In a hospital room in Madison, Wisconsin, Dave lay on a bed, looking at the trim around the ceiling. An air vent caught his eye. The sheen of metallic grate turned into pointed swords, and his mind filled with thoughts of Japanese martial arts and sword fighting. A few bright colors emerged, in contrast to the sanitized neutrals of the medical setting, and he heard notes of instrumental music. That’s all he remembers after receiving psilocybin, the active ingredient in magic mushrooms—though his trip lasted hours. (Dave requested a pseudonym because he worried that public knowledge of him taking psychedelics could hurt him professionally.)
During the session, researchers asked what he was thinking and feeling, and he apparently had “a long conversation about those points, of which I have no recollection at all,” he said.
It’s not that his trip wasn’t memorable. Dave’s memories were intentionally erased, enough that he recalls “probably not even 10 percent” of the trip. He was also injected with midazolam, a sedative that can be used to produce amnesia.
His experience—part of a pilot study involving eight people from the University of Wisconsin–Madison Transdisciplinary Center for Research in Psychoactive Substances—proved that it’s possible to combine these two drugs to give someone a close-to-normal mushroom trip, and then use the midazolam to wipe their memory. Why make someone trip, only to take away their memory of it?
Typically, when scientists try to isolate a drug’s effects, they do so with double-blind randomized clinical trials, or RCTs, in which participants (and their doctors) aren’t sure whether they received a drug or placebo. But “nobody’s going to confuse 200 micrograms of LSD for placebo,” said Balázs Szigeti, a postdoc at the Center for Psychedelic Research at Imperial College London. It can be painfully obvious whether someone has taken an active drug or not.
Psychedelic drugs have strong and unique effects, and, to complicate matters further, they are heavily influenced by context, such as a person’s mindset, environment, and beliefs. In other words, people's expectations about what happens on psychedelic drugs might play a role in what they experience. These problems have haunted the study of psychedelics since the first wave of research in the 1950s, and the Wisconsin study is a recent attempt to answer this enduring question: How much does a person’s subjective experience and expectation of a psychedelic trip, as opposed to only the drug’s chemical effects on the brain, influence the drug’s ability to alleviate conditions like depression, addiction, or post-traumatic stress disorder? Now that psychedelics are being noticed by federal regulators and the public, scientists are again asking: What’s the best way to study these compounds in order to truly understand their effects?
The first person to use “blinding,” a crucial part of an RCT, was probably a psychiatrist named William Rivers. Blinding means that patients are randomly assigned into groups where some get an active drug and others get a placebo, and they’re supposed to be ignorant to which group they are in. This ensures that both patients and practitioners don’t introduce bias into the study and affect outcomes.
In 1906, Rivers gave himself either an alcoholic or non-alcoholic drink made by a colleague, with the flavor masked so he couldn’t tell which was which. Then he observed how the drinks affected how easily his muscles became tired, noting that previous work on the same topic may have overestimated the effects of alcohol, because people knew whether they were drinking.
It’s now well established that skipping the blinding in studies can lead to an overestimation of a treatment’s effects. Yet blinding is not required for drug approval from the US Federal Drug Administration (FDA). And the unique nature of psychedelics means that true blinding might be close to impossible.
These challenges have even led Field Trip Health’s medical director, Ben Medrano, to claim that psychedelic treatments would “never be easily verifiable in a laboratory or a double-blind study.” (Field Trip recently had to file for creditor protection to restructure and sell assets to avoid bankruptcy, and closed several of its ketamine clinics.)
It’s an ironic position to take considering that psychedelic research has been vying for legitimacy for decades, and has just recently started to attain it. In the past 10 years, clinical trials on psychedelics have started to regularly appear in high-impact academic journals like The New England Journal of Medicine and Nature, and in 2021, the National Institute of Health announced the first government grant for psychedelic research in half a century. Now, psychedelics have been heralded as an “emerging new paradigm” in psychiatry. Drugs like psilocybin and MDMA are in Phase 3 trials, gathering data to submit to the FDA for approval.
