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

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.

Fig. 1. Experimental design and acute effects.

a Neither the subjects nor the investigators knew the content of the capsules (active dose or placebo) until the last steps of the data analysis stage. Each condition (active dose or placebo) corresponded to 1 week of the experiment, separated by 1 week. b Measurements conducted during each day of the week. c Timelines for the measurements performed during dosing days (Fridays and Wednesdays). d VAS total score (mean ± SEM) per condition, from Wednesday (first dosing day of the week) to Saturday (last day of the experiment), obtained from the “unblinded” (left) and “blinded” (right) subsets of the data. **p < 0.05, Bonferroni corrected (n = 4). e VAS scores per item, day of the experiment and experimental condition. The bottom matrix contains the difference between the active dose and the placebo. *p < 0.05, uncorrected for multiple comparisons.

Fig. 2. Results of the self-reported scales and questionnaires and creativity tests.

a Boxplots showing the scores of all questionnaires for the active dose and placebo. b WK originality, fluency and elaboration. c RAT total score and time (in minutes). d AUT fluency, originality, elaboration and number of repeated answers. No significant differences were found at p < 0.05, uncorrected. STAI State Trait Anxiety Inventory, PSS Perceived Stress Scale, PANAS Positive and Negative Affect Scale, TAS Tellegen Absorption Scale, BIEPS Well-being Scale, MWQ Mind Wandering Questionnaire, FSS Flow State Scale, CPS Creative Personality Scale, TECA Cognitive-Affective Empathy Test, CFS Cognitive Flexibility Scale, RAT Remote Associates Test, AUT Alternative Uses Task, WK Wallach–Kogan Test.

Fig. 3. Results of tasks used to assess perception and cognition.

The uppermost panel of each column contains a diagram of the task. a Backward masking. A target (number 7) is flashed and then masked; the time elapsed between target and mask is the stimulus onset asynchrony (SOA). Participants were queried for objective (Q1, comparison with number 5) and subjective (Q2) visibility. The panels below show the objective and subjective accuracy vs. SOA. b Binocular rivalry. Two different gratings were presented to each eye, resulting in alternation of the perceived grating, with the duration of the percept before switching being given by ∆T (dominance time). The panels below show the histograms of ∆T values and a comparison of <∆T> between conditions. c Attentional blink. A sequence of digits (separated by 100 ms) contains two target numbers (T1, T2), participants were required to identify both targets (Q1, Q2). Below, the rate of correct answers to Q1 and Q2. The visibility of the second target for lag 300 ms was reduced in psilocybin vs. placebo (p < 0.05, uncorrected). d Go / No Go. A mask is presented, followed by instructions to press a key (“Go”) or pass (“No Go”), registering accuracy and response times (RT). These two variables are shown in the panels below. Response times were slower for psilocybin vs. placebo (*p < 0.05, uncorrected). e Stroop. Participants were presented with the name of a color written in either the same (congruent) or different (incongruent) color, and asked to identify the color of the word (Q). The next two panels show the accuracy and the RT. f The participants were asked to join with lines dots with numbers (part A) or with alternating numbers and letters (part B), in both cases in increasing order. The remaining two panels show the rate of errors for each part of the task.

Fig. 4. Results of the resting state EEG analysis.

a LPSD vs. frequency (averaged across all channels) for eyes closed (left) and open (right), both for the placebo and the active dose (mean ± SEM). b Same as in panel A, but binned using the following bands: delta (1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz) and beta (12–20 Hz). c Global Lempel-Ziv complexity computed using the broadband EEG signal, compared between psilocybin and placebo conditions for eyes closed and open. d Topographic distribution of spectral power and Lempel-Ziv complexity for all combinations of active dose, placebo, eyes open and closed. e Results of the Local-Global ERP analysis. Left: global deviant minus local deviant ERPs located at AFz for the the placebo condition. Center: local deviant at AFz for placebo vs. psilocybin. Right: same as in panel C but for the global deviant. All ERP plots show mean ± SEM. The vertical dashed lines coincide with the timing of the last sound in the trial. *p < 0.05 for the comparison between placebo and active dose (corrected for multiple comparisons).

Fig. 5. Results of the physical activity analysis.

a Step count per week day. b Distance traveled per week day. c Resting time per week day. d Total activity time per week day. All plots show mean ± SEM. The small red capsules indicate the dosing days.