Seeking a Trippy Placebo

The psychedelic renaissance has a problem: Psychedelics distort perception so dramatically that it has been difficult so far to design placebo-controlled trials. Patients in clinical trials tend to ferret out what they have gotten—placebo or drug. This knowledge on both sides could contribute to exaggerating the therapeutic differences, making psychedelics appear more effective than they really are in clinical trial results.

In the meantime, the appetite for psychedelic medicines in the United States is growing. At the start of the year, a presidential executive order fast-tracked federal agencies to accelerate research, review, and approval of psychedelic therapies for serious mental illnesses, including depression, anxiety, and addiction. Earlier this week, the Food and Drug Administration held a public hearing to gather public and expert opinions on how to safely approve and deliver psychedelic medicines.

Read more: “The Problem with Psychedelic Research” Today, a team of researchers from the University of California, San Francisco, UC San Diego, and Stanford University penned an article in JAMA Psychiatry calling for a new rigorous approach to placebo-controlled trials: a cocktail of active drugs that together might replicate some of the effects of a psychedelic, along with incomplete disclosure, which could make it more difficult for trial participants to know exactly what they are getting and how much. I spoke to UCSF psychiatrist and coauthor Josh Woolley about how the new approach would work and what’s at stake. Some psychedelic clinical trials have tried using niacin as a placebo.

Why is niacin not a good placebo for psychedelic research? The psilocybin doses that we give in the trials are pretty high doses, so people are kind of incapacitated and hallucinate and stuff. They have very intense psychedelic experiences—visual changes, sensory changes, emotional things, spiritual bliss, unitary experiences, which are like feeling one with the universe.

Why was niacin thought to be a good potential placebo? I don’t think anyone thought it was good. It was just better than nothing because it causes some flushing, which is a little bit like what psilocybin does, but it doesn’t cause any psychological stuff.

We knew that it wasn’t going to be great even back in the ‘60s and ‘70s. They used it once or twice back then, and nobody was confused about whether they got psilocybin. The strategy you’re proposing would combine a cocktail of drugs with active ingredients, not just a sugar pill, and would reduce disclosure to the participants.