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Journal Club: "Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study"

Updated: Feb 24, 2023


Recently there has been quite a bit of discourse on the efficacy and utility of microdosing. Microdosing typically refers to a paradigm in which an individual consumes a relatively low dose of a psychoactive substance in a routine scheduled frequently. For example, someone might consume microdoses of LSD for two consecutive days, then take a break for two days, and then resume taking the microdoses. Ample anecdotal evidence points towards increases in creativity, cognitive ability, and various measures of peace. Despite this, there is little scientific evidence for any of these claims. That’s why when the article titled “Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study” was published in Nature on August 2nd, everyone was eager to read the findings. So, let's break down the paper here together!


Introduction

The authors state that 22% of psychedelics users actually use psychedelics in the context of microdosing, which is quite a hefty number underscoring the topical nature of this paper. The authors mention that this is done to “improve mood, cognitive function, and mental concentration, as well as to enhance creativity and problem-solving skills”. Despite this, the effects of microdosing on these various behavioral domains have not been adequately investigated. An important thing mentioned here also is that common psilocybin mushroom microdoses range within 0.1g to 0.5g of dried mushroom, and while 0.5 g seems like a normal recreational dose, they note their sample only contained about 640.2 μg/g of psilocybin which is on the much lower end of a microdose. The authors state that they set out to “investigate the effects of low doses of psilocybin on behavior, creativity, perception, cognition and the underlying brain activity (measured with EEG)”.


Methods

So what about participants? There was a total of 34 participants with about half having had previous psychedelic experience. These past experiences can bias the participants in these trials, because they most likely have a positive outlook and positive expectation for the current trial. This can lead to less reported challenging experiences with these drugs.


A big thing about this study is it's a randomized, double-blind placebo-controlled study. Meaning neither the researchers nor the participants knew which drug was taken- this was monitored by a third party- and that participants could also receive a placebo, in this case a non-psychedelic mushroom. The study also uses a 'within subject’s design', meaning comparisons were done using data from within the same participant. This can happen due to the crossover design, in which participants got placebo and psilocybin in different parts of the study.


Figure 1 goes through the study design and how there are only two dosing days per week, with the study lasting only two weeks with either placebo or psilocybin corresponding to one of the weeks. The time scale of these experiments is of note because microdosing is typically long-term administration of low doses, whereas this design is more directly testing the acute effects of two very low doses.


So what are they testing?

  • Changes in electrical activity at the level of the scalp via EEG recordings

  • Intensity of the psychedelic experience via VAS questionnaire

  • Divergent and convergent thinking using three different behavioral tasks

  • Anixety, suggestibility, stress, well-being, empathy, cognitive flexibility and more using a battery of 12 questionnaires

  • Auditory stimulation responses

  • Physical activity measured via FitBit


VAS Results

Remember, the VAS is a measure of the acute intensity of the experience. These results describe a phenomenon called "unblinding" where individuals were able to identify whether or not they got the psilocybin versus placebo. Interestingly, individuals taking the active drug are significantly different from the placebo group on dosing days only when unblinded- we do not see this significant difference in the blinded group.


This result is suggests that the placebo effect or some anticipatory effect plays a large role in the subjective experience of psilocybin microdoses.


The authors mention that 75% of participants correctly unblinded the experimental condition themselves mentioning that “information on the previous experimental condition facilitated the identification of the current condition”. This carry over in this cross-over design is highly troublesome and usually in cases of carry over, data from the second half becomes unusable. Despite this, the authors continue on with their various analysis.


Self-reported Scale and Questionnaire Results

Authors report no significant differences between the placebo and experimental groups. This suggests that these microdoses were not increasing any of these measures as subjectively reported by the participants. This is peculiar considering we see such a large placebo effect in the VAS scored where in these questionnaires there seems to be no difference between groups, blinded or unblinded.


Authors also report no significant differences between the placebo and experimental groups in measures of perception and cognition, except for a significant increase in the time required for part A of the TMT task, which measures impairments in responding to completing a task.


EEG and Local-Global Event Related Potentials

They show us spectral density plots, where we see the averaged spectra for each group. There is a significant difference in the theta band- specifically decreased theta power in the psilocybin group in the eyes closed condition. Theta rhythm is an oscillatory rhythm naturally occurring in the hippocampus and is associated with cognition, spatial navigation, and memory. There seems to be no significant difference in signal complexity as measured by Lempel-ziv complexity or in event related potentials from the auditory tasks. Similarly, there is no significant difference in various measures of physical activity between the placebo and experimental groups.


So what is the take away?

With this we conclude that there is a strong placebo affect on the intensity of the experience and that the acute effects of two low doses of psilocybin affect a decrease in theta rhythm as seen through EEG. But the results of the study are majorly weakened by the unblinding of participants. Other things that should be addressed in future studies include adding more participants to power study, including people who are naive to psychedelics. Using consistent doses and weight-adjusted doses could provide a more accurate picture. And considering that sometimes microdosing is longer in anecdotal practices, we need future studies to determine long-term effects on mood/overall health and wellbeing.


Although its exciting to have a study aimed towards uncovering more in the realm of microdosing- there is much to be improved on in terms of study design and standardization of dosing and paradigms.



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