Woolley separates intoxication from delirium and defends aggressive masking instead of a shift to comparative efficacy trial designs.
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
UMBRAA (unidentifiable multidrug blinding with reduced, authorized awareness) proposes combining agents from distinct mechanistic classes for disclosure to address unmasking rates exceeding 90% in psilocybin trials. The framework includes a consent model called authorized incomplete disclosure.
In an interview with HCPLive, Woolley addressed concerns the comparator resembles induced delirium rather than a controlled placebo condition.
“I would call it intoxication [with] alerted sensory processing,” Woolley said. “I think that's what psilocybin does.”
Woolley noted delirium is a nonspecific syndrome often caused by infection or metabolic abnormality, conditions carrying physiological risk independent of any drug effect. He separated this risk from the intoxication and altered sensory processing the comparator itself produces.
Woolley said reproducing a similar altered state through a different pharmacology, if the approach succeeds, would force investigators to rethink assumptions about the mechanisms behind psilocybin's effects. He described the pharmacological complexity of the multidrug comparator as a requirement for effective masking rather than a design flaw.
“Yes, it's a complex pharmacology, but I see that as [a] strength or required to achieve the goal of effective masking,” he said. “If there was something simpler, I’d happily use that, but it doesn't seem like there is.”
Woolley defended pursuing more aggressive masking instead of a shift to comparative efficacy trial designs. He said the field has not ruled it out through trial and error.
Some investigators have already moved toward comparative efficacy designs, arguing effective masking of high-dose psychedelics is not achievable. Woolley said this alternative, which compares psilocybin directly against another active treatment such as an SSRI, carries its own blinding problem, since masking still tends to fail and participants often learn which arm they are in.
He pointed to psychotherapy research on waitlist controls, where participants assigned to wait for treatment sometimes improve less than people who never enrolled in a study at all, a finding some investigators attribute to participants knowing they are not expected to improve. Woolley said this dynamic also appears in placebo response rates: sugar pills perform better in SSRI trials than in psilocybin trials because participants assigned to SSRI placebo remain uncertain of their assignment, and psilocybin trial participants who receive placebo typically know it.
“We're not sure that our approach is going to work,” Woolley said. “It may not be possible. You may throw everything at it, and people can still tell. That is possible, but no one's tried, so I think we're all just trying to figure out how to get reliable information.”
Watch parts 1 and 2 of the interview with Woolley here:
Editor’s note: A reported disclosure for Woolley includes Eli Lilly and Company.
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