To say that RCTs will inevitably falter in the face of psychedelics is like condemning a sprinter to stumble right out of the starting blocks. Yet, intentionally or not, Medrano was alluding to a very real problem: The way psychedelic RCTs have been conducted so far have not addressed the role of someone’s beliefs and predictions, alongside their knowledge of taking a psychedelic.
None of the recent landmark psychedelic trials have officially reported blinding. In 2021, University of Auckland neuropharmacologist Suresh Muthukumaraswamy and colleagues looked at placebo-controlled RCTs of ketamine for the treatment of major depressive disorder and found that of 43 studies, none had measured what people expected to happen in the trial beforehand, or their “pretreatment expectancy.” Five measured blinding, but none of them used blinding measures or scales that already exist. Only one study said that they successfully maintained the blind.
In a more recent analysis from May, researchers looked at all the randomized trials of psychedelics in humans conducted from 1940 through May 2020, specifically focusing on blinding. While 94 percent of the studies claimed to be blinded, only 17 percent included any blinding assessments—and only eight of the 14 studies that included them actually used those measurements.
Meanwhile, in the studies of esketamine, a different chemical formulation of ketamine, the placebo was made to taste bitter to emulate the taste of esketamine. Still, no one checked to see whether the esketamine placebo had effectively tricked people; the data was nonetheless submitted to the FDA and approved for treatment-resistant depression, because even if the FDA requires a blinded placebo group, it does not require any confirmation that blinding was successful.
Because of this challenge in study design, all the effect sizes from psychedelic trials so far could be inflated to an unknown degree. People in nonactive drug arms of trials could be suffering harms—called the nocebo effect—from knowing that they’re not receiving an active treatment, thus making the active treatment look even better. “People’s expectations about treatments are really important and really powerful,” said Jacob Aday, an experimental psychologist at the University of California, San Francisco, who coauthored a paper on expectation and psychedelic trials last year. “There probably hasn’t been a true double-blind study actually conducted with psychedelics.”
In the world of psychedelics, this is a moment of déjà vu. The decline in LSD research in the 1960s, often blamed on public backlash to recreational use, might be better explained by the difficulty of studying psychedelics through typical study designs.
Before 1962, studies on LSD rarely had control groups, and focused on small groups of patients who knew they were taking a hallucinogenic drug. By 1970, the FDA had begun requiring that new drug applications submit RCT results. (These amendments were developed in response to the thalidomide tragedy, when a widely used drug led to severe birth defects in thousands of children.) Psychedelic researchers then faced the same challenge that scientists are dealing with now: How do you fit psychedelics into a study design that seems unable to contain it?
Some studies that focused on correctly executing an RCT didn’t achieve positive results, like one double-blind study from 1969 on LSD treatment for alcoholism. All the patients expected to receive LSD, but some got a stimulant or tranquilizer as active placebos. The trial didn’t include any psychotherapy, and the LSD did no better than the control drugs. Historian Matthew Oram has argued that the general move to focus on clinical trial design came at the cost of focusing on the therapy that went alongside the drug treatment—leading to a lesser intervention effect.
Then, in 1970, US president Richard Nixon signed the Controlled Substances Act (CSA), prohibiting many psychedelics in the country, and research essentially came to a standstill. The issue of how to study psychedelics in a manner that could provide the right data for federal regulators remained unresolved.
Every month, interdisciplinary researchers get together on Zoom to worry about psychedelic trial design. The group, called Reimagining Psychedelic Trials, was started by Tehseen Noorani, an anthropologist at Durham University.
“RCTS are supposedly what the regulators want, which I think is also a bit of a farce, because I’m not sure ‘the regulators’ are one thing and that they want something clear,” Noorani said. “Rather, we’re all trying to figure it out, which is why I think this is so ripe for a kind of evolution of methodology across the sector.”
I visited the working group in February, and we discussed how it might be possible to measure the effects of media consumption on the expectations of clinical trial participants—if the type and amount of psychedelic journalism a person reads has any association with outcomes (an issue I have vested interest in). I learned quickly that there are no easy solutions.
