health

About a decade ago, many media outlets—including WIRED—zeroed in on a weird trend at the intersection of mental health, drug science, and Silicon Valley biohacking: microdosing, or the practice of taking a small amount of a psychedelic drug seeking not full-blown hallucinatory revels but gentler, more stable effects. Typically using psilocybin mushrooms or LSD, the archetypal microdoser sought less melting walls and open-eye kaleidoscopic visuals than boosts in mood and energy, like a gentle spring breeze blowing through the mind.

Anecdotal reports pitched microdosing as a kind of psychedelic Swiss Army knife, providing everything from increased focus to a spiked libido and (perhaps most promisingly) lowered reported levels of depression. It was a miracle for many. Others remained wary. Could 5 percent of a dose of acid really do all that? A new, wide-ranging study by an Australian biopharma company suggests that microdosing’s benefits may indeed be drastically overstated—at least when it comes to addressing symptoms of clinical depression.

A Phase 2B trial of 89 adult patients conducted by Melbourne-based MindBio Therapeutics, investigating the effects of microdosing LSD in the treatment of major depressive disorder, found that the psychedelic was actually outperformed by a placebo. Across an eight-week period, symptoms were gauged using the Montgomery-Åsberg Depression Rating Scale (MADRS), a widely recognized tool for the clinical evaluation of depression.

The study has not yet been published. But MindBio’s CEO Justin Hanka recently released the top-line results on his LinkedIn, eager to show that his company was “in front of the curve in microdosing research.” He called it “the most vigorous placebo controlled trial ever performed in microdosing.” It found that patients dosed with a small amount of LSD (ranging from 4 to 20μg, or micrograms, well below the threshold of a mind-blowing hallucinogenic dose) showed observable upticks in feelings of well-being, but worse MADRS scores, compared to patients given a placebo in the form of a caffeine pill. (Because patients in psychedelic trials typically expect some kind of mind-altering effect, studies are often blinded using so-called “active placebos,” like caffeine or methylphenidate, which have their own observable psychoactive properties.)

This means, essentially, that a medium-strength cup of coffee may prove more beneficial in treating major depressive disorder than a tiny dose of acid. Good news for habitual caffeine users, perhaps, but less so for researchers (and biopharma startups) counting on the efficacy of psychedelic microdosing.

“It’s probably a nail in the coffin of using microdosing to treat clinical depression,” Hanka says. “It probably improves the way depressed people feel—just not enough to be clinically significant or statistically meaningful.”

However despairing, these results conform with the suspicions of some more skeptical researchers, who have long believed that the benefits of microdosing are less the result of a teeny-tiny psychedelic catalyst, and more attributable to the so-called “placebo effect.”

In 2020, Jay A. Olson, then a PhD candidate 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 led to believe there was no placebo group. Other researchers who were in on the bit acted out the effects of the drug, in a room treated with trippy lighting and other visual stimulants, in an attempt to curate the “optimized expectation” of a psychedelic experience.

The resulting paper, titled “Tripping on Nothing,” found that a majority of participants had reported feeling the effects of the drug—despite there being no real drug whatsoever. “The main conclusion we had is that the placebo effect can be stronger than expected in psychedelic studies,” Olson, now a postdoctoral fellow at the University of Toronto, tells WIRED. “Placebo effects were stronger than what you would get from microdosing.”

More than a stick in the eye to the microdosing faithful, Olson maintains that the study’s key findings had more to do with the actual role, and power, of the placebo effect. “The public has a lot of misconceptions about the placebo effect,” he says. “There’s this assumption that placebo effects are extremely weak, or that they’re not real.”

Olson goes on to say that placebo effects in psychedelic trials can be further juiced by the hype around the drugs themselves. Patients may enter a trial expecting a certain experience, and their mind is able to conjure a version of that experience, in turn. In Olson’s study, it wasn’t a matter of microdosing effects not being real, but that those effects may be caused by environment, or patient expectation. As he puts it: “It can be true at the same time that microdosing can have positive effects on people, and that those effects are perhaps almost entirely placebo.”

This itself raises a sticky question about MindBio’s study. How could a placebo group, who thinks they’re taking LSD, perform better than an active control group, members of which both think they’re taking LSD and are actually taking it? The answer comes from the design of the study itself.

Using what’s called a “double-dummy” design, MindBio’s researchers informed patients that they’d either be receiving LSD, a caffeine pill, or a dose of methylphenidate, better known as Ritalin or Concerta. (No patients were actually administered the methylphenidate.) This means that patient expectation was lowered, as they could ascribe any perceived effects to either the LSD or either of the active placebos. Patients taking LSD microdoses may well have believed they were merely on a stimulant. All patients followed an adaptation of the “Fadiman protocol,” a popular microdosing programme that sees patients taking a small dose of the given drug once every three days.

Jim Fadiman, the veteran psychedelic researcher after whom the protocol is named, rejects MindBio’s conclusions, and trial design, out of hand. Because, Fadiman believes, patients were given the active caffeine placebo, their reported benefits may well be attributable not to a pure placebo effect, but to the actual psychoactive properties of that drug.

“Double-dummy is a remarkably apt term,” Fadiman, 86, sneers. “What I know is that if you take enough caffeine, you will not be depressed!”

Fadiman points to MindBio’s earlier, Phase 2A study, recently published in the journal Neuropharmacology, which drew markedly different conclusions. It was a non-blinded, so-called “open label” study, meaning patients knew definitely that they were being microdosed with LSD. This study found that MADRS scores decreased by 59.5 percent, with effects lasting as long as six months. It also found improvements in stress, rumination, anxiety, and patient quality of life. Fadiman says that this reportage is more consistent with his own research on microdosing. “Their prior study did wonderfully with LSD,” Fadiman says. “I have collected literally hundreds of real world reports over the years that validate those findings.”

MindBio’s Hanka stands by the science. “We are bewildered at the significant difference between the open label Phase 2A trial results and the Phase 2B trial results,” he says. “But that is the nature of good science—a properly controlled trial will get a proper 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 these lengths to control and blind a trial.”

Despite these findings, some microdosing true believers don’t seem especially shaken. In 2017, writer Ayelet Waldman (best known as the author of the Mommy-Track Mysteries series of novels that follow the adventures of stay-at-home-mom-cum-sleuth Juliet Applebaum) published A Really Good Day, a diaristic account of her own self-experiments using microdosing to treat an intractable mood disorder. She tells WIRED she’s not especially bothered by the implication that her positive shifts in mood may have merely been placebo. “In my book I took very seriously the possibility that what I was experiencing was the mother of all placebo effects,” Waldman says. “I wrote about this a number of times in various chapters and decided in the end it didn’t matter. What mattered was that I felt better.”

Perhaps that’s true enough. If the effects are measurable, and repeatable, then it should hardly matter if they’re attributable to a sub-perceptual dose of lysergic acid, or to the (perhaps equally profound) mysteries of the placebo. Still, one cannot help but wonder why anyone looking to use LSD to aid severe clinical depression would bother assuming the legal risk of procuring and consuming a drug still classified under Schedule I by the US Drug Enforcement Administration.

Certainly, for his part, Justin Hanka seems content to pivot MindBio’s research into a new field. His next project is “Booze A.I.”: a smartphone app that uses artificial intelligence to scan the human voice for relevant biomarkers that determine blood alcohol concentration. He’s leaving microdosing in the rearview. “I put millions of dollars into this myself,” he says. “Had I known six years ago what I know about psychedelics, I probably wouldn’t have ventured into the microdosing field.”

This story originally appeared on wired.com.