Microdosing With Psilocybin Mushrooms: A Double-Blind Placebo-Controlled Study

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According to a randomized trial, throwing spaghetti against the wall to determine whether it's cooked sufficiently doesn't effectively identify the ideal outcome. Under, over, and perfectly cooked strands all adhere similarly. So, I'll abandon that metaphor, although it was tempting to use it in regard to a new article on microdosing of psilocybin, which examined no less than 25 outcomes. Nevertheless, one very clear bottom line emerges from this study, and we'll get there. It's really an intriguing result.

Hi! Jim Phelps here for the Psychopharmacology Institute. At minimum, this article presents a useful review of the literature on microdosing of psilocybin. We could perhaps start by asking why are people doing this, but then I suppose you could ask why people ever fermented wheat to make beer or grapes to make wine. Skipping over that existential question, let's have a look at the outcome measures in this study because that will give you an idea of what some people might expect microdosing of psilocybin to do. For reasons we'll see in a moment, there was no primary outcome in this study. Instead, we find an array of 25 measures including EEG; Fitbit activity monitoring; the Big Five personality inventory; computer-based testing of routine psychological variables, including attention, inhibition, and visual perception; and more. The study used a crossover design. Participants received a microdose of psilocybin on Wednesday and Friday in the active dose week or placebo on those days in the control week. The weeks were randomly assigned, 50% placebo first, 50% psilocybin first.

Despite the myriad outcomes they measured, they did find a clear bottom line, I think. Here's the quote: "The reported acute effects were significantly more intense for the active dose compared to the placebo but only for the participants who correctly identified their experimental condition." Right. So, the placebo capsule, it was identical. It too contained 0.5 mg of dried mushroom, just not the psychoactive kind. But participants were able to guess which was the psilocybin week 75% of the time, and that's what drove their responses. If they guessed they'd had psilocybin, not placebo, they had all sorts of positive changes compared with their responses when they thought, mostly correctly, that they'd received a placebo. Even their EEGs were different.

Well, here's a further clue about this result. The authors cite 9 open-label studies that suggest that microdosing of psilocybin can improve mood, well-being, creativity, and cognition, but they point out that users make up a self-selected sample with optimistic expectations about the outcome of the practice. This positivity bias makes for a good placebo response, so those open studies with no control group really don't tell us much but that positivity bias makes for an even better response if participants think they've received an active dose in a controlled study. The breadth of these prior uncontrolled observations is the reason why the authors of this study elected to use so many outcome measures. Microdosing had basically not been studied rigorously, so all of the previous uncontrolled claims, even the EEG changes, needed to be reexamined.

In summary, this is just 1 study and it goes against multiple previous observations, so we should interpret it with some caution. But I think it sheds important light on all psilocybin research. Positive expectations could be driving a lot of the apparent efficacy, especially if blinding is not well preserved. Participants who know when they received psilocybin and strongly expect it to be beneficial will likely get better outcomes than those who hoped to receive it but suspect they've taken a placebo, which brings us to the New England Journal paper on psilocybin vs escitalopram for major depression. This was tackled in a previous Quick Take, linked here. It too is subject to this positivity bias because there was no control group. Participants knew that they were either going to get an antidepressant that ought to help their depression or psilocybin, which, since they volunteered for this study, they likely thought ought to help as well. Might psilocybin positivity bias have been enough to equal the benefits of escitalopram? Well, your answer probably depends heavily on your belief in the efficacy of escitalopram.

For more on this, the microdosing paper's introduction provides a useful summary of previous anecdotal and uncontrolled studies. And as for that randomized trial of throwing spaghetti against the wall, well, the conditions were not tightly specified in the video, so you might have to replicate this trial yourself.

The use of low sub-perceptual doses of psychedelics ("microdosing") has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies severely limits our knowledge of microdosing and its effects. Moreover, research conducted in standard laboratory settings could fail to capture the motivation of individuals engaged or planning to engage in microdosing protocols, thus underestimating the likelihood of positive effects on creativity and cognitive function. We recruited 34 individuals starting to microdose with psilocybin mushrooms (Psilocybe cubensis), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled experimental design, we investigated the acute and short-term effects of 0.5 g of dried mushrooms on subjective experience, behavior, creativity (divergent and convergent thinking), perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, but only for participants who correctly identified their experimental condition. These changes were accompanied by reduced EEG power in the theta band, together with preserved levels of Lempel-Ziv broadband signal complexity. For all other measurements there was no effect of microdosing except for few small changes towards cognitive impairment. According to our findings, low doses of psilocybin mushrooms can result in noticeable subjective effects and altered EEG rhythms, but without evidence to support enhanced well-being, creativity and cognitive function. We conclude that expectation underlies at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.

Reference

Cavanna, F., Muller, S., de la Fuente, L. A., Zamberlan, F., Palmucci, M., Janeckova, L., ... & Tagliazucchi, E. (2022). Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study. Translational Psychiatry, 12(1), 1-11.