Issue #003Clinical Science7 min readJuly 24, 2026

Two Phase 3 wins. What the evidence now establishes.

Two consecutive Phase 3 successes, a Zurich hospital study, and what Spravato's path tells us about where coverage likely goes next.

Jama Pitman

CEO, Rose Hill Life Sciences

The Rose Hill Review

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THE DISPATCH

In June 2025 and February 2026, Compass Pathways reported positive primary endpoints in two consecutive Phase 3 trials of synthetic psilocybin (COMP360) for treatment-resistant depression, the first time any compound in this field had reached that threshold twice.¹ ² In June 2026, a study published in The Lancet Regional Health reported findings from the first examination of psilocybin therapy delivered in a routine university hospital psychiatric department rather than a dedicated research protocol.³ Clinical outcomes noted in this study were considered impossible by the standard of care a decade ago in this literature was considered impossible by the standard.

In this issue:

→ What two consecutive Phase 3 wins actually establish, and where the evidence base still has gaps

→ What esketamine's path after its 2019 FDA approval reveals about how quickly the insurance system can move

→ The Zurich real-world study, a mixed result from JAMA Psychiatry worth reading carefully, and where the DEA clock stands

THE SCIENCE

In June 2025, Compass Pathways announced that COMP005, the first of two pivotal Phase 3 trials of synthetic psilocybin (COMP360) for treatment-resistant depression, had met its primary endpoint. A single 25-mg dose compared to placebo produced a statistically significant reduction in MADRS score of -3.6 points at week six (p < 0.001).¹ In February 2026, the second pivotal trial, COMP006, confirmed the finding using a different design: two 25-mg doses administered three weeks apart, compared to a 1-mg control, produced a MADRS reduction of -3.8 points at week six (p < 0.001).² The FDA requires two positive pivotal trials to support a New Drug Application, and both are now complete with consistent findings across different dose regimens.

Those two trials confirm that COMP360 produces a measurable, reproducible reduction in symptom severity against a comparator under controlled conditions. What they cannot answer is whether that effect holds in clinical practice, where dose flexibility, therapist training variation, and patient comorbidity patterns may differ from what a research protocol controls for.

The Zurich study begins to address that question. Published June 1, 2026 in The Lancet Regional Health, it examined 19 patients with treatment-resistant depression who received individualized doses of synthetic psilocybin ranging from 20 to 35 mg in a routine psychiatric department at the University Hospital of Psychiatry in Zurich.³ Mean MADRS scores dropped from 30.78 at baseline to 19.89 after treatment, a reduction of approximately 11 points consistent with a large effect size (Hedges' g = 1.37). The sample is small, there is no control group, and the study is retrospective. The direction and magnitude of effect are consistent with the Phase 3 controlled trial data, and the clinical setting, a routine hospital department rather than a dedicated research facility, is significant for what it suggests about scalability.

For context on where this evidence base is likely to lead on access, esketamine (Spravato) offers a useful precedent. The FDA approved Spravato in March 2019 for treatment-resistant depression, the first truly novel antidepressant mechanism approved in decades. Because Spravato required in-clinic administration, it fell under Medicare Part B, and coverage was established in the period following approval. Major commercial insurers began adding it to their formularies through 2019 and into 2020. Coverage required prior authorization at nearly every insurer, and access gaps remained. The path from FDA approval to meaningful insurance coverage for a novel psychiatric therapy with a supervised-session model took likely one to two years.

Psilocybin-assisted therapy differs from esketamine in one structurally important way: the required therapist time is substantially greater. A Spravato session involves administration plus two hours of monitoring. A psilocybin-assisted session runs six to eight hours and requires trained facilitation throughout. For that time to be reimbursable, billing codes must be established and accepted by payers. As covered in our June issue, Current Procedural Terminology (CPT), ICD-10, and HCPCS codes do not yet exist for psilocybin-assisted therapy, and establishing them requires action from CMS and professional coding bodies on a timeline that runs in parallel to the FDA pathway, not after it.

Compass's NDA submission is on track for Q4 2026. Under its Commissioner's National Priority Voucher (CNPV), the FDA review window compresses to as little as one to two months after submission. Following FDA approval, the Controlled Substances Act requires the DEA to initiate rescheduling within 90 days, though the process carries no statutory completion deadline. The Spravato precedent suggests the insurance system can respond quickly to a novel approval. Whether it does for psilocybin-assisted therapy depends on how much of the billing and coverage groundwork is in place before that approval arrives.

