An ongoing advanced clinical trial of psilocybin as a depression treatment reportedly shows great promise. Caution is required when the data have not yet been published. But if confirmed, this could be a landmark in the psychedelic drug’s journey toward federal approval as a medical treatment in the United States.
On June 23, biotechnology company Compass Pathways announced it had reached the primary endpoint of its Phase 3 clinical trial studying psilocybin for treatment-resistant depression (TRD). The researchers used a synthetic formulation of psilocybin, COMP360. After six weeks, they measured changes in baseline depression using the Montgomery-Åsberg Depression Rating Scale (MADRS)— comparing a group that received the drug to another that received a placebo.
According to the company’s announcement, a single dose of 25 milligrams of psilocybin “demonstrated a highly statistically significant reduction in symptom severity … and a clinically meaningful difference of -3.6 in change [of MADRS scores] at the primary endpoint.”
In total, the trial dosed 258 participants at 32 sites across the United States. Compass states that this is “the first study of an investigational, synthetic psilocybin, and the first classic psychedelic, to report Phase 3 efficacy data.”
“We are very encouraged by the initial positive results and the highly statistically significant and clinically meaningful change in the MADRS score.”
In terms of safety, the trial data were reviewed by an independent Data Safety Monitoring Board, which reportedly found “no unexpected safety findings and no clinically meaningful imbalance in suicidal ideation between treatment and placebo arms.”
“As we continue our Phase 3 program, we are very encouraged by the initial positive results and the highly statistically significant and clinically meaningful change in the MADRS score between the arms of the study 6 weeks after a single administration of COMP360,” said Guy Goodwin, MD, the company’s chief medical officer. “This progress marks an important milestone for patients living with TRD and highlights the groundbreaking work Compass Pathways is doing to bring innovative treatments to those who have been failed by multiple currently approved available treatment options.”
As this Phase 3 trial progresses, Compass is also running an additional, larger Phase 3 trial with 568 planned participants and a different study protocol. Here, people will be given either psilocybin or a placebo on three occasions, three weeks apart, starting at 25 mg, then tapering to 10 mg and 1 mg. The company plans to publish the first batch of data from this trial, with a 26-week endpoint, in 2026.
Compass is not the only organization studying psilocybin for depression. The Usona Institute, a research nonprofit based in Madison, Wisconsin, is also currently in Phase 3 trials.
These trials involve about 240 participants who will be given a single dose of psilocybin, either 25 or 5 mg, or a placebo. Researchers will assess participants 43 days after dosing, and one year later, to see how they tolerate the drug and if it affects depression symptoms. The results of Usona’s Phase 2 trials were published in 2023, and stated that psilocybin “was associated with a rapid and sustained antidepressant effect, measured as change in depressive symptom scores, compared with active placebo. No serious treatment-emergent adverse events occurred.”
The psychedelic research space more broadly was rocked by the Food and Drug Administration’s 2024 decision to reject an application to approve MDMA as a treatment for post-traumatic stress disorder (PTSD). To date, no Schedule I psychedelics, including psilocybin or MDMA, have been approved by the FDA for medical use. If and when that happens, it will be historic.
If drugs like psilocybin or MDMA are approved by the FDA, treatment costs may still be prohibitively high for many patients.
While federal approval of these drugs remains elusive for now, important policy changes have been happening at the state level. Oregon and Colorado have both legalized psilocybin for supervised use at licensed facilities by voter initiative, with psilocybin centers now open to the public. New Mexico lawmakers also recently approved a new law legalizing psilocybin for patients with severe medical conditions, though it’s several years away from authorizing treatment.
If drugs like psilocybin or MDMA are approved by the FDA, treatment costs may still be prohibitively high for many patients because of the length of required supervised sessions with psychotherapists, or potential overnight clinic stays. That could create a conflict with health insurance providers, who may be hesitant to reimburse for psychedelic therapy.
Vincent Joralemon, in a blog post for the Petrie-Flom Center at Harvard Law School, highlighted Johnson & Johnson’s Spravato (esketamine), an FDA-approved formulation of ketamine, as an example of pharmaceutical and insurance companies agreeing a model to make psychedelic therapies more accessible. The Spravato model includes a dual co-payment reimbursement for both the drug and the monitoring of patients. The pharmeceutical giant also offers financial support for certain patients on low incomes through its nonprofit foundation.
“Psychedelic-assisted therapies require substantial upfront costs; although there are ways to minimize those expenses (e.g., with group therapy sessions), they will still be a hard pill to swallow for price-conscious payers,” Joralemon wrote. “Yet, these psychedelic therapies may carry immense clinical promise for a host of difficult-to-treat conditions. Getting insurers to see that potential will go a long way.”
Photograph (cropped) by Rohan523 via Wikimedia Commons/Creative Commons 3.0
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