Q&A: Woolley on UMBRAA's Multidrug Approach to Psilocybin Trial Masking

More than 90% of participants in high-dose psilocybin trials correctly identify their treatment, compared with roughly 60% in antidepressant trials. In a recent Viewpoint published online in JAMA Psychiatry, the authors argue active placebos such as niacin and diphenhydramine never plausibly matched psilocybin's intensity, and even phenomenologically richer candidates, including tetrahydrocannabinol, salvinorin A, and dextromethorphan, fail to reproduce its full experiential breadth as single agents.¹ Some investigators have concluded effective masking of high-dose psychedelics is not achievable and have shifted toward comparative efficacy trial designs instead.¹

Josh D. Woolley, MD, PhD, corresponding author of the Viewpoint and a member of the Department of Psychiatry and Behavioral Sciences at the University of California, San Francisco, proposes an alternative called UMBRAA (unidentifiable multidrug blinding with reduced, authorized awareness). The framework combines active placebos built from multiple drug classes with a consent model called authorized incomplete disclosure, in which participants agree in advance not to be told certain design details, such as the number of treatment arms.² Woolley argues regulators have held active placebos to an outpatient tolerability standard irrelevant to a single supervised psilocybin session, which routinely requires 8-hour monitored dosing days with 2 providers present.¹

In the following Q&A, Woolley discusses why current active placebos fail, how UMBRAA's multidrug comparator addresses critiques comparing it to induced delirium, and what he sees as the framework's realistic next steps.

Q&A: Woolley on UMBRAA's Multidrug Approach to Psilocybin Trial Masking

HCPLive: Why has masking failed so badly, and why has the field been slow to address it?

Josh Woolley, MD, PhD: Why it's failed is pretty clear. The doses we use in these trials are high doses, and people have big experiences: visual changes, intense experiences of bliss, unity, [and] feeling one with the universe. In most trials, two-thirds of people say it's among the top 5 most meaningful experiences of their life, compared with sitting there looking at the walls, nothing happening, or even worse in trials using niacin, where, as we say in the paper, either you meet God or you get itchy.

Having blinded assessors helps, but the patient isn't blinded; the patient knows, and probably the treatment they get is quite different. If the preparation is preparing people for a high-dose experience, that actually makes people, when they know they didn't get it, probably disappointed.

Masking failure…hasn't really been addressed in pharmacology or pharmaceutical trials more broadly. For some things, it might be possible to address this with active placebos, but active placebos aren't without their own challenges. Inactive placebos are obviously cleaner; give someone niacin and now you have side effects from the placebo you have to deal with, and how are you sure your active placebo doesn't make people less depressed or more depressed?

There's been a real reluctance to use active placebos in general, and with psychedelics, because the experience is so big, people have felt it was impossible and haven't really tried.

HCPLive: Why do regulators hold placebos to an outpatient tolerability standard when a psilocybin session isn't outpatient tolerable?

Josh Woolley, MD, PhD: People say psilocybin is quite tolerable and the safety is pretty high, which is true; the clinical trials haven't had many adverse outcomes. But that's in the setting of a very intensive delivery model.

People come in; they have all this preparation and screening, and then they're there all day with 2 providers in the room, vital signs monitored, and an MD on call. That's not outpatient; that's a procedure. I'm just saying it's tolerable given all of that.

The point we're making is that expecting some drug you could give as an outpatient to match that is like comparing apples and oranges. It's not a fair comparison because we're not talking about chronic dosing, which is what FDA approval typically requires.

We've gotten pushback when we've said we want to give doses that have been studied at higher levels in single-dose sessions in healthy people, and we're confident it's at least as tolerable as psilocybin, and we've been told we can't do that.

HCPLive: Can you walk me through the UMBRAA framework?

Josh Woolley, MD, PhD: The umbra is the area of totality of the shadow during an eclipse; a penumbra is the area of partial shadow. We picked that acronym partly because of the idea of blinding.

Our proposal…is a combination of 2 arms, because this is a really hard problem. One arm is active placebos: we argue we should be using them, and a single agent as an active placebo for high-dose psilocybin might work.

And do those drugs have therapeutic efficacy? Dextromethorphan is one example. Some healthy-volunteer studies show people can confuse it with psilocybin, but it's ketamine-like, with an NMDA mechanism, and it's being used as an antidepressant. Not at a single high dose, but still, no one knows, and we can't say it doesn't have antidepressant effects, so that's a problem.

What we suggest is to think more broadly. Maybe we can't find it in a single drug, but maybe we can make it happen by combining drugs… [to] confuse people, because that's the goal.

