One weekend evening in 2018, a group of college students gathered in the lobby of the Montreal Neurological Institute of McGill University. They had responded to an ad to take part in a research study—one that would pay them $40 Canadian, or about $28 US, to take a psychedelic drug. As they waited, one person remarked that their friend did the same study the previous week, and “had a blast.”

They were ushered into a room with trippy posters, changing colored lights, and bean bags and cushions placed on the floors. A DJ played ambient music, while a projector played the movies Baraka and _Samsara—_films with no spoken words, but colorful and alluring visuals.

Scientists wearing white coats explained they would be taking a small dose of a drug called iprocin, similar to psilocybin, the active ingredient in magic mushrooms. The study would be testing the effects of psychedelics and their environment on creativity.

The iprocin would hit quickly, the students were told—within 15 minutes, then peak in about an hour, and fade. The effects could include any of the following: "improved mood, heightened cognition, emotional sensitivity, light sensitivity, hallucinations, sleepiness, tingling sensation of the skin, vivid recall of memories, increased perspiration, slurred speech, mild anxiety, slower reflex response, and dizziness.”

One by one, the students grabbed a two-centimeter long pink capsule. A researcher checked their mouth with a flashlight, to make sure they had swallowed it.

After about half an hour, people began to watch the films, and sway to the music. Parker, one the study's participants, who didn't want to use her last name because she discussed prior drug use, said she felt a gentle surge of physical sensations, and that her heart was starting to beat a little faster. “I felt more social and comfortable, and way more relaxed, less self conscious.”

She started to feel loopy. She stood in front of a poster with white and black twisting lines, and stared closely and deeply into the pattern. “I saw the lines shifting and moving over themselves, swirling a bit," she said. "The edges of the painting were bending slightly.”

The movies that were playing also began to look odd. “They seemed more strange to me visually than they had before,” she said. “It was like [being] on shrooms, when you see something that looks weird already, but it looks way more strange and ugly.”

As researchers were monitoring her blood pressure, she told them: “I’m feeling really good, and it’s fun—but it’s not that much. I could probably handle like four more pills, and then I’d be pretty high.” During the come down, the sensations gradually faded away, and she had a slight headache.

Then, came the strangest experience of the night: The researchers told them they hadn’t taken a drug at all. The pink pill was a placebo, and they were actually in a study to see if psychedelic effects could be evoked in a placebo response. Parker couldn't believe it. “I thought it was a joke for several minutes," she said.

Another person said: “So we were all sober and just watching these paintings for 45 minutes?!”

Psychedelics elicit intense effects—and in past psychedelic studies, placebo groups haven’t shown a similarly strong response. But Jay Olson, a visiting fellow at Harvard University and PhD candidate at McGill, suspected a psychedelic placebo response might still exist. He is the first author on a paper published recently in Psychopharmacology, about the experiences Parker and others had that night.

The experiment was not set up to “debunk” psychedelics, or imply that they are predominantly placebo. Instead, their findings reveal that, when it comes to taking hallucinogenic drugs, context may matter in deeper ways than previously assumed.

If context could influence some people to experience psychedelic effects without a drug, it means that it might also play a role in how a person feels when taking the active substance. As the research in psychedelics takes off for mental health issues, researchers have been learning about the importance of the mindset and environment a person takes psychedelics in, called "set and setting." This can include the lighting or music, as well as the interactions with therapists guiding a psychedelic experience, or a person’s view of psychedelic drugs and their expectations.

When it comes to taking hallucinogenic drugs, context may matter in deeper ways than previously assumed.

“The importance of set and setting has long been recognized and addressed by psychonauts and psychedelic researchers,” said Samuel Veissière, an assistant professor of psychiatry at McGill University and senior author on the study.

