Sign up for a clinical trial of a psychedelic drug and you’re agreeing to a potentially bizarre experience. “All of a sudden, your dead grandma or Satan is in front of you,” says psychiatrist Charles Raison of the University of Wisconsin–Madison. Some think this consciousness-altering “trip” underlies the potential benefits of drugs such as psilocybin and LSD, which are under study to treat depression, trauma, chronic pain, and more. But the trip can also be a roadblock to assessing the drugs’ effects, making it near-impossible to conceal who is getting an active substance and who’s been assigned to placebo—a trial strategy called blinding that aims to keep participants’ expectations from skewing their response to a drug.
This “functional unblinding” is not unique to psychedelics, but it’s especially pronounced in this drug class. The U.S. Food and Drug Administration (FDA) has expressed concern about the issue in psychedelic trials. And it was among the critiques FDA advisers leveled at Lykos Therapeutics, whose application for MDMA to treat post-traumatic stress disorder (PTSD) FDA rejected last summer.
Now, scientists and companies are experimenting with trial designs meant to shield participants from recognizing what they’re getting, or to separate expectations from the drug’s impact on health. These include incorporating a range of doses; giving the drug, with permission, to people who are asleep; and misleading participants about how a trial is set up.
Companies running large-scale psychedelic trials mostly view unblinding as inevitable. Participants “are going to feel” the drug, “that’s just how it is,” says Rob Barrow, CEO of MindMed, which has late-stage trials underway to test LSD’s ability to ease anxiety. But he believes there are ways to parse a drug’s efficacy even if people know they’re getting it. In one recent trial, MindMed recruited 198 people with anxiety, giving some a placebo and the others LSD at one of four doses. Virtually all who received active drug correctly guessed that they’d gotten it. But those on the two higher doses saw clinically meaningful reduced anxiety, whereas those on the lower doses didn’t. That split means the benefit “has to be due to something other than thinking you’re getting drug,” Barrow says. MindMed is using a lower, nontherapeutic dose as well as a higher dose in an ongoing phase 3 trial, and hopes to report results next year.
Compass Pathways, a biotech testing psilocybin in treatment-resistant depression, tried a different twist: giving everyone the drug, at different doses, so that all might expect benefits. This study, too, showed a greater reduction of depression at higher doses.
Academic researchers, meanwhile, are running smaller trials with more unorthodox strategies that might blunt the risk of unblinding and shed light on how the “trip” plays into drug effectiveness. Raison has been experimenting with having people sleep through their trips, as a way to understand how much a conscious psychedelic experience matters. Two volunteers received psilocybin while in a deep sleep with a sedative, and 1 week later both “swore they got placebo,” Raison says. He is now developing a larger study in which people with self-reported reduced emotional well-being will be randomized to get psilocybin or placebo while either awake or asleep, to tease out how the trip influences longer term effects on emotional state.
Raison is also studying psilocybin alongside the sedative midazolam, which makes participants drowsy throughout their trip and disrupts their memory of it afterward. He’s preparing to launch a study with 68 people with reduced emotional well-being who will get either an ultralow or higher dose of psilocybin, with or without midazolam. Raison hopes to learn whether a trip that’s experienced but then forgotten can still confer benefits.
Another approach is to administer psychedelics to patients under general anesthesia for preplanned surgery, who cannot possibly know whether they got a drug or a placebo. Boris Heifets, an anesthesiologist at Stanford University, tried this a few years ago with ketamine, an anesthetic that can have hallucinogenic effects. (A form of the compound was approved to treat depression in 2019.) He found that the placebo group reported more improvement in depression than is common in psychedelic drug studies, which he anticipates was because of participants’ beliefs they may have gotten ketamine and benefited from it.
But studies in anesthetized patients have their own challenges. Some types of anesthesia and sedation can themselves have antidepressant effects or otherwise impact the brain, notes Katherine Nautiyal, a behavioral neuroscientist at Dartmouth College. She is trying to sort out those effects by studying psychedelics administered alongside various anesthetics in mice.
Other researchers are using innovative strategies in awake participants. One involves giving the control group an “active placebo” that mimics some immediate effects of a psychedelic without its potential psychiatric benefits. One study that aims to begin recruiting later this year, led by Stanford psychiatrist Carolyn Rodriguez that Heifets helped design, compares MDMA with another psychoactive substance, methamphetamine, in people with obsessive-compulsive disorder. Another, in active-duty service members with PTSD, compares MDMA with amphetamine.
Still other studies aim to confuse participants about how the experiment is set up. Harriet De Wit, an experimental psychologist at the University of Chicago (UChicago), has run such studies of psychoactive drugs, including psychedelics, in healthy people to parse the drugs’ biological effects. She tells participants they might get any one of a number of different compounds—a stimulant, a tranquilizer, or a placebo, for example—when in fact only one drug and a placebo are part of the study. This strategy makes it harder for volunteers to discern what they’re given. Someone handed placebo who slept poorly the night before may think they received a sedative, for example. De Wit can then better isolate drug biology, without the confounding effects of expectations.
Typically, “we cannot deceive” participants in trials, for example by not disclosing a drug they might get, says Christopher Daugherty, a medical oncologist at UChicago and chair of the institutional review board that has reviewed many of De Wit’s studies. But telling participants they could receive one of four drugs and alerting them to possible side effects—even if two of those drugs aren’t on offer—“are all true statements,” Daugherty explains.
Heifets and psychiatrist Josh Woolley at the University of California, San Francisco make a similar case for their psilocybin study, which is recruiting 30 people with chronic lower back pain. Participants are told they’ll get psilocybin within a range of dosages, perhaps with a stimulant or a sleeping pill, or with placebo. But the trial may not include all those combinations; its true design hasn’t been publicly released. As with De Wit’s studies, the researchers hope participants’ uncertainty about what they got will reduce the impact of their expectations and yield more reliable results.
In January, Woolley and colleagues published a paper in JAMA Psychiatry analyzing studies that embrace this strategy. They acknowledged “significant ethical risks,” but also the potential to “improve interpretability and impact” of psychedelic trials. Informed consent is the foundation for ethical research, but good research also demands studies designed to give clear answers, Woolley says. It’s “unethical to do uninformative studies,” he says, “studies where you don’t actually learn anything.”
More: https://www.science.org/content/article/psychedelic-drug-studies-face-potent-source-bias-trip