The second element is… the idea of incomplete disclosure. The ethics of the regular placebo-controlled trial haven't always been obvious, because you're a clinician giving someone an inactive treatment on purpose and not telling them whether it's happened, an incomplete disclosure. You tell people, look, you can participate, you might get the active treatment, or you might get inactive, you have a 50-50 chance, and I can't tell you which you're getting.

We argue, in this article and in one from 2025, psychedelics and psychedelic-like treatments may require a more aggressive version of that.² Just as you don't tell people exactly what they'll get in a double-blind trial, we argue there are other elements of the trial design you can ethically not disclose, like the number of treatment arms, a 2-arm trial versus a 3-arm trial. If you tell people you're withholding that information, they can consent; it's called authorized incomplete disclosure.

HCPLive: Critics say a multidrug comparator sounds more like inducing delirium than a legitimate control. How do you respond?

Josh Woolley, MD, PhD: I'd ask what they mean by delirium. Delirium is a nonspecific syndrome, and the psychedelic state is different from a drug-induced delirium in some ways; people lose track of time and have cognitive difficulties, among other things. If you separate out the physiological parts, delirium is often caused by infection or metabolic abnormalities, which are quite risky on their own, apart from being intoxicated and having something that alters how you process the world.

If you want to call that second part delirium, I'd call it intoxication, altered sensory processing, and other things, and I think that's what psilocybin does. We have to figure out how to do something similar enough that people get confused.

Yes, it is an altered state, and yes, it's a complex pharmacology, but I see that as a strength, or a requirement, to achieve effective masking. If there were something simpler, I'd happily use it, but there doesn't seem to be.

HCPLive: Why do you think the shift toward comparative efficacy designs instead of masking is the wrong call?

Josh Woolley, MD, PhD: I wouldn't necessarily call it the wrong call. These are interesting, different approaches. Comparative efficacy can work, but it's tricky, because in an unblinded situation, like a trial comparing an SSRI with psilocybin, masking still fails.

We're also not sure our approach is going to work; it may not be possible; you can throw everything at it, and people may still tell. That's possible, but no one's really tried. I think when people say masking doesn't matter or that it's impossible, so it doesn't matter anyway, that's 1 point of view, but I don't agree with it.

HCPLive: How worried are you that a comparator like dextromethorphan could confound the outcome you're measuring?

Josh Woolley, MD, PhD: Finding any active placebo is challenging. They add complexity, they can add their own side effects, and they may add their own therapeutic outcomes, whether antidepressant or pro-depressant. We don't usually run studies to prove something isn't an antidepressant; that's not something you typically do, and it would actually be quite hard to do.

Dextromethorphan has this challenge in particular because it's already being explored as an antidepressant. That doesn't mean you couldn't still use it as a comparator; people have talked about comparing ketamine to psilocybin, where you might be able to get participants to confuse the 2. There are challenges around time course, but it's possible; ketamine is clearly an antidepressant, but if you believe the literature, a single dose should have an effect over days, versus weeks to months with psilocybin.

Even though ketamine is an antidepressant, it's a well-characterized one, and you could still see a differential outcome despite that effect. Having antidepressant effects isn't necessarily bad, but an unknown antidepressant effect is a problem, and we don't really know what a single high dose of dextromethorphan does.

HCPLive: What's the realistic next step for UMBRAA?

Josh Woolley, MD, PhD: We and others are beginning to do studies with incomplete disclosure. Trying this out and seeing how well it works…is 1 step.

The other is these drug combinations. People have talked about combinations like THC and dextromethorphan, and there's been a little work, but not much.

I don't want to give up on masking before we've really given it a good try.

Watch parts 1, 2, 3, and 4 of our interviews with Woolley here:

• UMBRAA Framework Aims to Fix Blinding Failures in Psychedelic Trials
• UMBRAA Framework Targets Blinding Failures in Psilocybin Trials
• Defending Multidrug Masking in Psilocybin Trials, With Josh Woolley, MD, PhD
• Confounding Risk in Psilocybin Trial Comparators, With Josh Woolley, MD, PhD

Editor’s note: A reported disclosure for Woolley includes Eli Lilly and Company.

References

1. Yang KH, Heifets BD, Krystal A, et al. The case for more aggressive masking in psychedelic trials. JAMA Psychiatry. Published online September 16, 2026. doi:10.1001/jamapsychiatry.2026.2858

2. Matvey M, Kelley DP, Bradley ER, Chiong W, O'Donovan A, Woolley J. Modifying informed consent to help address functional unmasking in psychedelic clinical trials. JAMA Psychiatry. 2025;82(3):311-318. doi:10.1001/jamapsychiatry.2024.4312