If psychedelics are approved as treatments for depression, addiction, or post-traumatic stress disorder (PTSD), this could be a crucial thing to remember, said Ido Hartogsohn, an assistant professor at the Science, Technology and Society Studies program at Bar Ilan University in Israel, who wasn’t involved in the study. Just doling out a psilocybin capsule in “a sterile, fluorescent-lit clinic, with an uncaring practitioner who treats you coldly" might not lead to the best outcomes.

The placebo response isn’t something “fake,” it’s a physical reaction the body produces in response to an external, information-providing signal. That signal could be in the shape of a pill, that’s providing “information” that your pain will lessen, or that you’ll be high. Placebo effects are present in all medical, therapeutic, and drug experiences.

Yet, placebo effects are not an entirely predictable or uniform experience. In Olson's study of college students, there was big variation in the groups: Some felt nothing at all, while others felt things “typically associated with moderate or high doses of psilocybin,” Olson wrote. Overall, 61 percent said they felt some effect from the "drug" while the rest felt nothing.

Veissière said they curated the surroundings of the study to look like a typical setting someone might take psychedelics in, and added “all kinds of symbolic and ritual layers of 'medical' authority”—like the people in white coats with clipboards and medical equipment to measure vitals. They also gave the participants a very specific and detailed list of what they might feel and brought in people to act as though the drug was working; it’s been shown that when people observe others experiencing effects, the placebo effect can increase. (It was one of these people who said, in the lobby, that their friend had done the study before and had a great time. )

Parker wasn’t the only one to hallucinate. A few saw the paintings on the wall “move” and others felt, and one had a ‘come down’ before another ‘wave’ hit her,” Olson wrote.

One person said “I had not been feeling anything until looking at this [painting]. It’s moving. The colours aren’t just changing, it’s moving. It’s reshaping itself.” Another person said she felt tense, but then friendly and open after taking the pill. Her senses felt heightened, and sounds and colors were more vibrant.

One person had a nocebo effect—taking the inactive capsule brought on negative feelings. She felt nauseous, hot and sweaty, and that her arms and legs were heavier. Another reported: “I didn’t feel anything until we were doing the drawings. And everything kind of dropped a little bit and maybe I had a headache...maybe, low energy...I think it was a sinking feeling. Like gravity [had] a stronger hold on me or something...mostly [in] my head. Specifically in the back of my head."

“So we were all sober and just watching these paintings for 45 minutes?!”

One man said later he had trouble comprehending what people were saying for about 20 minutes—“as if their words did not register.” Two people felt that time was moving faster or slower than usual, one saying: “The way we live is too active...too fast for me.” One said that his torso was tingling, like he had drank coffee.

To qualify for the study, you weren’t supposed to have taken psychedelics before—but Parker had taken mushrooms previously. “Maybe that wasn’t the best choice, but I was a first year and being a little rebellious,” she said. She later admitted that she had taken shrooms and MDMA in the past. Olson and his colleagues found that some of the other participants had taken psychedelics before, and didn’t make that a criteria for the second sample they tested.

Luana Colloca, a placebo researcher at The University of Maryland, said that when she heard Parker's story, she expected that to be the case. “When you've already experienced that, there’s a sort of pharmacological memory that can be consolidated by prior exposure,” Colloca said.

Olson wrote in the study that while their sample size was too small to say for certain, that they actually didn’t see that strong of a relationship between past drug use and response to the placebo. Half of the people who had taken psychedelics before felt effects, and half didn't, and people who had never taken psychedelics had a response too.

When the researchers asked one group afterward if they thought they had taken a placebo, 35 percent said they were certain they had, 53 percent weren’t sure, and 12 percent were certain they had taken a psychedelic.

Though rare, it's not the first time psychedelic placebos have been observed. In a 1955 study people were given tap water and told it contained LSD. People had some physical symptoms, like sweaty palms, drowsiness, headaches, and anxiety, and some even reported seeing the world around them distort, feeling unusual sensations, or like they were in a dream. One person even had these symptoms for 10 hours, and needed “considerable care...to maintain an experimental situation that was not traumatic.”

