UCSF researchers urge more convincing placebos in psychedelic trials

UC San Francisco researchers are weighing in on one of the biggest challenges in psychedelic science, arguing that clinical trials need more convincing placebo treatments to better measure the drugs' true effects.

The debate hinges on "masking," the clinical trial gold standard that keeps patients and researchers from knowing who receives the active drug or a placebo. Because psychedelics produce such distinctive effects, participants can almost always tell whether they got the real thing. That makes it hard to separate a drug's effects from the power of expectation, including the disappointment patients feel when they realize they did not receive the psychedelic.

In a perspective published Sept. 16 in JAMA Psychiatry, researchers from UCSF, UC San Diego, and Stanford University call for a more aggressive approach to preserving masking in psychedelic clinical trials. The paper arrives as psychedelic research gains momentum and regulators face growing pressure to decide how these treatments should be evaluated and approved.

Instead of relying on active placebos such as niacin, which can cause flushing but little else resembling a psychedelic experience, the researchers propose carefully designed combinations of approved drugs to create a more convincing placebo. They also recommend limiting what participants are told about the study, making it harder to guess which treatment they received.

Psychedelics for serious mental illness have drawn growing interest because many patients do not respond to existing treatments. The authors argue that if researchers too readily accept failed masking as unavoidable, these compounds will never be rigorously tested.

People say psychedelics can't be masked, so we should stop trying and just move on, because the effects are so obvious. But medicine has been fooled by obvious effects before. Heart stents for stable chest pain and knee arthroscopy for arthritis both looked effective until sham-controlled trials showed they weren't. We're excited about this paper because it outlines a novel approach that might finally make effective masking possible for psychedelics."

Josh D. Woolley, MD, PhD, associate professor in residence of psychiatry and behavioral sciences at UCSF and the paper's senior author

The proposed strategy, called UMBRAA, short for Unidentifiable Multidrug Blinding with Reduced, Authorized Awareness, combines giving carefully selected FDA-approved drugs with limited disclosure to study participants about what drugs they are receiving to make it harder for them to guess whether they are in the active treatment or the placebo-controlled arm of the study.

For example, a placebo might combine drugs from different classes, such as a sedative, a stimulant, and a cannabinoid. The researchers hypothesize that pairing drugs with different effects could create an intense, unfamiliar altered state that is harder to distinguish from psilocybin than current controls.

The researchers acknowledge that UMBRAA raises safety and ethical concerns and would require careful screening, close medical monitoring, and regulatory oversight.

They stress that the framework is a proposal, not a proven method. Future research will need to identify safe drug combinations, test whether they improve masking, and establish appropriate safeguards.