Confounding Risk in Psilocybin Trial Comparators, With Josh Woolley, MD, PhD

In a recently published JAMA Psychiatry Viewpoint, Josh D. Woolley, MD, PhD, of the University of California, San Francisco, and colleagues proposed the UMBRAA blinding framework for high-dose psilocybin trials, which uses a multidrug comparator to mask the placebo.¹

Active placebos have historically been rare in psychiatric trials because they add complexity, carry their own adverse events, and may produce therapeutic effects of their own. Dextromethorphan (DXM), 1 candidate comparator, illustrates this risk directly, since its N-methyl-d-aspartate (NMDA) antagonism at dissociative doses has drawn interest as a standalone antidepressant.

“Even though it's an antidepressant, it's a well-characterized antidepressant, and you could still have a differential outcome, even though it has an antidepressant effect,” Woolley told HCPLive. “Having antidepressant effects is not necessarily bad, but an unknown antidepressant effect is problematic.”

DXM and Ketamine Illustrate the Confounding Comparator Problem

Woolley said researchers do not typically design studies to prove a drug is not an antidepressant, since disproving a therapeutic effect is difficult to demonstrate. He pointed to ketamine as a further example: investigators have proposed comparing ketamine with psilocybin because participants may confuse the 2 experiences despite differing time courses, with ketamine's effects reported within days and psilocybin's extending across weeks to months.

Woolley contrasted DXM with agents such as zolpidem and niacin, neither of which is considered an antidepressant. He said if a combination of drugs not believed to have antidepressant properties produced a delirium-like state matching high-dose psilocybin's outcomes, the finding would suggest the treatment effect is not pharmacologically specific to psilocybin. Woolley called this scenario a genuinely radical result forcing investigators to rethink how psilocybin works.

UMBRAA's Next Steps: Incomplete Disclosure and Drug Combinations

Woolley said authorized incomplete disclosure is not new to psychedelic research, citing early studies from Johns Hopkins University in the early 2010s testing psilocybin in patients with cancer. Those studies told participants they would receive psilocybin from within a stated dose range without disclosing the exact number of trial arms, an early form of incomplete disclosure.² Woolley said he and other investigators are now beginning to test the approach directly to determine whether it improves masking success.

A second priority is testing specific multidrug combinations, since limited empirical work has been done despite years of informal discussion. Woolley pointed to tetrahydrocannabinol (THC) and DXM as 1 combination with only preliminary testing. He said this work could proceed in healthy volunteers or within active clinical trials designed to improve outcomes for participants.

Woolley's comments reflect the Viewpoint's central argument: current active placebos do not adequately mask the effects of high-dose psilocybin, leading some investigators to consider comparative efficacy designs instead.¹ Woolley said UMBRAA remains untested and that its authors have not endorsed a single drug combination for all investigators to use.

"I don't want to give up on masking before we've really given it a good try," Woolley said. "Scientists and patients should advocate for that, because they don't want something that waste[s] their time and money [and] puts them at risk without being pretty sure it works."

Watch parts 1, 2, and 3 of the interview with Woolley here: UMBRAA Framework Aims to Fix Blinding Failures in Psychedelic Trials, UMBRAA Framework Targets Blinding Failures in Psilocybin Trials, and Defending Multidrug Masking in Psilocybin Trials, 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