A recent study* led by Balazs Szigeti at Imperial College London has made headlines for suggesting that microdosing may be no more than a placebo effect. This study used a groundbreaking self-blinding approach for creating a placebo-controlled setup, relying on 200 participants to prepare and self-blind their own microdoses and placebos at home. One of the major benefit of this method was that it allowed researchers to navigate around the legal and funding challenges typically faced when studying the effects of microdosing psychedelics.
Until recently, the largest bodies of evidence concerning the potential benefits of microdosing fall in the category of anecdotal evidence: the collection of personal reports from individuals around the globe, who have microdosed on their own initiative. The most notable example is Dr. James Fadiman’s analysis of 2000 microdosing reports. His reports reveal substantial anecdotal evidence that microdosing leads to mental, emotional, and physical improvements. In addition, between 2018-2021, survey-based research by Toby Lea, Rotem Petranker, Thomas Anderson, and Vince Polito also demonstrates that the perceived benefits of microdosing are vast.
We humbly acknowledge that so far, there is minimal clinical evidence supporting these reports and the efficacy of microdosing. Additionally, we recognize that the placebo effect may be one of the factors that contributes to the microdosing experience. Still, there is more to the story of microdosing, the placebo effect, and the research.
So, what exactly is the placebo effect?
A placebo is a substance, often inactive (such as vitamin C, sugar pill, or saline injection), used in clinical research as a control to test the efficacy of a drug or medical treatment. The placebo effect refers to a phenomenon in which symptoms of a test subject improve despite being given a placebo.
Clinical trials utilizing double-blind, placebo-controlled procedures are considered one of the most rigorous forms of scientific inquiry into the efficacy of drugs. This method involves masking the identities of a placebo and the test substance or treatment from both the researchers and subjects—therefore called a double-blind—to minimize expectation bias.
When researchers observe a placebo effect in clinical trials, it has historically been considered a failure. However, more and more researchers agree that if a test substance shows improved measures, even if they also observe a placebo effect, it doesn’t deny the efficacy of the test substance. Instead, when the placebo effect is present, it provides evidence of the natural healing abilities of the human body. Therefore, the more important question should be whether the test drug or treatment is more effective than an observed placebo effect.
Still, we want to highlight that the placebo effect is a complex experience, and little is understood about how it works. If you’d like more information on the history and current understanding of the placebo effect, listen to this highly recommended podcast How the Placebo Effect Works by Stuff You Should Know.
Why placebo-controlled microdosing studies face challenges
The intrinsic mind-altering nature of psychedelics makes it challenging to blind participants and researchers from a placebo. This is demonstrated by the Good Friday Experiment, a study from 1962 led by Walter Pahnke at Harvard University. This study sought to investigate psilocybin’s potential to induce mystical experiences and tested it against an active placebo. The study researchers selected niacin as the active placebo because of its ability to produce mildly altered sensations; hoping that it would blind all parties to which substance each participant was given.
However, the mind-altering qualities of psilocybin are usually very prevailing, and after the psilocybin had taken effect, it was clear to both subjects and researchers who had received the placebo. Unfortunately, this led to a “broken blind” during the experiment, which caused bias in the study results.
The principle idea of microdosing is that it should be sub-hallucinogenic, meaning it doesn’t produce the typical mind-altering states attributed to high doses of psychedelic substances. However, while microdosing is sub-hallucinogenic, it’s not sub-perceptual; many microdosers report increased awareness, sensations, and connection to their bodies. From our experience coaching hundreds of microdosers, we have also noticed that these effects increase when individuals microdose repeatedly or for an extended amount of time.
This subtle yet increasing effect of microdosing causes two big problems for researchers; firstly, choosing a suitable placebo for double-blind trials is challenging, and secondly, most test subjects in published studies to date have prior experience with microdosing. As a result, these subjects are more likely to identify if they took a placebo or a psychedelic substance, leading to strong expectation bias in study results.
The legal landscape provides additional challenges
In most countries, including the United States and the UK, substances commonly used for microdosing are listed as Schedule 1 drugs—meaning the government deems them to have no accepted medical use and a high potential for abuse. As a result, receiving approval from ethics commissions for research involving administering subjects to these types of substances, no matter how small the dose, is next to impossible.
To navigate around these restrictions, most microdosing studies—including the one of Imperial College London—have to lean on methods in which test subjects provide their own substance and perform assessments outside a lab setting. This is problematic because researchers can’t possibly verify which substance and in what dose subjects are using.
An ingenious self-blinding approach attempts to overcome research challenges
The clever self-blinding approach developed in the study by Imperial College London allowed researchers to overcome two of the largest hurdles in psychedelic research—legal and funding barriers. The self-blinding method required the participants to prepare their own psychedelic substances and placebos and place them into blank envelopes. They labelled these envelopes with QR codes from the study website and shuffled to conceal the contents. During the experiment, participants were then instructed which envelopes to choose each day.
