Microdosing and the Placebo Effect with Balázs Szigeti, PhD

Psychedelic Medicine Podcast with Dr. Lynn Marie Morski

In this episode of the Psychedelic Medicine Podcast, Balázs Szigeti, PhD, joins to discuss his research on the intersection of microdosing psychedelics and the placebo effect. Dr. Szigeti studied physics at Imperial College, after which he earned a PhD in computational neuroscience from the University of Edinburgh. He has worked as a biomedical software engineer at the Icahn Genomics Institute and he has conducted the largest placebo-controlled study on psychedelics to date. In his research, Dr. Szigeti uses novel statistical and experimental techniques to explore the intersection of psychedelics and placebo effects.

Dr. Szigeti begins this conversation by discussing the design of his placebo-controlled microdosing study, “Self-blinding citizen science to explore psychedelic microdosing” which appeared in the journal eLife in March 2021. For this study, Dr. Szigeti and his team employed citizen science to collect placebo-controlled observational data from participants, allowing this experiment to take place outside of a clinical environment. Participants self-blinded by preparing identical psychedelic and placebo microdose capsules and data was submitted using QR codes so that the researchers were knew whether the participant was in the psychedelic group or the control group, while the participants themselves remained in the dark.

The results from this study showed a statistically significant improvement of wellbeing among both the microdose and placebo groups, with no statistical significant difference between the two groups in terms of any of the outcomes. Dr. Szigeti talks about the media reception of his research, which tended to present the findings as suggesting microdosing is ineffective since there was no difference between the two groups. However, Dr. Szigeti has a different takeaway. He suggests that the practice of microdosing can indeed lead to improved wellness as the study showed—the takeaway is simply that this effect is harder to distinguish from a placebo than originally anticipated. He emphasizes the very real medical power of this placebo effect, and discusses how triggering one’s own placebo effect either through microdosing or some other practice can be transformative.

However, beyond what the data may suggest about the impact of microdosing psychedelics, Dr. Szigeti emphasizes the broader takeaways from his study, which bring into question the efficacy of placebo-controlled studies as a gold-standard in the context of psychedelic trials. Because psychedelics cause notable shifts in perception, trial participants will quickly become aware whether they are in placebo or psychedelic groups, particularly in the case of trials exploring doses beyond the microdose range. This causes an immediate unblinding effect, and makes control groups less useful than in other contexts where a participant does not find out which group they were a part of until the trial’s conclusion. Dr. Szigeti affirms the methodology of placebo-controlled trials as an essential tool for researchers which deserves its reputation for providing high-quality evidence, but he urges the field of psychedelic studies to pay closer attention to questions of methodology, as there may be yet undiscovered modes of scientific investigation which would be better-suited to psychedelic trials.

Dr. Szigeti is currently working on a follow-up blinded study on microdosing which he hopes will address some of the shortcomings of the original investigation. In particular, he mentioned that the participants in the original study had high levels of well-being already at the start of the trial, so improvements may have been less significant than in a population with a lower level of well-being to start. As such, he and his team hope to recruit a more diverse sample in this upcoming trial to further explore the extent of both placebo and microdosing impacts on wellness. Information for the upcoming study can be found at the website: https://selfblinding-microdose.org/

In this episode:

• How Dr. Szigeti set up his self-blinded placebo-controlled study of microdosing outside of a clinical environment
• What is “citizen science” and how this differs from other methodologies
• The issue of tolerance in microdosing and how this may differ between LSD and psilocybin
• How Dr. Szigeti uses statistical analysis to further interpret data where participants realize which group of the study they are in

Quotes:

“The results of this microdose trial were mixed because you can make an argument that this change over time is the more important outcome and that was statistically significant, but the comparison of the magnitude of change in the placebo group versus the magnitude of change in the microdose group, that was not significant anymore. It was not significant on any of the scales, I should add.” [14:45]

“Nobody ever checks whether the placebo control was really working as intended, which is just like—I don’t know how it could have happened. There is such a big emphasis on the methodological superiority of placebo-controlled trials and then nobody is checking whether its really working or not.” [21:09]

“With psychedelics this issue [of placebo groups] is going to come to the forefront because, yes with microdosing there is some wiggle room in people recognizing their treatment, but when it comes to 200μg of LDS versus placebo, there is zero uncertainty. Everybody will recognize when you’re in the active placebo treatment.” [28:13]

Links:

Upcoming trial website

Dr. Szigeti’s study: “Self-blinding citizen science to explore psychedelic microdosing"

Dr. Szigeti’s recent article: “On the fallibility of placebo control and how to address it: a case study in psychedelic microdosing"

Dr. Szigeti on Twitter

Psychedelic Medicine Association

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