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Friday, May 17, 2024

Microdosing's Feel-Good Benefits Might Just Be Placebo Effect

In 2018, volunteers with an interest in microdosing—regularly taking tiny amounts of psychedelic drugs such as LSD—began taking part in an unusual experiment. For four weeks, researchers at Imperial College London asked them to swap some of their drugs with empty capsules—placebos—so that when they took them, they didn’t know if they were microdosing or not. They then completed online surveys and cognitive tasks at regular intervals, aimed at gauging their mental well-being and cognitive abilities. The idea: to explore if microdosing produces the benefits to mood and brain function that some people claim. 


In a paper published in the journal eLife, the researchers revealed their findings. After the month-long testing period, they found that all psychological outcomes had improved since the start of the experiment for those in the microdosing group, including “in the domains of well-being, mindfulness, life satisfaction, and paranoia.” However, the same was true for the placebo group—with no significant differences between the two.

“So, in a way, microdosing did increase a lot of these psychological variables,” says Balazs Szigeti, a research associate at Imperial College London Centre of Psychedelic Research and the lead author of the study. “But so did taking placebos for four weeks.”

The researchers conclude that the anecdotal benefits of microdosing can therefore be explained by the placebo effect. That’s not to say that people who claim to feel benefits from microdosing are wrong, Szigeti says—on the contrary, the study suggests that they do feel these benefits—but that these outcomes may not be the result of the pharmacological effect of the drug but instead due to their psychological expectations.

People who microdose take very small amounts of psychedelic drugs such as LSD or psilocybin (found in magic mushrooms)—usually around a tenth of the amount you’d take to get a full psychedelic experience. Some people claim that microdosing has mood-enhancing effects, while others claim cognitive benefits or say it makes them feel more creative or effective at work. Others microdose in an attempt to self-medicate conditions such as depression. But there is very little scientific evidence on the effects of microdosing, and it is difficult to run controlled trials (not least because of the illegal nature of these drugs in many countries.)

The Imperial team turned to volunteers who planned to microdose independently, and asked them to complete the surveys and cognitive tasks at specific times during their microdosing schedule. The volunteers never came into the lab, and the researchers did not provide the drugs. In order to “self-blind” so that they didn’t know whether they were taking a microdose or placebo, volunteers were instructed to put their microdoses into opaque pill capsules and then put a week’s worth of capsules into an envelope with a QR code. They then mixed these up so that some of the envelopes contained microdoses and others contained placebos. Some people would take only microdoses for four weeks, others only placebos, and some half-half. After the study, the QR codes acted as a key to determine which were which.

While the study also measured effects a few hours after taking a microdose, and on a weekly basis, it was the monthly accumulative effect that showed most interesting results. A week after the dosing period had ended, participants were asked to report on psychological measures relating to well-being, mindfulness, life-satisfaction, and paranoia. For both the microdosing group and the placebo group, these showed overall improvement compared to a baseline taken before the start of the study, with no significant difference between the two groups. Overall, cognitive measures—which are less subjective—showed no significant improvement for either group. “So people are cognitively performing at the same level before and after these four weeks long dose period,” Szigeti says.

For Szigeti, the “coolest part” of the study, and the thing that makes him most convinced a placebo effect may be at play, is what happened when researchers asked participants whether they thought they were taking a microdose or a placebo. They found that people scored better on self-reported psychological outcomes for that day or week when they believed they had taken a microdose—regardless of whether that was actually the case or not. “What is driving the differences in the data is not what you have taken, but what you think you have taken,” Szigeti says.

A study published in January, also involving Imperial researchers, found that microdosers’ positive expectations before they started a microdosing regimen were predictive of their subsequent improvements in well-being: essentially, if they thought they would experience certain benefits, they did. The authors of that paper write that this is “suggestive of a significant placebo response,” and say their study “cautions against zealous inferences on [microdosing’s] putative therapeutic value”.

