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Psilocybin for Treatment-Resistant Depression Could Help Shape the Future of Mental Health
Psilocybin has shown rapid and sustained effects in clinical trials for treatment-resistant depression, potentially offering an alternative option for the future of mental health care. COMPASS Pathways speaks to States of Mind about its Phase 3 results and what’s next for its psilocybin treatment — COMP360.
With global estimates of 100 million people living with treatment-resistant depression (TRD) and relatively few developments in mental health care in the past 70 years, there is a desperate need for new treatment options.
COMPASS Pathways’ two Phase 3 clinical trials investigating COMP360 (a proprietary psilocybin formulation) for the treatment of TRD have shown positive results, with rapid, sustained effects up to six months, and a well-tolerated safety profile.
Dr Steve Levine, Chief Patient Officer at COMPASS and board-certified psychiatrist, says that COMP360 offers a faster onset and requires fewer treatments than traditional antidepressant options.
The company has now begun regulatory submissions, aiming to reach commercial launch in the US by the end of 2026.
Significant Reductions In Depression Symptoms
COMPASS reports that the second of its two Phase 3 trials has achieved its primary endpoint.
The trial evaluated two fixed doses of the synthetic psilocybin formulation COMP360 in two groups (a 25mg and a 1mg group) administered three weeks apart. The primary endpoint was the difference in change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) scores between the groups after six weeks.
The results demonstrated a “highly statistically significant” reduction in symptom severity, Levine explains, with improvements observed in 25mg arm of both trials: 25% of participants in COMP005 and 39% in COMP006 reported at least a 25% improvement in their depressive symptoms.
“That level of reduction is considered to be clinically meaningful, and that number rose to 40% in our second study.” It’s worth noting, however, that many researchers consider a 50+% reduction in MADRS scores the more widely accepted benchmark for “clinically meaningful” treatment response.
The study also showed a well-tolerated safety profile.
The COMP360 treatment also considers the long-term psychological safety of participants, “because of the in-office administration and because this is a psychedelic that comes with a novel experience for most people, we take some time to prepare participants for the study,” Levine says.
This involves developing psychological trust and safety — building trust and rapport between the patient and the care team, and teaching participants basic principles to help them navigate the day of treatment.
Although participants are continuously monitored, “there isn’t direct therapeutic intervention from the study team on the day of administration,” says Levine.
“This is autonomously self-navigated by the participant, so they are instructed in principles such as present moment focus to help them attend to the experience and stay with it, even if it should produce any kind of anxiety or become more challenging.”
According to Levine, the role of the session monitor is to help participants maintain focus on the treatment while they’re wearing an eye mask, lying down, and listening to music. In terms of safety, they also monitor participants for adverse effects, including nausea, increases in blood pressure, and psychological distress.
Following the treatment, participants undergo follow-up safety monitoring and discuss their experience on the day of administration.
How COMP360 Differs From Traditional Options
The benefits seen from the treatment were sustained for up to six months in the first Phase 3 trial.
Levine says that this is a profile of “rapidity and durability that we have never seen anything like in psychiatry before, including for patients with treatment-resistant depression”.
Current options for treatment-resistant depression include ketamine therapy, transcranial magnetic stimulation, and electroconvulsive therapy.
“There are many other antidepressants out there that typically are taken on an everyday basis that have tried to show efficacy in this population and failed,” says Levine.
Many of these current treatments need repeated administration to sustain their benefits; however, the results from the COMP360 trials show immediate effects with long-term benefits after just one or two treatments.
“What we anticipate, but we still need more data to learn more about, is that, on average, patients might expect somewhere in the neighborhood of two to four treatments in a year.”
This marks a step-change from daily antidepressants or regularly repeated treatments.
A New Hope For Mental Health Care?
In the US alone, an estimated 2.8 million adults live with treatment-resistant depression, pointing to a huge unmet need for new mental health treatments.
With very few pharmacological treatment options available, COMP360 could offer new hope for the future of mental health care.
Levine explains that the treatment will fit into already established models for ketamine treatments that are being delivered along with forms of neuromodulation like transcranial magnetic stimulation.
“Because Spravato was FDA approved back in 2019, an infrastructure has been built that focuses on delivering in-office treatments, and typically multi-hour in-office treatments,” explains Levine.
“That’s a type of structure sometimes known as interventional psychiatry. Fortunately, COMP360 fits very neatly into this delivery model.”
“On top of that, we’ve been working with a network of strategic collaborations that are live sites of care delivery.”
According to Levine, these collaborations span many types of delivery infrastructure including decentralized models, community behavioural health hospital systems, and integrated delivery models.
“Part of the work with them is understanding what kind of support they will need, or what kinds of capabilities they will need to build to also be able to deliver more interventional treatments.”
“This work will go a long way towards ensuring broad and equitable access.”
With this delivery infrastructure in place, Levine says that scaling the treatment isn’t a barrier, but more needs to be done to educate healthcare providers and increase awareness to help identify people with TRD earlier.
“We need to educate them that there now are specific treatments that have an evidence base and are indicated for, and available for, people with TRD,” says Levine.
“Because unfortunately, today, too many of these patients just languish receiving antidepressants that have already failed them and are unlikely to change the course of their illness.”
What’s Next For COMP360
With strong Phase 3 results and Breakthrough Therapy Designation under its belt, COMPASS Pathways has been in ongoing talks with the U.S Food and Drug Administration (FDA).
The company has already conducted preliminary discussions with the agency about an accelerated submission and review timeline.
“We are now working together with the FDA on a plan to start submitting our application on a rolling basis for a potential “rolling review” which can shorten review timelines,” Levine explains.
Donald Trump, president of the United States, recently signed an executive order that aims to support the research and development of psychedelics.
Levine says this could have some additional bearing on review timelines, as it was announced that three National Priority Vouchers would be issued to psychedelics in the near term.
This could move timelines up for potential approvals, including for COMPASS.
COMP360 has now been selected to receive a priority voucher under the new Executive Order, which will entitle the company to benefits including enhanced communications and a shortened one to two month review time following filing of a New Drug Application (NDA).
Levine says that COMPASS has also begun building out its commercial infrastructure.
“We want to make sure that at the first possible moment post-approval, that we can get our product to the patients who are waiting,” says Levine.
“That means work we need to do with educating payers and to start to establish the reimbursement infrastructure for this treatment.”
COMP360 already has an Innovation and Licensing Pathway (ILAP) designation in the UK — a recently established pathway to accelerate promising, the most transformative medicines into the UK health system.
“The UK is a very important market for us, and we will look to file in the UK post-FDA filing.”
Expert Board Member
Treatment-resistant depression affects a significant proportion of people living with depression, for whom existing options offer limited and often temporary relief. This article covers COMPASS Pathways' Phase 3 findings, while acknowledging the need for further data on long-term outcomes, safety, and real-world implementation. A valuable overview of a rapidly evolving field still undergoing scientific validation.
