Coffee Beats Microdosing for Depression? New Study Says Yes

For roughly a decade, the practice of microdosing – taking sub-perceptual amounts of psychedelic drugs like psilocybin or LSD – has captivated the public imagination, particularly within Silicon Valley’s biohacking circles. The promise? Gentle boosts in mood, energy, and focus, a subtle enhancement of well-being without the full-blown hallucinatory experience. Anecdotal evidence painted microdosing as a versatile tool for everything from increased creativity to improved libido, and most importantly, a potential treatment for depression. But a recent, rigorous study casts significant doubt on these claims, suggesting that a simple cup of coffee might be more effective in alleviating symptoms of major depressive disorder.

MindBio Therapeutics’ Phase 2B Trial: A Reality Check

Melbourne-based biopharma company MindBio Therapeutics conducted a Phase 2B clinical trial involving 89 adult patients diagnosed with major depressive disorder. The study investigated the effects of microdosing LSD, administering doses ranging from 4 to 20μg (micrograms) – well below the threshold for hallucinogenic effects – over an eight-week period. The primary metric for evaluating efficacy was the Montgomery-Åsberg Depression Rating Scale (MADRS), a widely accepted tool for clinical depression assessment.

While the full study hasn’t yet been published in a peer-reviewed journal, CEO Justin Hanka shared the topline results on LinkedIn, framing it as a crucial step in microdosing research. He described it as “the most vigorous placebo-controlled trial ever performed in microdosing.” However, the results were surprising: patients receiving LSD microdoses actually exhibited worse MADRS scores compared to those in the placebo group. This suggests the microdosing had a negative, or at best, neutral effect on clinical depression symptoms.

The Power of the Placebo – and Caffeine

The placebo wasn’t a simple sugar pill. MindBio employed an “active placebo” – a caffeine pill – to account for the expectation of psychoactive effects common in psychedelic trials. This design revealed a striking conclusion: a moderate dose of caffeine may be more beneficial in treating major depressive disorder than a tiny dose of LSD. A potentially sobering realization for those hoping for a psychedelic solution to depression.

“It’s probably a nail in the coffin of using microdosing to treat clinical depression,” Hanka stated. “It probably improves the way depressed people feel—just not enough to be clinically significant or statistically meaningful.” This admission signals a potential shift away from microdosing as a primary therapeutic target for MindBio.

Skepticism and the Placebo Effect

These findings align with the long-held skepticism of some researchers who believe the perceived benefits of microdosing are largely attributable to the placebo effect. The power of expectation and belief in treatment can significantly influence outcomes, even in the absence of a pharmacologically active substance.

“Tripping on Nothing”: McGill University’s Experiment

In 2020, Jay A. Olson, then a PhD candidate at McGill University, conducted a compelling experiment demonstrating the potency of the placebo effect. He administered a placebo to 33 participants, falsely informing them it was a psilocybin-like drug. Participants were led to believe there was no placebo group, and researchers staged a psychedelic-like environment with trippy lighting and visual stimuli to enhance the expectation of a drug experience.

The results, published in the paper “Tripping on Nothing,” revealed that a majority of participants reported experiencing effects consistent with a psychedelic drug – despite receiving only a placebo. “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, explained to GearTech. “Placebo effects were stronger than what you would get from microdosing.”

Olson emphasizes that the public often underestimates the strength and validity of the placebo effect. He also notes that the hype surrounding psychedelic drugs can amplify this effect, as patients may enter trials expecting a specific experience and their minds subsequently conjure it.

Study Design and the “Double-Dummy” Dilemma

MindBio’s study utilized a “double-dummy” design, informing patients they would receive either LSD, a caffeine pill, or methylphenidate (Ritalin). No patients actually received methylphenidate. This approach aimed to minimize expectation bias by allowing patients to attribute any perceived effects to either the LSD or the active placebos. However, this design also introduced a potential complication.

How could a placebo group, believing they were receiving LSD, perform better than an active control group actually receiving LSD? The answer lies in the potential for the caffeine placebo to exert its own psychoactive effects. Jim Fadiman, a veteran psychedelic researcher and proponent of the “Fadiman protocol” for microdosing, argues that the caffeine placebo may have been responsible for the observed benefits in the placebo group.

Fadiman’s Critique of the MindBio Study

Fadiman dismisses MindBio’s conclusions and study design, stating, “What I know is that if you take enough caffeine, you will not be depressed!” He points to MindBio’s earlier, Phase 2A study – an open-label study where patients knew they were receiving LSD – which showed a 59.5% decrease in MADRS scores. Fadiman believes this earlier study is more consistent with his own research and anecdotal reports on microdosing.

MindBio’s Response and Future Directions

MindBio’s Hanka stands by the scientific rigor of the Phase 2B trial, emphasizing its triple-blind, double-dummy, active placebo-controlled design. He acknowledges the discrepancy between the Phase 2A and Phase 2B results but maintains that a properly controlled trial yields a more accurate result.

Despite these findings, some microdosing enthusiasts remain unfazed. Ayelet Waldman, author of A Really Good Day, a memoir detailing her self-experimentation with microdosing, isn’t particularly concerned about the possibility that her positive experiences were due to the placebo effect. “In my book I took very seriously the possibility that what I was experiencing was the mother of all placebo effects,” Waldman told GearTech. “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.”

The Bottom Line: Effectiveness vs. Perception

If measurable and repeatable effects are observed, perhaps the underlying mechanism – whether a sub-perceptual dose of lysergic acid or the profound power of the placebo – is less important than the positive outcome. However, the question remains: why would someone seeking treatment for severe clinical depression risk the legal ramifications of procuring and consuming an illegal substance when a legal and readily available alternative like caffeine might be more effective?

MindBio’s Pivot: From Psychedelics to AI

Justin Hanka appears to be shifting MindBio’s focus. His next project, “Booze A.I.,” is a smartphone app utilizing artificial intelligence to analyze vocal biomarkers for blood alcohol concentration. He’s leaving the field of microdosing behind. “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 research highlights the importance of rigorous scientific investigation in the realm of psychedelic medicine. While the potential of psychedelics for treating mental health conditions remains a promising area of exploration, the current evidence suggests that microdosing for depression may not be the panacea it was once believed to be. For now, a good cup of coffee might be a more reliable – and legal – option for boosting mood and energy.