“The psychedelic range of effects is wide,” Hartogsohn said. “They can have effects on many levels, both subtle and intense. The power of suggestion is immense. Set and setting—more specifically expectation, intention and mental state—shape our experiences not only when we take psychedelics, but in countless other situations.”

He thinks the study was a clever way to show how psychedelic effects are entangled with other factors, but said that the effects are probably still not as intense as taking a high dose of an active psychedelic.

This might be why placebo responses for psychedelics have been hard to find: Placebo is stronger when someone believes they have taken a drug. After taking a pill and not feeling anything, they may guess they’ve consumed an inactive substance—and since psychedelic effects are so pronounced, it could be easier to come to this conclusion.

In Harvard University professor and psychedelic advocate Timothy Leary’s autobiography, High Priest, he recounted the Good Friday experiment, when divinity students took psilocybin with the goal of having mystical experiences. Some of them, though, received a placebo. “The placebo managed to fool some for some time, but their illusions were soon shattered once they confronted students experiencing the ‘real thing,’” Hartogsohn said.

Leary described escorting two students to the bathroom and they were discussing how they thought they had received the mushrooms, and could feel it. Then, another student walked by. “No greetings. He walked to the window and stood for a long time looking out. 'Jesus,' he cried, ‘God is everywhere. Oh the Glory of it!’ Then he walked out without a word,” Leary wrote, "The two red faced students looked solemn. Hopes dashed.”

Set and setting—more specifically expectation, intention and mental state—shape our experiences not only when we take psychedelics, but in countless other situations.

The high-dose psychedelic experience was so dramatic, it left no room for a placebo, Hartogsohn said. But it doesn’t mean that when someone is on a large dose, that the context doesn’t matter.

Unlike other drugs such as stimulants or antidepressants, psychedelics can have many very different effects. They can make one person anxious, another serene or spiritual, another creative. Context, expectation, environment, and individual mindset are important factors in the experience a person will have.

Robin Carhart-Harris, Head of the Centre for Psychedelic Research at Imperial College London, wrote in an opinion article from 2018 that, “neglect of context could render a psychedelic experience not only clinically ineffective but also potentially harmful.” He also wrote that in situations where set and setting were neglected, like military experiments with psychedelics in the 1950s and 60s, people are reported to have had more anxious and upsetting experiences than those seen in recent clinical trials.

“It needs to be part of the picture,” Hartogsohn said. “Attempting to ignore set and setting will only lead to subpar results."

Colloca said since different people respond to placebo responses differently, set and setting should be studied and measured in those people to see how to best curate the context that makes their experience a positive one. Different environments, music, and decorations could be studied in comparison with one another.

Just like Olson and his colleagues had some actors tell participants they were feeling the symptoms in an effort to encourage those responses in others, clinicians could try to show people videos of others having positive experiences on psychedelics in order to encourage good outcomes.

“Unfortunately, this is something that clinicians may still not acknowledge,” Colloca said. “Clinically, if we needed to treat a difficult patient, there are so many ways to help placebo effect expectation, to boost the response to [active] treatment. This sort of placebo component of the active treatment can be so beneficial for patients to experience a reduction of their symptoms.”

Olson also said it’s possible that if the context was set up in the right way, people could have more powerful experiences, potentially even at lower doses—which could improve safety for certain people at some kind of risk for taking psychedelics—those with pre-existing cardiac conditions, for example. (He doesn’t think that someone would feel very much if they tried to induce a psychedelic placebo response on themselves at home. The effects are smaller because they wouldn’t have the elaborate social context they set up.)

Parker said that before the study, she may have doubted how much seemingly simple things like suggestion and a pink, inactive pill, could impact what a person feels. But now, she has a more open mind.

“What I experienced was crazy, and whenever I tell people, they’re like, ‘I don’t believe you, that’s crazy. I get that maybe if you think there’s alcohol in your drink and there’s not, you’d feel a little loopy or something. But to see things move and to hallucinate, that just seems wild. But I experienced it.”

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