Denis Katz, M.D. Founder & Medical Director, Salience Clinical LLC
Introduction
The optimism surrounding psilocybin is not unfounded. Early clinical findings have been striking enough to attract serious scientific attention, substantial investment, and a level of public interest that neuropsychiatric drug development almost never generates. Treatment-resistant depression. End-of-life anxiety. Alcohol use disorder. These are conditions where existing treatments consistently fail patients, and the enthusiasm reflects that unmet need.
But enthusiasm has a way of outpacing infrastructure.
I’ve spent enough time in clinical development and regulatory strategy — including direct FDA interactions on submissions that didn’t go the way sponsors expected — to recognize when a field is moving faster than its evidence base. Psychedelic medicine is in that position right now. Not because the science is weak, but because some of the foundational questions haven’t been answered yet, and not everyone is being honest about that.
The FDA’s 2024 non-approval of MDMA-assisted therapy was a hard lesson. Methodological weaknesses don’t get overlooked just because the science feels compelling or the patient need is real. Regulators did their job. The April 2026 executive actions aimed at accelerating breakthrough mental health treatments have reopened real opportunities — but only for sponsors who do the work rigorously. The window is open. Whether the field walks through it or stumbles is a different question.
Here are the five issues I keep coming back to.
1. Is Drug Working, or Is the Therapeutic Environment Working?
This question gets debated constantly, and for good reason — it has real regulatory consequences that some sponsors are not taking seriously enough.
Psilocybin is almost never given in isolation. Most clinical protocols include extensive preparation sessions before dosing, six to eight hours of supported monitoring during the session itself, and multiple integration sessions afterward. Patients receive substantial psychological support at every stage. So when outcomes improve, the honest question is: what actually caused that?
From a regulatory standpoint, this isn’t just interesting — it’s a problem. Agencies evaluate drug products. They don’t regulate psychotherapy. If a meaningful, inseparable portion of the treatment effect comes from the therapeutic container rather than the molecule, then defining the independent variable becomes genuinely complicated — and your development program needs to address that directly.
I’ve seen submissions where this question was essentially deferred, treated as something that could be sorted out post-approval. It can’t be. Sponsors need to design studies that can meaningfully distinguish pharmacologic effect from psychological scaffolding. That’s hard. It’s also a baseline requirement for a credible regulatory package.
2. Can Psilocybin Trials Truly Remain Blinded?
Blinding is foundational to clinical research. The problem with psilocybin is that its effects are so distinctive — perceptual, somatic, emotional — that most participants figure out whether they received it. So do most therapists. Functional unblinding is the rule, not the exception.
Once that happens, expectancy bias becomes a serious confound. A patient who believes they’ve received a transformative medicine may report improvement for reasons that have nothing to do with the drug’s pharmacology. That’s not a theoretical concern. It’s the precise vulnerability that regulators flagged in the MDMA submissions, and it will come up again.
The honest response is to stop designing trials around inert placebos and build more credible control conditions. That means active comparators like low-dose stimulants, niacin, or sub-therapeutic microdoses, combined with centralized raters who are blinded to the patient’s dosing experience and kept structurally separate from the therapeutic team. These designs are harder to execute and more expensive. They’re also what the regulatory bar now requires. Sponsors who haven’t internalized that yet are going to find out the hard way.
3. Can Psychedelic Therapy Be Scaled Within Modern Healthcare Systems?
Clinical trial success and commercial viability are different things. In the case of psilocybin, they may be very different things.
Under current FDA draft guidelines, a single acute dosing session can require up to eight hours of continuous monitoring by at least two qualified clinicians — typically a licensed lead therapist and an assistant monitor. Add mandatory training programs, specialized treatment environments, and post-session follow-up, and you have a delivery model that works in a well-funded research setting and becomes genuinely difficult everywhere else.
Here’s what I don’t think gets said plainly enough: most of the U.S. mental health infrastructure is already overwhelmed. Wait times are long, reimbursement is poor, and the workforce pipeline is inadequate. Dropping a labor-intensive, session-based pharmacotherapy model into that system — without a clear reimbursement pathway and without workforce planning — is not a commercial strategy. It’s a hope.