Not everyone is so convinced that the effects of microdosing can be fully explained by the placebo effect, however. Kim Kuypers, an associate professor at Maastricht University in the Netherlands who has run lab-based placebo-controlled trials with microdoses of LSD, says microdosing is difficult to study and the results often have to contend with a lot of noise. In a small, placebo-controlled dose-finding study, she and her colleagues found that microdoses of 5-20 micrograms of LSD had beneficial effects on mood and attention for some participants, which were not explained by the placebo effect. She also believes that timing may be an important factor—effects may vary depending on how much time has passed since someone took a microdose—and says that effects may vary a lot between individuals.

For her, the most convincing sign that microdosing may cause some effect is a study she led that found evidence of an increase in brain-derived neurotropic factor (BDNF), a protein linked to brain plasticity, a few hours after microdosing. This was detected in blood tests. While the study was not able to link this finding to any measures of well-being or cognition, Kuypers says, “this shows to me that something is happening, and we need to investigate this more.” In future studies, she is also looking at how microdosing may affect specific patients, such as those with ADHD or Parkinson’s.

The design of the new Imperial study has benefits and limitations. The citizen science approach means it was able to recruit a large number of participants; Szigeti believes it is the largest placebo-controlled trial on psychedelics to date, with 191 subjects completing it. But it also means there are many variables that could not be controlled. Participants chose which psychedelic substance to use and how much to take, and had to be trusted to follow the protocol. Lab-based studies can control for more factors, but are very expensive and can be difficult to do with illegal drugs. Bernhard Hommel, a professor of general psychology at Leiden University in the Netherlands says that controlling for the type and amount of drug could yield more reliable results. He questions the Imperial team’s choice of cognition tests, and warns against combining different aspects of cognition into one overall score. “‘Does it make me better or worse’—the brain is not like that,” he says. “Some things improve, some things get worse.”

He also questions how we think about the placebo effect, and notes that just because there is no difference between a placebo group and a microdosing group doesn’t mean any effects are “just made-up stuff.” He suggests that an experienced drug user may become conditioned to a drug’s effect, so that a state that was originally produced pharmacologically could then be induced in a different way. “If you are an experienced user, you may be able to just create the same state without the drug,” he says. He would like to see if there is a difference in placebo-controlled studies with experienced users compared to those who have never microdosed before (the nature of the Imperial study means most participants were likely experienced microdosers.) Perhaps people who are naive to psychedelics would not have the same response.

Harriet de Wit, primary investigator at the University of Chicago’s Human Behavioral Pharmacology Laboratory, says she was impressed that the researchers were able to do a placebo-controlled study outside of the lab. “I thought it was very honest of them to report that there really wasn't much of a difference between the placebo and the drugs,” she adds. “It's kind of refreshing that people don't try to build up a minor finding or something.”

Like Hommel, she says it would be interesting to compare experienced and inexperienced users. One way that her team tries to control for the expectancy effect is by telling people they may get not just a psychedelic or placebo, but also a tranquilizer, stimulant, or alcohol—“so in any study that they're participating in, they have no idea what they're going to get.” She is also interested in exploring whether microdosing could show improvements for someone who is already experiencing a negative condition or cognitive impairment, as opposed to just the impact on healthy volunteers. De Wit, who is currently running further microdosing studies, says she remains open-minded: “There could be some modest benefit, or it could be all placebo effect. I'm not invested in one side or another.”

Szigeti says there is still a lot of uncertainty around microdosing, and he doesn’t think this study will change many minds in the microdosing community. “I think most microdosers don't care that much whether it's a pharmacological or placebo effect, they’re just going to enjoy the effects that they get,” he says. There are hints of disappointment from some in the psychedelics community, however; they supported the study with the hope of proving that microdosing wasn’t a placebo effect. “But it is what it is, I'm only responsible for collecting and analyzing the data, not what the data shows,” he says.

After the study was completed, several people who had been in the placebo group emailed Szigeti to complain that he must have got it wrong; they were sure they had been microdosing. But when they checked their leftover capsules, they found they had been taking placebos. One participant, quoted in the study, said, “I have just checked the remaining envelopes and it appears that I was indeed taking placebos throughout the trial. I'm quite astonished […] It seems I was able to generate a powerful 'altered consciousness' experience based only the expectation around the possibility of a microdose.” Another wrote, “You put spirituality into an empty pill here… wow!”

This story originally appeared on WIRED UK.

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