About a decade there are many media, including CABLE– focused on a strange trend at the intersection of mental health, drug science, and Silicon Valley biohacking: microdosingor the practice of taking a small amount of a psychedelic drug to seek not full-blown hallucinatory delights, but milder, more stable effects. Typically using psilocybin mushrooms or LSD, the archetypal microdoser was less about melting walls and open-eyed kaleidoscopic visuals than about mood and energy enhancements, like a gentle spring breeze blowing through the mind.
Anecdotal reports present microdosing as a sort of psychedelic Swiss army knife, providing everything from increased concentration has a peak libido and (perhaps most promising) a decline in depression levels. For many, it was a miracle. Others remained wary. Could 5 percent of a dose of acid really do the trick? all that? A large new study from an Australian biopharmaceutical company suggests that the benefits of microdosing may indeed be significantly overstated, at least when it comes to treating symptoms of clinical depression.
A Phase 2B trial of 89 adult patients conducted by Melbourne-based MindBio Therapeutics, studying the effects of microdosing LSD in the treatment of major depressive disorder, found that the psychedelic was actually outperformed by a placebo. Over an eight-week period, symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), a widely recognized tool for the clinical assessment of depression.
The study has not yet been published. But MindBio CEO Justin Hanka recently released key findings from his LinkedIneager to show that his company was “ahead in microdosing research.” He called it “the most vigorous placebo-controlled trial of microdosing ever conducted.” It was found that patients given a small amount of LSD (ranging from 4 to 20 μg, or micrograms, well below the threshold for a mind-blowing hallucinogenic dose) had an observable increase in their sense of well-being, but worse MADRS scores, compared to patients given a placebo in the form of a caffeine pill. (Because patients participating in psychedelic trials typically expect some sort of mind-altering effect, studies are often conducted blinded using so-called “active placebos,” such as caffeine or methylphenidate, which have their own observable psychoactive properties.)
This essentially means that a moderately strong cup of coffee may prove more beneficial in treating major depressive disorder than a tiny dose of acid. Good news for habitual caffeine consumers, perhaps, but less so for researchers (and biopharmaceutical startups) who rely on the effectiveness of psychedelic microdosing.
“This is probably a nail in the coffin for using microdosing to treat clinical depression,” says Hanka. “It probably improves how depressed people feel, but not enough to be clinically or statistically significant.”
Desperate as they are, these results are consistent with the suspicions of some others skeptical researcherswho have long believed that the benefits of microdosing are less the result of a tiny psychedelic catalyst, but rather attributable to what’s known as the “placebo effect.”
In 2020, Jay A. Olson, then a doctoral student in the Department of Psychiatry at McGill University in Montreal, Canada, conducted an experiment. He gave 33 participants a placebo, telling them it was actually a dose of a psilocybin-like drug. They were made to believe that there was no placebo group. Other researchers who were involved staged the effects of the drug, in a room treated with trippy lighting and other visual stimulants, in an attempt to stage the “optimized anticipation” of a psychedelic experience.
The result papertitled “Tripping on Nothing,” found that a majority of participants reported feeling the effects of the drug, even though no actual drug existed. “The main conclusion we made is that the placebo effect may be stronger than expected in psychedelic studies,” Olson, now a postdoctoral researcher at the University of Toronto, told WIRED. “The effects of the placebo were stronger than what you would get with microdosing.”
More than a stick in the eye of microdosing enthusiasts, Olson maintains that the study’s main findings have more to do with the real role and power of the placebo effect. “The public has a lot of misconceptions about the placebo effect,” he says. “It is assumed that placebo effects are extremely small or not real.”
Olson goes on to say that placebo effects in psychedelic trials may be further enhanced by hype around the drugs themselves. Patients may participate in a trial expecting to have a certain experience, and their minds are in turn able to conjure up a version of that experience. In Olson’s study, it wasn’t a question of non-effects of microdosing. realbut that these effects can be caused by the environment or by the patient’s expectations. As he puts it: “It may be true at the same time that microdosing can have positive effects on people, and that those effects may be almost entirely placebo. »
This raises a thorny question about the MindBio study. How does a placebo group, which think they take LSD, have better results than an active control group, whose members both think they are taking LSD and are actually taking it? The answer comes from the design of the study itself.
Using what’s called a “dummy double” design, MindBio researchers informed patients that they would receive either LSD, a caffeine pill, or a dose of methylphenidate, better known as Ritalin or Concerta. (No patient actually received methylphenidate.) This means that patients’ expectations were lowered, because they could attribute the perceived effects either to LSD or to one or other of the active placebos. Patients taking microdoses of LSD may well have believed they were simply taking a stimulant. All patients followed an adaptation of the “Fadiman protocol,” a popular microdosing program in which patients take a small dose of the administered medication once every three days.
Jim Fadiman, the veteran psychedelic researcher after whom the protocol is named, dismisses MindBio’s findings and the trial design out of hand. Given that, according to Fadiman, the patients received an active caffeine placebo, the reported benefits may well be attributable not to a pure placebo effect, but to the actual psychoactive properties of this drug.
“Dummy double is a remarkably apt term,” sneers Fadiman, 86. “What I do know is that if you get enough caffeine, you won’t get depressed!” »
Fadiman highlights MindBio’s previous Phase 2A study, recently published in the journal Neuropharmacology, who drew significantly different conclusions. This was an unblinded, so-called “open-label” study, meaning that patients knew with certainty that they were receiving a microdose of LSD. This study found that MADRS scores decreased by 59.5 percent, with effects lasting up to six months. The study also found improvements in patients’ stress, rumination, anxiety and quality of life. Fadiman says this reporting is more consistent with his own research on microdosing. “Their previous study was found to be wonderfully effective with LSD,” says Fadiman. “I have collected literally hundreds of real-world reports over the years that validate these results.”
MindBio’s Hanka sticks to the science. “We are disconcerted by the significant difference between the results of the open-label Phase 2A trial and the results of the Phase 2B trial,” he said. “But that’s the nature of good science: a properly controlled trial will give a correct result. Our Phase 2B trial was of the highest standard, a triple-blind, double-dummy, active-placebo-controlled trial. I haven’t seen another psychedelic trial that has gone to such lengths to control and blind a trial.”
Despite these findings, some microdosing true believers don’t seem particularly shaken. In 2017, writer Ayelet Waldman (best known as the author of Mom-Track Mysteries series of novels which follow the adventures of Juliet Applebaum, housewife and detective) published A very good dayan account of his own experiences using microdosing to treat an intractable mood disorder. She tells WIRED that she’s not particularly bothered by the implication that her positive mood swings might just be a simple placebo. “In my book, I took very seriously the possibility that what I was experiencing was the mother of all placebo effects,” says Waldman. “I talked about it several times in different chapters and ultimately decided it didn’t matter. What mattered was that I felt better.”
That may be true enough. If the effects are measurable and reproducible, it does not matter whether they are attributable to a sub-perceptual dose of lysergic acid or to the (perhaps equally profound) mysteries of the placebo. Still, one can’t help but wonder why anyone seeking to use LSD to relieve severe clinical depression would bother to assume the legal risk of obtaining and consuming a drug still classified as Schedule I by the United States Drug Enforcement Administration.
Certainly, for his part, Justin Hanka seems content to pivot MindBio’s research into a new area. His next project is “Booze AI”: a smartphone application that uses artificial intelligence to scan the human voice for relevant biomarkers that determine blood alcohol concentration. He leaves microdosing in the rearview mirror. “I’ve invested millions of dollars in it myself,” he says. “If I had known what I know about psychedelics six years ago, I probably wouldn’t have ventured into the realm of microdosing.”