Payers think about this differently than sponsors do. Where a sponsor sees an efficacy signal, a payer sees staffing ratios, infrastructure overhead, and a billing code that doesn’t exist yet. Sponsors who treat scalability as someone else’s problem are likely to find that approval doesn’t translate into a viable product.
4. What Will Safety Look Like Outside Clinical Trials?
The safety data we have for psilocybin comes almost entirely from highly screened populations. Trials have appropriately excluded individuals with personal or family histories of psychotic disorders, bipolar disorder, and certain personality disorders. That makes scientific sense during early development.
The problem is that real-world clinical practice doesn’t work that way.
Patients who seek treatment for depression or anxiety frequently carry complex psychiatric histories, multiple concurrent medications, and varying levels of social support. Some have cardiovascular or metabolic conditions that could interact unpredictably with a potent serotonergic agonist. Many will have exactly the comorbidities that trial protocols were designed to exclude. We genuinely don’t know how psilocybin performs in that population — because we haven’t studied it there yet.
That’s not a reason to halt development. It is a reason to stop pretending the current safety picture is complete. Robust post-marketing surveillance and real-world evidence generation aren’t optional add-ons; they’re the mechanism by which we find out what we don’t yet know. Building that infrastructure before approval, not after, is both a regulatory expectation and an ethical obligation.
5. Is Psilocybin a Drug, or a Drug-Plus-Therapy Intervention?
This is the question that will define the commercial architecture of the entire field. It doesn’t have a clean answer, and anyone who tells you it does is oversimplifying.
Traditional drug approvals deal with molecules. The therapy, if any, is incidental. Psilocybin doesn’t fit that model cleanly because the psychological experience appears to be part of what makes the treatment work — though the field hasn’t fully resolved whether that’s because the journey itself is therapeutic, or because the underlying neurobiological and synaptic effects operate independently of what the patient consciously experiences. That distinction matters enormously for how you design your development program.
If a sponsor pursues molecule-only approval, a gap opens immediately: who pays for the therapeutic hours required to deliver it safely? Private insurance rarely covers them. If a sponsor pursues a co-approval model — drug plus therapy together — they’re navigating novel legal territory involving provider certification, standardized delivery protocols, and enforcement across state licensing boards that operate independently and often inconsistently.
Regulators will almost certainly require a REMS program, like what governs esketamine. That part is manageable. The harder part is building the full delivery and reimbursement architecture before the approval comes, not scrambling to figure it out afterward. The sponsors who get this right will have thought through it years in advance. The ones who haven’t are going to face an expensive and avoidable reckoning.
Conclusion
The science is real. Psilocybin is not a fad, and the conditions it targets are genuinely underserved. I’m not skeptical of the potential — I’m skeptical of the assumption that potential is enough.
Drug development history is full of promising molecules that failed not because the biology was wrong, but because the development program wasn’t built to withstand scrutiny. The MDMA non-approval isn’t ancient history. It happened two years ago, and several of the vulnerabilities it exposed are still present in programs currently in development.
The federal prioritization of breakthrough mental health treatments is a real opportunity. Whether psilocybin makes it through that window depends on whether the people building these programs are willing to confront the hard questions now — before they become fatal ones in a regulatory submission.
The field is capable of doing this right. The question is whether it will.
Denis Katz, M.D. is the Founder and Medical Director of Salience Clinical LLC, a strategic consulting and clinical development organization focused on advancing innovative therapies and precision medicine initiatives. Dr. Katz has held leadership roles spanning regulatory affairs, clinical development, and medical affairs across the biotechnology, pharmaceutical, and advanced therapeutic sectors. His expertise includes direct FDA interactions, pivotal clinical trial leadership, and strategic guidance supporting product development from IND-enabling activities through commercialization.
The views expressed in this article are those of the author and are intended to foster discussion regarding emerging regulatory and clinical development considerations in psychedelic medicine.