The U.S. Food and Drug Administration issued its first formal guidance on how to design and run clinical trials for psychedelic drugs, a move that directly clears a path for psilocybin, the active compound in magic mushrooms, to reach patients with severe depression. At the same time, Compass Pathways is running two Phase 3 trials of its synthetic psilocybin formulation, COMP360, in people whose depression has not responded to standard treatments. Together, these developments represent the most concrete regulatory and clinical progress psilocybin has made toward potential FDA approval.
FDA Lays Out Rules for Psychedelic Drug Trials
For years, researchers studying psychedelics operated without a clear regulatory playbook. That changed when the FDA released a draft guidance titled psychedelic guidance, filed under docket number FDA-2023-D-1987. The document spells out what the agency expects from companies seeking to bring psychedelic therapies to market, covering study design, safety monitoring, the role of psychotherapy during dosing sessions, dose-response relationships, durability of treatment effects, and compliance with Drug Enforcement Administration controlled-substance rules.
The guidance matters because it signals the FDA is not simply reacting to psychedelic research but actively shaping the evidentiary standards these drugs must meet, a key step that moves psilocybin (magic mushroom) therapy closer to potential FDA approval. Before this document, sponsors had to guess at what trial features the agency would accept. Now there is a published framework that addresses specific pain points, including how to handle the well-known blinding problem in psychedelic studies, where participants can often tell whether they received an active dose or a placebo. That issue proved damaging in the MDMA space. An FDA advisory committee rejected MDMA as a treatment for PTSD, citing concerns about trial integrity, blinding flaws, and safety, according to reporting from the Associated Press. The psilocybin field now has a chance to design around those pitfalls from the start.
Two Phase 3 Trials Target Treatment-Resistant Depression
Compass Pathways is the company closest to bringing psilocybin through the FDA’s approval process, and it is doing so with a pair of late-stage trials aimed at treatment-resistant depression, or TRD. The first, designated COMP005, uses a randomized, placebo-controlled, single-dose design divided into study parts A, B, and C. It was initiated before the second trial and is structured to isolate the effect of a single COMP360 administration against placebo under controlled psychological support conditions. The COMP005 listing on ClinicalTrials.gov describes a primary outcome focused on changes in depression severity scores, with secondary measures that track functioning and safety over time.
The second trial, designated COMP006, goes further by evaluating the efficacy, safety, and tolerability of two separate administrations of COMP360, with follow-up tracking participants through 52 weeks. That year-long observation window is significant. One of the biggest open questions about psilocybin therapy is whether its antidepressant effects last or fade after a few months. By building a full year of follow-up into the trial design, the COMP006 protocol directly addresses the FDA guidance’s emphasis on durability, a requirement that could make or break an approval bid. The comparison between one-dose and two-dose strategies, and the extended safety monitoring, are likely to be central to how regulators weigh the overall risk–benefit profile.
What Earlier Data Showed, and Where It Fell Short
The Phase 3 program builds on results from Compass’ earlier Phase 2 study, which enrolled 233 participants with treatment-resistant depression and compared three psilocybin dose levels: 25 milligrams, 10 milligrams, and a 1-milligram control, all paired with psychological support. A peer-reviewed paper published in the Journal of Affective Disorders reported patient-level outcomes on depression severity, anxiety, daily functioning, and quality of life. The 25-milligram dose showed the strongest effects across those measures, with more participants achieving rapid and clinically meaningful reductions in depressive symptoms than in the lower-dose arms.
But the Phase 2 data also carried acknowledged weaknesses. The same paper noted methodological limitations, including functional unblinding, where participants could likely tell they received the active dose because of psilocybin’s perceptible psychoactive effects, and the absence of an active comparator drug. These are exactly the kinds of flaws that sank the MDMA application. The Phase 3 trials appear designed to address at least some of these gaps, with COMP005’s placebo-controlled structure and COMP006’s extended follow-up providing a more complete evidence package. Whether these design choices fully satisfy the FDA’s new expectations remains an open question until results are in, but they reflect a clear attempt to align the development program with the regulatory roadmap now on the table.
Why the MDMA Rejection Sharpens the Stakes
The FDA advisory panel’s rejection of MDMA for PTSD sent a clear message to the broader psychedelic therapy field: promising early data is not enough if trial design and safety monitoring do not hold up under regulatory scrutiny. The panel’s concerns centered on trial integrity, the difficulty of blinding participants to a drug with obvious subjective effects, safety and abuse potential, and allegations of misconduct in the research process. Every one of those issues applies, in varying degrees, to psilocybin research as well, especially given the intense expectations and advocacy that surround psychedelic-assisted psychotherapy.
This is where the FDA’s new draft guidance and Compass’ trial designs intersect in a meaningful way. The agency’s press announcement on psychedelic trials makes clear that regulators expect rigorous control of set and setting, systematic assessment of adverse events, and careful management of psychotherapy components so that drug effects can be distinguished from talk therapy alone. If Compass can demonstrate that its Phase 3 data satisfies those standards, particularly on durability and safety, psilocybin could avoid the fate that befell MDMA. But the burden of proof is high, and the agency has shown it will not approve a psychedelic therapy on enthusiasm alone or on short-term symptom changes that cannot be sustained.
Next Steps for Psilocybin on the Road to Approval
The draft guidance is not yet final, and the FDA has invited public comment through the official docket process. That means patient advocates, clinicians, researchers, and industry sponsors all have an opportunity to weigh in on how strictly the rules should be interpreted, and whether additional clarifications are needed on issues such as long-term follow-up, management of suicidality risk, and standards for psychotherapy training. Once comments are reviewed and a final guidance is issued, sponsors will have a more stable regulatory target, but they may also face tighter expectations on data completeness and post-marketing surveillance.
For psilocybin developers, the combination of formal guidance and late-stage clinical trials marks a turning point. The regulatory pathway is no longer hypothetical: it is being tested in real time by COMP360’s Phase 3 program. If those studies show robust, durable benefits in treatment-resistant depression without unacceptable safety signals, they could put psilocybin therapy on a clearer track toward FDA approval and establish a template for future psychedelic approvals in other indications. If they fall short, whether on efficacy, blinding integrity, or long-term risk, the bar for the entire field could rise further. In that sense, the FDA’s evolving framework and Compass Pathways’ data will not just determine the fate of one drug; they will help define how psychedelic medicine is judged in the United States for years to come.
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*This article was researched with the help of AI, with human editors creating the final content.