Researchers observed small yet statistically significant improvements in microdosers for measures including well-being, mindfulness, life satisfaction, paranoia, and neuroticism. Improvements in mindfulness and paranoia were also observed when participants were on a placebo. Ultimately, however, the measured benefits greater than placebo were small, leading the researchers to conclude that microdosing LSD produced effects that weren’t markedly distinguishable from a placebo.
While the self-blinding method provides a groundbreaking alternative to a clinical double-blind, placebo-controlled trial, it continues to face the typical limitations related to microdosing research:
- Like most studies to date, participants were responsible for sourcing their own substance and preparing their own microdoses, eliminating the possibility of verifying the dose or substance consumed.
- Furthermore, participants had prior experience with microdosing, creating expectation bias that may not be present in people who have never microdosed.
- Finally, while accounted for in the final analysis, 72 percent of the participants were able to identify when they were on an active microdose, effectively “breaking the blind.”
We applaud the ingenuity of the study’s self-blinding approach. Still, while the method is groundbreaking, the small scale of the results and the limitations mentioned above make it challenging to form concrete conclusions from the study results. Above all else, this continues to highlight the many struggles in looking at microdosing under a rigorous scientific lens.
Is there evidence of microdosing being more than a placebo?
As of the publishing date of this article, the only example of a double-blind, placebo-controlled microdosing study is an LSD dose-finding study from a recent collaboration between Beckley Foundation and Maastricht University in The Netherlands. This study intended to investigate the smallest dose of LSD needed to affect mood and cognition. Twenty-four subjects received a placebo, as well as 5, 10, and 20 micrograms of LSD before being assessed on mood and cognition in a lab setting.
Highlights from this study include evidence that microdoses of LSD increased pain tolerance in subjects and may provide an alternative to conventional pain management techniques. Additionally, increased levels of BDNF, a protein involved in memory and learning, were measured in subjects’ blood levels at doses as low as 5 micrograms of LSD.
At doses of 20 micrograms, researchers also noted improvements more significant than placebo in positive mood markers, friendliness, and focus. On the flip side, it’s important to note that many participants also experienced increased levels of anxiety and confusion greater than placebo, illustrating that microdosing can induce some unpleasant effects next to reported benefits.
These measured physiological and neurological effects provide the first clinically rigorous evidence that the effects of a psychedelic substance in microdoses are beyond that of “a placebo effect.”
The future of microdosing research
It’s apparent that future microdosing research will require a more intelligent design, preferably in the form of long-term studies that monitor psychedelic naïve subjects in a natural setting taking microdoses that are correctly measured and consistent in quality and potency. Clinical double-blind trials comparing microdosing psychedelics to conventional treatments and therapies to medication are also on the wish list.
Nevertheless, given the growing and widespread interest in the healing potential of psychedelics—both macro-and microdoses—we hope legal and funding barriers diminished to make way for more rigorous study. Double-blind clinical trials comparing microdosing psychedelics to conventional treatments, therapies, and medications for depression (following the psilocybin therapy vs. Escitalopram trial), ADHD/ADD, anxiety, and other challenging conditions are high on the wish list.
What microdosing studies are on the horizon?
Despite the many hurdles, several exciting microdosing studies are on the horizon, including a second version of the Imperial College London self-blinding study through their Mydelica app. Notably, this will be the first study to examine the long-term effects of microdosing over a 3-5 months period. In addition, a Dutch team led by Michiel van Elk will conduct a follow-up trial to investigate the role of expectations, prior experience with psychedelics (micro-and macrodoses), prior mystical experiences, worldview, spirituality, and other factors on the psychedelic experience of subjects (read the announcement here).
Furthermore, a follow-up study investigating the potential pain-killing properties of LSD by the Beckley/Maastricht team is currently underway. Beckley Foundation has also recently announced a study investigating the impact of microdosing psilocybin in people suffering from Covid-19 related anxiety. Finally, Maastricht University/Mindmed is organizing a microdosing study with cluster headache patients (read the press release here).
Microdosing is a powerful tool for transformation
While the Beckley/Maastricht study provides the first scientific evidence of physiological and neurological effects beyond a placebo effect, science has yet to provide significant evidence for what citizen science has been demonstrating; namely that microdosing offers benefits more significant than a placebo experience. We feel that it would be regrettable to discount the thousands of humans that have reported improvements to their health, well-being, and quality of life due to microdosing.
Finally, rather than viewing it in a negative light, we honor the placebo effect as evidence of the incredible self-healing power of the human body and mind. While this phenomenon is likely a factor that contributes to the microdosing experience, we appreciate that the power of the mind—especially when combined with a mind-expanding psychedelic substance—can be an exceptional tool for personal transformation.
*Microdosing Institute collaborated with the research team at Imperial College London on the setup of the self-blinding study.
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