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.
And niacin just makes you itchy.
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. Are you proposing a specific combination of drugs?
Not specifically, no. It’s more of an approach. The active placebo wouldn’t have therapeutic effects, but it would cause some other effects. Pharmacology research or clinical trials has been very reluctant to use active placebos because they’re a little bit messy. Now you have this other drug that does things, and how do you really prove that it doesn’t have any antidepressant effect, for example, or it doesn’t make people more depressed or have its own side effects. There hasn’t been a lot of interest in using active placebos, but that’s a big problem because you have these trials, especially with psychedelics, where almost 100 percent of people know what they got, and they know it immediately and completely. And therapists know too.
This problem of unmasking or unblinding has fooled medicine before. There are surgeries and different procedures and things where we thought it was a good idea. It seemed like a good idea, but when we did actually mask trials, it turned out it wasn’t a great idea. This is a risky thing, so we are saying that the field of psychopharmacology, and psychedelics in particular, have not tried hard enough to achieve effective masking.
It’s like the weather. Everyone talks about it, but no one does anything about it. Niacin and Benadryl, nobody actually thinks those would work. People have talked about alternatives like THC or dextromethorphan, which is a ketamine-like drug, and it’s been studied a little bit in healthy people, but nobody has done a clinical trial. We are proposing that might work, but it’s hard to get a single agent like THC to be confused with psilocybin. They’re different. We are suggesting that maybe we should open up our toolbox and consider combining drugs from different classes to create unusual experiences, like a cocktail—a little of this, a little of that—and work on creating experiences that don’t engage the same pharmacology as say psilocybin, but that people could confuse with psilocybin. That is the multi-drug approach, which is new.
What about the disclosure part of the equation?
When the regular double-blind trial was introduced, where someone could get placebo or an active drug, there was a lot of debate about whether it was ethical. People were like, "Well, you’re giving people an inactive treatment, so you’re not treating them, and they don’t know.” But we decided as a field, as a society, that it was worth it because if we don’t do that, we don’t get answers to these questions about effective treatments.
Now we’re saying that you can go a step further, where you give people incomplete information about the trial, but you tell them that you’re giving them incomplete information, just like in a double-blind trial. For example, you might tell them, “You may get a psilocybin dose of between one and 30 milligrams, and we can’t tell you how many different groups there are in the trial or exactly what your percentage chances are of getting any specific dose.” Then people can decide whether that’s okay with them.
You wouldn’t tell them that there’s a placebo either, for instance?
There are no lies. So, yeah, we could also tell them, “you might get one or two or zero of these other medications from other classes that are there to improve masking.” It’s critical for the incomplete disclosure that there are no undisclosed risks. You don’t want to surprise people. There are no drugs that you haven’t warned them about. We argue that you only do that if masking is a big challenge, which it is in psychedelics. It’s a really important question, especially as the FDA is getting ready to possibly approve these drugs.
Are you mostly thinking this approach would work for psychedelics like psilocybin or LSD? For something like 5-MeO-DMT, which has a reputation for just completely obliterating your sense of self, really radically altering the psyche, it seems like it would be impossible.
I think this could work for any drug that’s hard to mask. You might use different combinations. For example, 5-MeO has a different time course. There are a lot of different dimensions on which people can tell the drugs apart. If you tell them, “You’re going to get one milligram or 25, or niacin or 25,” that becomes a binary choice, and it makes it very easy for them to know which arm of the clinical trial they’re in. You need to use disclosure that creates more ambiguity and uncertainty, which is the goal of masking.
How long do you think it might take before scientists could try your approach?
We’ve tried aspects of it already. But we’re working away at putting it all together. This viewpoint is mostly a call to action: “Don’t give up. We can try.” There have been a lot of calls like, “Oh, masking psychedelics is impossible, and it doesn’t matter.” And we’re saying, “Well, it does matter,” and we haven’t even really tried it yet. 
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