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

This double-blind placebo-controlled study (n=34) explored the effects of microdosing psilocybin (0.5g of dried mushrooms) on subjective experience, behaviour, creativity, perception, cognition, and brain activity. In participants who correctly identified their experimental condition, the acute effects were more intense for the active dose compared to placebo and these effects were accompanied by reduced EEG in the theta band. However, in another blow to microdosing, no evidence was found to support enhanced well-being, creativity and cognitive function. It is likely that expectation underlies the positive effects of microdosing.

Abstract

“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.”

Authors: Federico Cavanna, Stephanie Muller, Laura A. de la Fuente, Frederico Zamberlan, Matias Palmucci, Lucie Janeckova, Martin Kuchar, Carla Pallavicini & Enzo Tagliazucchi

Summary

INTRODUCTION

Over the last decade, the use of small doses of psychedelics to enhance mental function has attracted a significant amount of interest from the general public and the scientific community. However, the effects of low doses of psychedelics have not been extensively investigated to date.

Research suggests that serotonergic psychedelics can produce lasting positive changes in behavior, personality and mental health. Furthermore, some individuals microdose psychedelics to self-medicate for cluster headaches, depression and anxiety, among other conditions.

Microdosing of serotonergic psychedelics is an underground practice that lacks standardized procedures that are accepted and replicated by the community. LSD and psilocybin are the most frequently used compounds, and the most popular dosing schedule is one dosing day followed by two days without dosing.

Microdosing with psychedelics is thought to enhance mood, creativity and cognition and reduce anxiety and depression. However, studies with double-blind and placebo-controlled experimental designs have shown that low doses of LSD can have opposite effects to those expected by individuals who microdose.

Several studies have investigated the effects of microdosing LSD on mental health, mood, creativity and cognition, but only one has used electroencephalography to investigate the effects of low doses of LSD on brain activity.

Here, we investigated the effects of low doses of Psilocybe cubensis on behavior, creativity, perception, cognition and the underlying brain activity in individuals who were planning to start a microdosing protocol.

Participants

A total of 34 participants were recruited via word-of-mouth, social media advertising, and workshops on psilocybin mushrooms and microdosing. All participants were fluent in Spanish and successfully completed all instances of the experiment.

This study was conducted at the Universidad Abierta Interamericana (Buenos Aires, Argentina) and approved by the Committee for Research Ethics. Written informed consent was obtained from all participants.

Experimental design

This study used a randomized, double-blind, placebo-controlled, within-subjects design, with 2 weeks of active and placebo conditions. The order of the conditions was randomized by a third party, and blinding was not performed by the participants themselves.

Questionnaires and tasks

Participants completed self-reported scales 2 days before the first dosing day of each condition, and completed a battery of scales on Fridays.

We assessed the following questionnaires: Big Five Inventory, State-Trait Anxiety Inventory, Short Suggestibility Scale, Positive and Negative Affect Schedule, Mind Wandering Scale, Perceived Stress Scale, Tellegen Absorption Scale, Psychological Well-being Scale, Creative Personality Scale, and Cognitive Flexibility Scale.

Participants’ expectation of change in several domains were assessed. The analysis will be reported in a future publication.

We implemented and used several computer-based tasks to determine the impact of psilocybin on perception and cognition.

Resting state EEG recording, preprocessing and analysis

EEG was recorded with a 24-channel research-grade mobile system attached to an elastic electrode cap. Eyes were open and closed for 5 min each, and during an auditory Local-Global paradigm.

EEG data was preprocessed using EEGLAB, and then filtered, notch-filtered, and divided into 2 s epochs. Infomax independent component analysis (ICA) was applied to each individual participant’s data for the identification and removal of remaining recording artifacts.

We estimated broadband signal complexity using the Lempel-Ziv lossless compression algorithm applied to binary time series obtained via Hilbert transform after Z-score conversion.

Local-global auditory stimulation paradigm

The Local-Global paradigm consists of auditory stimulation designed to evaluate responses to violations of local and global regularities. The experiment consisted of 5 brief sounds separated by 100 ms, with the final sound being either identical to the others or different, leading to local standard and local deviant trials.

EEG data was epoched and preprocessed, and then ERPs were constructed for the drug and placebo conditions. A threshold of 10 consecutive samples with p 0.05 was used to determine which channels showed larger amplitudes of the global compared to the local deviants.

Physical activity

Fitbit’s tracking of steps taken during the day was shown to be accurate by direct comparison with estimates based on video recordings.

Statistical analyses

Results from the active dose and placebo conditions were compared using non-parametric paired Wilcoxon signed-rank tests. Chi2 squared tests were applied to determine whether participants were breaking the blind, both after the first and second measurement week.

Frequentist methods were complemented with Bayesian statistics to compare the evidence in favor of the null hypothesis and the alternative hypothesis.

Chemical characterization of samples

Each participant consumed 1 g of dried Psilocybe cubensis for the active condition, separated in two doses of 0.5 g. Three independent sources for the mushrooms were used, and 150 mg of powder was collected for chemical analysis.