As Noorani has written, expectations are all around us. It’s not just what we read, but the communities we live in and the cultural values we hold. We are immersed—like the fish parable that David Foster Wallace once opened a graduation speech with: An older fish says to two younger fish, “Morning, boys. How’s the water?” The two young fish swim on for a bit before one of them looks over at the other and goes, “What the hell is water?”
The anthropologist Anthony Wallace noticed in the 1950s that Euro-American subjects who took mescaline in the lab had very different experiences than Native Americans who ate peyote buttons as part of religious ceremonies. He suggested the concept of a “culture-controlled trial,” which would test the same drug and the same dose but in different social and cultural contexts. “There is always hidden machinery and circuitry that is going on, and we’re not describing it,” University of Auckland’s Muthukumaraswamy said. “And there are all these hidden interactions that, frankly, we’re brushing under the carpet.”
These factors make the efficacy of a medical intervention “unstable over time and potentially at the whim of social zeitgeist.” Noorani is also credited with the term “the Pollan effect,” or the impact that Michael Pollan’s book How to Change Your Mind has had on public perception of psychedelics and, inadvertently, the expectations of clinical trial participants. Public perceptions of psychedelics weasel their way into trial results through placebo effects and people’s expectations, and those trial results then further impact public perceptions.
There’s no agreement on the best way to find out whether the study participants or researchers can guess what group they’re in, or what their expectations are going into the study. But one way to start addressing this problem is simply to start checking. “Everybody pretends that if you have a placebo control group, that is sufficient to control for the placebo effect,” Imperial College London’s Szigeti said. “That’s not exactly true. You also need to show that blinding worked as intended, some empirical evidence.”
Szigeti developed a Correct Guess Rate Curve to assess the quality of blinding—how often people guess the treatment correctly. If there are two treatments to choose from and people are guessing randomly, the CGR should be around 50 percent. For classic antidepressants, it’s somewhere between 60 to 70 percent. For microdosing, it’s around 70 to 75 percent. “When it comes to macro-dosing, it’s probably around 95 percent,” Szigeti said.
But when Szigeti approached the mental health company Compass Pathways about helping them to include blind breaking and expectancy measures in their upcoming Phase 3 trials of psilocybin for treatment-resistant depression, they said no. “Costs for them would be basically zero, just a few questionnaires here and there,” Szigeti said. “I even emphasized that I would be happy to analyze it separately from the main trial, not to mess with their business.” They still turned him down.
Active placebos are one way to make a trial participant uncertain about what drug they’ve taken. It’s a substance with some kind of impact on the body or mind that could confuse a person into thinking they’ve taken a psychedelic, and lead them to have the same kinds of expectations without the effects of the drug being studied, since it’s another drug altogether. But they don't always guarantee that people won’t be able to guess what treatment group they’re in.
A study from 1966 on LSD for alcoholism used a 60-milligram dose of ephedrine sulfate as an active placebo. In 19 of the 20 drug sessions, the therapists correctly guessed which drug the patients got. Famously, in the Good Friday Experiment, divinity school students took either psilocybin or niacin, a B vitamin with some physiological effects, like facial flushing. “Before long, it became clear which participants had been assigned to which condition, as those in the psilocybin group had intense subjective reactions and often spiritual experiences, whereas the niacin group ‘twiddled their thumbs’ while watching on,” Aday wrote.
Newer studies have tried harder to make their active placebos convincing. A study from 2021 made a fake version of ayahuasca using “a mixture of cocoa powder, unspecified vitamins, turmeric powder, quinoa, traces of coffee, and potato flour.” They fooled a few people, but the majority still correctly guessed which treatment arm they belonged to.
At the end of Muthukumaraswamy and his colleague’s recent study on antidepressant responses to ketamine, which used an active placebo called remifentanil, 27 people were asked to guess which day they’d received ketamine. They guessed correctly 88 percent of the time.
It’s also not just the study’s active placebo and design that matter, but also how the patients are told about the study and the information sheets they read before and after—all elements that are rarely reported and shared. “We just don’t see this published with their trials,” Muthukumaraswamy said. “It should be compulsory. We should be seeing what they tell the patients, because that is what shapes their expectancy.”
