Interest in psychedelic drugs has grown in recent years alongside research into their potential as tools to treat mental health. That’s especially true in Colorado where, in 2022, voters approved the establishment of a regulated industry around psychedelic-assisted therapy.

While the bulk of formal studies focus on the effects of ingesting large doses, the wellness industry has popularized a concept called microdosing, which involves taking small amounts of drugs like psilocybin or LSD as a supplement. This idea is to enhance physical and mental well-being without inducing a full psychedelic experience or trip.

Most psychedelic drugs are still illegal in the eyes of the federal government, however, so even though microdosing has inched its way into the mainstream lexicon, it simultaneously remains part of an underground culture. A Colorado company is working to create a microdosing drug for approval by the U.S. Food and Drug Administration, but until that happens doctors cannot prescribe microdoses to patients.

And there’s another catch: To be approved as a medicine, microdosing needs to be proven to work. Right now, scientists don’t agree on if it does.

Microdosing hasn’t been studied extensively, but the various methods used to do so often produce varying results. Much of the available data comes from observational studies in which users share anecdotal information about their experiences. Reports are usually overwhelmingly positive with people citing benefits from improvements in mood, focus and athletic performance to relief from chronic pain and anxiety.

Studies in placebo-controlled settings, however, tell a different story. In these cases, researchers often find minimal differences between people who get an active drug versus a placebo, suggesting participant bias is at play. Simply put, when people expect to see positive results from microdosing, they perceive them that way.

This paradox has sparked debate in psychedelic circles and caused friction between the traditional methods of investigating new drugs and burgeoning enthusiasm for psychedelics’ potential medical applications.

We spoke to researchers who’ve conducted both types of studies to understand the nuances of investigating psychedelic drugs and how their various methods may shape the future of the sector.

Microdosing in the natural world

Many people credit researcher Jim Fadiman with popularizing the microdosing concept in his 2011 book, “The Psychedelic Explorer’s Guide.” Fadiman began studying psychedelics in the 1960s, primarily focusing on the effects of ingesting large doses. He became interested in microdosing after hearing that Swiss chemist Albert Hofmann, the first person to synthesize LSD, had done it.

In 2010, a curious Fadiman launched an experiment that he bills as the first formal research into modern microdosing. He worked with a colleague to create blotters, each with 10 micrograms of acid, and mailed them to 100 willing participants nationwide, asking them to write back about their experiences.

“I got reports like a little outline, like two lines a day, and also got people who wrote well over 2,000 words a day,” Fadiman said. “I got a lot of indication that said there’s something here. There is some real effect and people notice it.”

Fadiman, who lives in Northern California, stopped mailing out microdoses, but he kept collecting testimonies. To date, he’s received about 5,000 personal accounts from people in at least 50 countries. The vast majority report positive effects in using small doses of psychedelics to manage conditions like depression, anxiety and attention-deficit/hyperactivity disorder, to treat chronic pain, and improve cognitive function.

Based on his trove of anecdotes, Fadiman likens microdosing to a tune-up for the whole system.

“Medications are very symptom-specific. If you have a headache, a backache, a stomachache, a tremble, those all (need) different medications,” he said. “But if you take a vitamin, the assumption is it helps your system. Microdosing is much more akin to a vitamin than to a medication.”

Given few standards exist around the practice, another ongoing observational study launched in 2019 seeks to understand how and why people currently microdose. It’s called microdose.me and to date, there are more than 9,000 participants worldwide.

According to principal investigator Zach Walsh, who is also a professor at the University of British Columbia and a clinical psychologist, the results offer real-world insight into microdosing and distinguish trends among those who do it.

The most popular reasons for microdosing are to enhance mindfulness (82.9%), to improve mood (76.1%), to enhance creativity (74.1%), to enhance learning (58.1%) and to decrease anxiety (57.4%).

Walsh said enough people signed up who do not actively microdose that he was able to compare the two cohorts. Using self-reported data like the Depression Anxiety Stress Scales and other measurements, his team found that individuals who microdosed psilocybin showed greater improvements in mood and mental health after one month compared to those who didn’t.

“When we followed people for a month, there were some modest decreases in measures of mental distress,” Walsh said. “Because it wasn’t placebo-controlled and it wasn’t blind, we can’t tease apart whether or not it was just the act of microdosing and being active with your health that made the difference, or whether it was specific to microdosing. I don’t think it has to be either or.”

Controlled studies

What scientists know about the neurological effects of microdosing has primarily come from studies involving high doses. Research done at Johns Hopkins University and other institutions suggests psychedelics promote neuroplasticity and allow otherwise segregated portions of the brain to communicate. That’s why some scientists see promise in their ability to treat major depressive disorder, addiction, and end-of-life anxiety, among other ailments.

These studies are typically done in double-blind, placebo-controlled formats — the gold standard for evaluating the efficacy of pharmaceutical drugs. However, psychedelics present unique challenges since participants often break the blind, meaning they successfully guess whether or not they received an active drug or placebo. That’s especially true in studies using large doses – participants either trip or they don’t.

Harriet De Wit, a professor of psychiatry and behavioral neuroscience at the University of Chicago, said it’s easier to maintain the blind in microdosing studies since users take a fraction of the dose needed to cause effects like hallucinations. However, it’s also challenging because the exact amount, known as a threshold dose, varies by the individual, she said.

De Wit, who has studied the effects of drugs for 40 years, heard the anecdotes heralding microdosing’s benefits and sought to understand how it affects people’s mood, cognitive performance and responses to emotional tasks. So she conducted a study in which 56 adults took repeated doses of either a placebo, 13 micrograms of LSD or 26 micrograms of LSD for several weeks. (The university has a license from the Drug Enforcement Administration to conduct research.)

“When people microdose in the natural world they have strong expectancies of what it’s going to do for them and that it’s going to have beneficial effects, and we don’t know how much the expectancies are influencing their responses to the drug. Our laboratory is set up to control those expectancies,” she said.

Many in the highest dose group reported feeling stimulated, energetic, amphetamine-like effects, De Wit said. However, microdosing did not improve their mood or cognitive performance, leading researchers to conclude it is safe, but has negligible effects in healthy volunteers. Subsequently, De Wit decided to investigate microdosing in individuals with depression symptoms and found the drug produced more marked improvements in mood.

“That’s kind of a novel finding and opens the door to maybe there is something to the microdosing. That is, some people who have symptoms to begin with might benefit from the drug, even if healthy volunteers don’t so much,” she said.

One of the most talked about studies, published in 2021, similarly found statistically insignificant differences between groups that took microdoses and placebos. Researcher Balázs Szigeti, then at Imperial College London, relied on citizen science by creating a unique self-blinding methodology that reduced the cost and approvals normally required to study psychedelics.

Participants created their own microdoses and placebo pills at home using non-transparent capsules that they either filled with their own psychedelic substance or left empty. After randomly selecting certain capsules to consume during the study’s four-week period, the 191 participants ended up in one of three groups – those who took only placebos, those who took only microdoses, and those who took half and half. QR codes helped Szigeti and his team track dosing data and survey results.

All groups reported improvements in subjective factors like well-being and life satisfaction, but comparatively, the differences were marginal. Szigeti attributed the benefits of microdosing to the placebo effect, causing swift backlash from the psychedelics community.

Szigeti, who now studies psychedelics at the University of California San Francisco, tells The Denver Post he was surprised by the study’s results and does not believe they are at odds with people’s lived experiences. (It’s also worth noting that most participants broke the blind.)