Unblinding of the experimental condition

Participants correctly unblinded the experimental condition in 49 of 64 measurement weeks (75%), and in the second measurement week (70%), which could indicate that the previous experimental condition facilitated the identification of the current condition.

Acute effects

We first computed the sum of all items in the VAS and divided this result into two subsets depending on whether the subjects correctly identified the active dose/placebo or failed to do so.

We found that participants’ VAS total scores were significantly higher for the active dose vs. the placebo on both dosing days, but not on days when no dose was consumed. The blinded group showed a trend towards higher VAS total scores, but only for the first dosing day.

Figure 1E shows that while differences were found for some VAS items, these differences did not remain significant after applying the Bonferroni correction for multiple comparisons.

Self-reported scales and questionnaires

We scored the scales and questionnaires in Table 1 and summarized the results in Tables S1 and S2 of the supplementary methods. There were no significant differences between conditions at p 0.05, uncorrected, and the majority of BF10 values were 1/3, indicating moderate evidence in support of the null hypothesis.

Creativity tests

We used the RAT and the WK creativity test to measure convergent and divergent creativity, and normalized the originality, repetitions and elaboration scores by the fluency score to avoid confounds due to different levels of fluency.

The results of this analysis show that there were no significant differences between conditions at p 0.05, uncorrected, and that all BF10 values were below 1/3, favoring the null hypothesis.

Perception and cognition

We investigated whether microdosing with psilocybin mushrooms modulated perception and cognition across several tasks, and found that decreased visibility of the second target with 300 ms lag in the attentional blink task and increased response times in the Stroop task were significant.

Resting state EEG and Local-Global ERPs

Figure 4 presents the results of the resting state EEG analysis. The active dose resulted in decreased power in the theta range (4 to 8 Hz) compared to the placebo (p 0.05, both uncorrected and Bonferroni corrected with n = 4).

We computed the ERPs associated with local and global deviants from the Local-Global auditory stimulation. The central-frontal channel AFz presented the largest effects, and the global deviant presented a more sustained amplitude after 300 ms.

Physical activity

Figure 5 shows the results of the physical activity analysis based on data provided by the Fitbit Charger 4 wristband. We did not find differences between the active dose and placebo conditions.

DISCUSSION

According to our results, 0.5 g of dried mushroom material had no significant impact on creativity, cognition, physical activity levels, or self-reported measures of mental health and well-being.

Although some open-label observational studies have suggested that microdosing can improve mood, well-being, creativity, and cognition, these studies are vulnerable to experimental biases, including confirmation bias and placebo effects.

To date, there have been few human studies of microdosing with psychedelics. Yanakieva and colleagues investigated three low doses of LSD and concluded that the drug affected time interval estimation. Bershad and colleagues investigated three different doses of LSD and found that the highest dose increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other studies have found that low doses of LSD can increase brain-derived neurotrophic factor blood plasma levels. Szigeti et al. and Van Elk et al. found positive effects of microdosing on the primary outcome, however, these results could be explained by breaking of the placebo condition.

Our results add to the series of double-blind placebo-controlled studies questioning the validity of anecdotal evidence for microdosing. In the case of tasks to assess cognitive function, few uncorrected differences were found, which are consistent with previous experiments and with the observation that higher doses negatively affect cognitive functions. We investigated the potential influence of Psilocybe cubensis microdosing on conscious perception using a backward masking paradigm and the Global-Local paradigm.

We found that theta oscillations were reduced during the effects of the psilocybin microdose, but the Lempel-Ziv complexity analysis failed to reveal differences between conditions. Reduced vigilance may be a potential non-pharmacological mechanism underlying the observed changes in theta power.

Daily levels of physical activity are a proxy for the potential effects of microdosing on mood and well-being. However, our results did not reveal an effect of microdosing on this domain.

We studied the effects of microdosing with Psilocybe cubensis mushrooms, but the effective dose could have been higher or lower depending on the source of the mushrooms consumed by each participant. Our samples contained approximately 0.5 mg of psilocybin, which is within the expected values for mushrooms consumed in the context of microdosing. However, other studies used truffles with higher concentrations of psilocybin, which may have caused our samples to lose potency.

This study investigated the effects of two doses per week, but could not assess the cumulative effects of microdosing over periods of several days. Instead, it included time-consuming assessments that required active participation of the research team.

In this study, we focused on the acute effects of microdosing instead of its potential cumulative effects, and we also explored whether the positive effects of microdosing can be selectively enabled or facilitated by certain long-term dosing schedules.

In conclusion, we conducted a controlled study of individuals who were already planning to start their own microdosing protocol. The results indicate that small amounts of dried Psilocybe cubensis mushrooms reliably induced significant subjective effects, but their impact in other domains was negligible.

ACKNOWLEDGEMENTS

This study was funded by the Ministry of Health of the Czech Republic and the Grant Agency of the Czech Republic.

ADDITIONAL INFORMATION

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