Rotem Petranker, the director of the Canadian Centre for Psychedelic Science, agreed that these contextual factors are critical, including the therapeutic element. “That, to me, seems to be the most significant extra pharmacological factor,” he said. "And we basically know nothing about it."
In the end, the placebo-controlled trial just may not be the best fit for studying all aspects of psychedelics. There are other study design components, some that Muthukumaraswamy evaluated in his paper, that could work better.
One way to reduce expectations would be to completely conceal the dose or treatment from study participants—giving them little information to form expectations around. Another could be to conduct a “deceptive trial” in which people are told there’s an active group, but in reality, everyone gets a placebo. Both designs raise ethical concerns about misleading patients. Reformatting a consent form to list all potential drug effects could also undermine expectation.
There’s also an option called “pragmatic clinical trial design,” which measures a treatment’s overall effectiveness rather than distinguish how or why it’s different from a placebo group. This design would accept that expectation and placebo are playing a role in how people feel, and would simply accept it so long as people’s depression scores decrease.
In one example of a well-executed study design, Harriet De Wit and her team gave patients either MDMA or methamphetamine and had them report how pleasant touch felt. Participants were asked to guess which drug they got—and the people who believed they got MDMA but really got methamphetamine were used as the control group. “They [had] all the expectations baked in, but they actually didn’t get the drug,” says Boris Heifets, an anesthesiologist and neuroscientist at Stanford University. That group didn’t experience the same level of pleasantness to touch as those who got MDMA—suggesting that the effect on touch is specific to MDMA.
In a recent preprint study led by Heifets, people with moderate to severe depression were given either ketamine or a placebo during surgical anesthesia. The differences were not clinically significant between the groups—they all started feeling a lot better. Heifets and his colleagues are preparing to do a similar study with anesthesia and psilocybin, and the team at the University of Wisconsin–Madison will be probing the effects of psilocybin administered during deep sleep stages.
There are pros and cons to all of these models, and of course, the FDA still accepts only the RCT as data for approval. But experts say that other designs, even if not submitted to federal agencies, could help us learn more about psychedelics and how they work.
“I think placebo-controlled trials are definitely overrated, particularly in psychopharmacology,” said Nicolas Langlitz, an associate professor of anthropology at the New School for Social Research who leads a psychedelic humanities lab. “I don’t think there is a superior method to replace them, but if that’s the gold standard, then you should also have a silver standard and a bronze standard, and those should also provide interesting information.”
Anecdotal or open-label data may be messy and dirty, but if we ignore it because it’s not a randomized placebo-controlled trial, Langlitz said, we could miss out. “I would really urge people to pluralize,” he said. “And to have more of a conversation about the epistemological costs and benefits of different approaches.”
Because expectations may be one of the key ingredients in psychedelic therapy, instead of doing away with them, we should learn about them and their role in order to better manipulate them.
In Heifets’ ketamine and anesthesia study, for instance, there was one woman who received the placebo while under anesthesia, remembered nothing, and felt a remarkable improvement—from just the expectation that she got ketamine. “I was taking six college classes while waiting for surgery,” she reported after. “I was able to take all six exams from the hospital bed, passed them all with As and Bs.”
“The main thing that I take away from it isn’t that ketamine doesn’t work,” Heifets said. “What it does mean is this incredible power of suggestion, expectation, planning, and thinking about the future, and ceding control to the care of others for a vulnerable period. Maybe it doesn’t matter whether you’re there for it or not.”
Dave was a little bummed that he doesn’t remember his trip. It was his first time taking psilocybin, and it vanished somewhere into the recesses of his midazolam-altered mind. After his forgotten trip, Dave didn’t notice any differences in his day-to-day life. There are plenty of caveats—Dave isn’t depressed, so his psilocybin experience may not have had much of a needle to move—but it’s still not clear what the most important part of a psychedelic experience is in regards to lasting change: the experience, the therapy, the biology, the expectation, or all of the above.
“None at all,” he said. “I could not tell you any difference it made.”