ever psilocybin trial shows promise in combating TRD

For this trial, participants were given a single dose of COMP360 – either a 1 milligram (mg) comparator dose, or active doses of 10 mg or 25 mg – with specially trained therapists present to provide psychological support.

The effect on the participants’ mental health was measured regularly using the 60-point Montgomery–Åsberg Depression Rating Scale (MADRS), where scores between 7 to 19 indicated “mild depression,” 20 to 34 indicated “moderate depression,” and scores above 35 indicated “severe depression.” Participants were also asked to report any adverse effects believed to be related to their treatment.

The patients receiving the higher 25 mg dose showed an average 6.6-point reduction on the MADRS scale compared to the 1 mg group by the three-week follow-up. The difference between the 10 mg group and the 1 mg group at three weeks was deemed to be statistically insignificant.

Approximately double the number of participants in the 25 mg group showed improvements in their MADRS score versus the 1 mg group (29 patients vs 14 patients) after three weeks. Similarly, 23 patients in the 25 mg group were in remission (defined here as a MADRS score less than 10) in week three, versus just six patients from the 1 mg group.

Synthetic psilocybin therapy has a sustained effect on TRD

Twelve weeks after the initial treatment session, approximately 24 percent (19 patients) of the group given a 25 mg dose of COMP360 continued to show good improvements in their MADRS score, compared to just 10 percent (8 patients) in the 1 mg comparative dose group.

“In this groundbreaking study, a single dose of psilocybin, given in conjunction with psychological support, generated a rapid response that lasted up to 12 weeks,” David J Hellerstein, a professor of Clinical Psychiatry at the Columbia University Irving Medical Center and the trial’s principal investigator, said in a statement. “Remission rates appear to be higher than seen in traditional medication studies.”

“We now have evidence from a large well-designed trial that psilocybin may be effective for people with treatment-resistant major depressive disorder. These findings suggest that COMP360 psilocybin therapy could play a major role in psychiatric care, if approved.”

COMP360 was generally well tolerated in all groups throughout the course of the trial. Although 179 of the 233 participants reported at least one treatment-emergent adverse event (TEAE), 90 percent of these were mild or moderate events. Headache, nausea, fatigue and insomnia were the most frequently reported adverse events across the study population. In total, 12 patients reported a serious adverse event, predominantly from the 25 mg and 10 mg groups. These included suicidal behavior, intentional self-injury, and suicidal ideation – all of which are fairly commonly observed patient groups with treatment-resistant depression.

Psychedelics and mental health

An estimated 300 million people worldwide are thought to suffer from depression. Of these, between 10 to 30 percent do not respond well to traditional antidepressants, and so are said to have treatment-resistant depression (TRD). People with TRD have higher all-cause mortality rates than those with a major depressive disorder that does respond to treatment and finding novel treatment options that can address TRD is an important facet of current mental health research.

Psychedelics such as psilocybin and ketamine have been investigated as a part of this focus on TRD, with one nasal spray formulation of the ketamine enantiomer, esketamine, already receiving FDA approval for use against TRD. COMPASS Pathways’ COMP360 formulation of synthetic psilocybin received “Breakthrough Therapy” status from the FDA in 2018. Breakthrough therapies are supported by the FDA throughout the clinical development program to maximize the efficiency of the process, reflecting the crucial need for better TRD therapeutics.

COMPASS Pathways is now conducting additional secondary analyses on this data from the Phase 2b trial, which it expects will further inform the clinical development program for COMP360 psilocybin therapy.

“This is an important and exciting moment for the mental health care community,” Robin Carhart-Harris PhD, director of the Psychedelics Division at the Weill Institute for Neurosciences at the University of California San Francisco, said in a statement referring to the new COMPASS Pathways trial.

“It builds upon more than two decades of research into the viability of psychedelic compounds to treat mental health conditions and demonstrates the potential it has in helping people living with treatment-resistant depression. It’s encouraging to see how far this field has progressed in the last 20 years and I look forward to further research.”