What Psychedelic Clinical Trials Could Teach Psychiatry

Treatment-resistant depression (TRD), a condition where patients do not respond adequately to standard antidepressant therapies, remains one of the most difficult areas of psychiatry to study, treat and translate into real-world care. 

For patients who have cycled through multiple therapies without meaningful improvement, the clinical challenge is not only symptom persistence, but also diminishing treatment expectations, functional decline and a widening gap between available options and patient need. 

Xtalks spoke with Steve Levine, MD, Chief Patient Officer at Compass Pathways and a board-certified psychiatrist, about why TRD is uniquely difficult to study, how psychedelic clinical trials differ from traditional antidepressant trials and what the company’s key clinical program could mean for future psychiatric research.

“Depression is a great equalizer,” Dr. Levine told Xtalks, underscoring how broadly and deeply the condition can affect patients and families. But in clinical research, depression also presents a set of scientific challenges that remain difficult to overcome.

“Major depression in general is difficult to study in part because we have to rely on subjective assessments as opposed to objective markers like we would have in non-psychiatric indications, as well as high placebo response rates that make it difficult to show a significant treatment effect,” Dr. Levine said. 

Depression trials, he added, have historically been difficult to replicate, with similar study designs sometimes producing conflicting results.

And patients with TRD face added challenges as they’ve often experienced long disease episodes and multiple prior treatment failures. According to Dr. Levine, the longer the episode and the greater the number of previous unsuccessful treatments, the less likely patients may be to benefit from another intervention. This makes TRD not only a high-need indication, but also a demanding test case for new therapeutic models.

Depression affects hundreds of millions of people worldwide, but for patients with TRD, the care gap is especially stark. In the US, one analysis estimated that nearly one-third of adults with medication-treated major depressive disorder have TRD, a subgroup that accounts for almost half of the annual economic burden of medication-treated depression. 

Yet Compass Pathways estimates that fewer than 5% of the approximately 4 million US patients with TRD receive an FDA-approved treatment indicated for the condition, highlighting the need for new approaches in one of psychiatry’s most difficult-to-treat populations.

Compass Pathways is developing COMP360, a synthetic psilocybin treatment being investigated as a potential option for TRD. 

In April 2026, the FDA granted Compass Pathways a rolling New Drug Application (NDA) review request and selected COMP360 for the Commissioner’s National Priority Voucher (CNPV) program, following positive data from two ongoing Phase III trials. Compass Pathways said the program may allow for enhanced FDA communications and a shortened review timeline while maintaining standard safety and efficacy requirements.

How Psychedelic Clinical Trials Differ From Traditional Antidepressant Trials

Unlike many approved antidepressants that are taken daily at home, psychedelic-assisted treatment models are built around supervised administration, patient screening, monitoring and support. 

For COMP360, that means the treatment is being evaluated as a structured clinical intervention rather than a conventional daily medication.

“The biggest difference is that treatment is being administered in a supervised setting with monitoring and support as opposed to at home,” Dr. Levine said. 

Treatment is also administered once or a limited number of times, rather than on a chronic daily basis like selective serotonin reuptake inhibitors (SSRIs).

This model has brought trial design questions into focus, particularly around blinding. Because psychedelic compounds can produce noticeable acute effects, maintaining a double-blind, placebo-controlled design can be difficult. However, Dr. Levine noted that unblinding is not unique to psychedelics.

“A lot of attention has been paid to this issue of unblinding, the difficulty of maintaining double-blind, placebo-controlled clinical trials because of the obvious acute psychedelic effects of these compounds,” he said. “But it’s actually true of all antidepressants and all psychiatric drugs.”

The FDA has also acknowledged that psychedelic clinical studies raise unique design considerations. In its 2023 draft guidance, the agency said psychedelic drugs are being evaluated for conditions such as depression, post-traumatic stress disorder and substance use disorders, but emphasized that studies must be designed to generate interpretable data capable of supporting future drug applications. The FDA also stated that the evidentiary standard for effectiveness is the same as for other drugs, even though sponsors may need to account for unique trial design factors.