THE STORY

Practicing psychiatrists at the University Hospital of Psychiatry in Zurich administered individualized doses of synthetic psilocybin to 19 patients with treatment-resistant depression in a routine clinical department, outside research protocol conditions. They selected doses between 20 and 35 mg based on individual patient factors: prior treatment history, clinical presentation, and professional judgment.³ Mean MADRS scores dropped from 30.78 at baseline to 19.89 following treatment, consistent in direction and magnitude with what the Phase 3 protocols had documented.

One hospital psychiatric department has demonstrated that psilocybin-assisted therapy can be administered in a routine clinical setting with outcomes that track the controlled evidence base. The billing infrastructure that would allow those clinical hours to be reimbursed is still being built, requiring action from CMS and professional coding bodies on a timeline independent of FDA approval.

Rose Hill Life Sciences is a psychedelic research organization – specializing in the production and research of Psilocybe cubensis operating at the intersection of science and therapeutic integration.

ON OUR RADAR

① DEA Rescheduling: What the 90-Day Clock Means From Here With Compass Pathways' CNPV compressing FDA review to as little as one to two months post-NDA submission, and submission targeted for Q4 2026, an FDA approval decision could likely come in early 2027.² Under the Controlled Substances Act (21 U.S.C. § 811(j)), the DEA is required to initiate the rescheduling process within 90 days of FDA approval. The process completion timeline carries no statutory deadline, but the current executive order environment makes sustained delay less likely than it would have been historically. Watch for DEA public notice of proposed rescheduling as the first procedural signal.⁴

② EPISODE Trial, JAMA Psychiatry: Mixed Results Worth Reading Carefully A Phase 2b randomized trial published in JAMA Psychiatry, the EPISODE study, enrolled 144 adults with treatment-resistant depression across four arms receiving two doses of psilocybin 25 mg, psilocybin 5 mg, or nicotinamide active placebo over six weeks. The primary endpoint, response rate on the Hamilton Rating Scale for Depression at week six, was not statistically significant. Secondary outcomes on the MADRS scale showed clinically meaningful reductions for psilocybin 25 mg. The study also recorded a higher rate of suicidal ideation on dosing days for the 25-mg arm (4%) versus comparators (1 to 2%), though worsening of suicidal ideation from baseline was comparable across all arms. This is Phase 2b, preliminary data; the COMP360 Phase 3 evidence operates in a different evidentiary tier. The primary endpoint miss and safety signal are worth tracking alongside the broader evidence base.⁵

③ COMP360 Long-Term Data Presented at ASCP 2026 Annual Meeting Breaking poster data at the 2026 American Society of Clinical Psychopharmacology annual meeting examined extended follow-up from both COMP005 and COMP006 Phase 3 trials. Preliminary data suggest therapeutic effects were maintained at follow-up timepoints beyond the primary six-week endpoint, supporting a durable rather than transient benefit profile. Conference poster data is not peer-reviewed; full follow-up publication is the next milestone to watch from this dataset.⁶

YOU ASKED

Q: "As a psychiatrist, how should I think about the difference between trial results and what I'd actually see treating a patient?"

The controlled trial setting is built to maximize internal validity: it answers whether the compound produces a measurable effect under precisely controlled conditions. Clinical trials are designed to determine the benefit/risk profile for the intended treatment population and although key design elements try to account for how a therapy will be used in the real world it is difficult for a clinical trial to account for varaitions in clinical practice. The Zurich study, published June 2026 in The Lancet Regional Health, is the first published examination of psilocybin therapy delivered in a routine hospital psychiatric department rather than a research protocol. MADRS reductions were consistent in direction and magnitude with the Phase 3 controlled trial data, though without a control group, and the effect surviving the move from protocol to practice is the first real-world signal the field has produced.

This week's takeaway: the clinical evidence for synthetic psilocybin (COMP360) is now two Phase 3 trials strong, with a real-world hospital study adding the first consistency check from outside a controlled protocol. The Spravato precedent suggests the insurance pathway can open within one to two years of FDA approval, provided the billing infrastructure is built in parallel. Whether the coverage timeline follows the approval timeline or lags behind it depends on how much of that groundwork is done before the NDA decision comes.

A question worth sitting with: if billing codes and payer acceptance for psilocybin-assisted therapy were established before FDA approval, rather than after, what would the first year of covered access look like?

Read the Compass COMP006 Phase 3 results directly: Compass Pathways — Second Phase 3 Trial Results

If a clinician in your network is fielding patient questions about psilocybin therapy and isn't sure where to point them, this is the source. Forward it to one colleague navigating the same conversation.

— Jama Pitman