What COMP360’s Phase III Program Has Shown So Far

Compass Pathways’ Phase III program includes two pivotal trials, COMP005 and COMP006, evaluating COMP360 in TRD. In June 2025, Compass announced that COMP005 met its primary endpoint, with a single 25 mg administration of COMP360 demonstrating a statistically significant and clinically meaningful reduction in symptom severity versus placebo as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at Week 6. The trial enrolled 258 participants with TRD across 32 sites in the US.

In February 2026, Compass announced that COMP006, the second Phase III trial, also met its primary endpoint. COMP006 enrolled 581 participants across North America and Europe and evaluated two fixed doses of COMP360 given three weeks apart.

Dr. Levine said one of the key findings across the program is that COMP360 has been generally safe and well-tolerated. He also pointed to the possibility that, for some patients, one or two treatments could produce rapid and durable benefit. “Really excitingly for some patients, one or two treatments may have an almost immediate, meaningful and durable benefit out to at least six months,” he said. 

In COMP005, he noted that 25% of participants receiving the 25 mg dose had a clinically meaningful benefit at the Week 6 primary endpoint after a single administration, and 40% of those who received a second administration went into remission. In COMP006, he said nearly 40% of participants had a clinically meaningful benefit after receiving two 25 mg doses.

From a clinical research standpoint, the consistency of the findings is encouraging, as psychiatric drug development has long struggled with reproducibility, high placebo effects and heterogeneous patient populations. Dr. Levine said Compass Pathways has now studied more than 1,000 participants across its Phase IIb and Phase III program, with positive primary endpoints across three studies.

Why Patient-Reported Outcomes Matter in TRD

While MADRS remains central to regulatory review, Dr. Levine said symptom reduction does not always fully capture what matters most to patients.

“While MADRS is the primary outcome measure and the most important one for FDA review, it’s not a scale commonly used in the real world, and it doesn’t necessarily measure what we’ve heard from patients is most important, which is quality of life and level of function as opposed to the symptom reduction,” he said.

That is where patient-reported outcomes (PROs) may become especially important. In TRD, where patients may have lived with persistent symptoms for years, outcomes such as social functioning, ability to work, daily activity and overall quality of life can help clinicians, payers and patients understand whether a treatment’s impact extends beyond rating-scale improvement.

Compass Pathways has included PROs in its studies, and Dr. Levine said those data will be important in evaluating the full potential of COMP360 once available.

Regulatory Standards Still Apply

As psychedelic medicines move closer to potential regulatory review, one of the central questions is whether they should be treated as a fundamentally different class of psychiatric therapies. Dr. Levine cautioned against what he called “psychedelic exceptionalism.”

The regulatory standards for demonstrating evidence of safety, efficacy and quality are no different than for any other psychiatric compounds, he explained. Although the FDA’s psychedelic drug development guidance addresses design issues such as unblinding, Dr. Levine said the broader takeaway is that “the usual standards of evidence apply.”

That framing may be important for the field. Psychedelic medicine has drawn substantial public attention, but for regulated treatments to enter mainstream care, sponsors will need to demonstrate not only efficacy, but also operational feasibility, safety monitoring, appropriate patient selection and quality-controlled delivery models.

For Dr. Levine, the work is also personal. Before joining Compass Pathways, he spent much of his career treating people with TRD.

“It’s really quite a thing to sit across from somebody who is saying to you, ‘I have severe depression. I have tried everything. Nothing has helped me. I’m losing hope,’” he said. To now be part of a program showing the potential for a safe, well-tolerated, rapid-acting and infrequently administered treatment, he added, “this is what I’ve been waiting my whole career for.”

Compass Pathways’ program could help set expectations for how psychedelic treatments are studied, regulated and potentially integrated into psychiatric care. It may also serve as a test case for whether new treatment models can meet standards in one of psychiatry’s hardest-to-treat populations.