Psilocybin microdosing does not affect emotion-related symptoms and processing: A preregistered field and lab-based study

This double-blind placebo-controlled microdosing study (n=75) showed that psilocybin microdoses (0.7g dried truffles, 15mg psilocybin, about 1/10th a high dose) didn’t alter self-awareness or modulated emotion processing. The confirmatory analysis also didn’t find any effects, but an exploratory analysis did show some reduction of depression and stress in only the first block.

Abstract

Background: Microdoses of psychedelics (i.e. a sub-hallucinogenic dose taken every third day) can reduce symptoms of depression, anxiety and stress according to anecdotal reports and observational studies. Research with medium to high doses of psilocybin points towards potential underlying mechanisms, including the modulation of emotion and interoceptive processing.

Aims: In this preregistered study, we investigated whether psilocybin microdoses alter self-reported interoceptive awareness and whether repeated microdosing over 3 weeks modulates emotion processing and reduces symptoms of anxiety and depression.

Methods: We used a double-blind, placebo-controlled, within-subject crossover design. Participants completed the Multidimensional Assessment of Interoceptive Awareness Questionnaire 1½ h after self-administering their second dose (or placebo), and the emotional go/no-go task and the shortened Depression Anxiety Stress Scale 1½ h after self-administering their seventh dose.

Results: Our confirmatory analyses revealed that psilocybin microdosing did not affect emotion processing or symptoms of anxiety and depression compared with placebo. Our exploratory analyses revealed that psilocybin microdosing did not affect self-reported interoceptive awareness, that symptoms of depression and stress were significantly reduced in the first block compared with baseline, that participants broke blind in the second block and that there was no effect of expectations. Further research in a substance-naïve population with clinical range anxiety and depressive symptoms is needed to substantiate the potential beneficial effects of microdosing.”

Authors: Josephine Marschall, George Fejer, Pascal Lempe, Luisa Prochazkova, Martin Kuchar, Katerina Hajikova & Michiel van Elk

Summary

Introduction

Microdosing has become increasingly popular over the last decade, and may have antidepressant and anxiolytic effects. Users with mental health conditions, such as anxiety and obsessive-compulsive disorder, report microdosing as a form of self-medication.

The available evidence regarding the efficacy of microdosing for mental health remains inconsistent. Three of the four existing experimental studies on humans found no evidence for the alleged antidepressant and anxiolytic effects, while the fourth study found positive mood but also anxiety.

Psychedelics reduce symptoms of depression, anxiety and stress.

A self-blinded experimental study found mixed effects of psychedelic microdosing on anxiety and fear extinction, but reduced immobility in the forced swim paradigm and less freezing behaviour following fear extinction training.

This study aimed to further reconcile inconsistent findings by investigating the effect of psilocybin microdosing over the course of 3 weeks, at one consistent dosage, on humans. It found that psilocybin interfered with the processing of negative facial expressions and induced a bias towards positive emotions.

In this study, we assessed the effects of psilocybin microdosing on mood and anxiety symptoms, emotion processing, and interoceptive awareness. We found that psilocybin increased reaction times for negative and neutral go stimuli compared with positive go stimuli, thereby inducing a bias to positive stimuli.

Hypotheses and preregistration

This study was part of a larger collaborative project with researchers of different research interests. It investigated the effect of microdosing psilocybin on awe and art perception, temporal recalibration, creativity and bistable perception.

We preregistered the hypotheses and analysis plans regarding the DASS-21 and emotional go/no-go task, but did not preregister the hypotheses regarding the MAIA.

We preregistered that we would include a between-subjects factor for block-order to test whether effects are related to practice and stronger in the first compared with second block.

Participants

Of all contacted participants, 75 passed the screening questionnaire and signed up for the subsequent lab sessions. They were asked to abstain from psychoactive substances for 2 weeks and to self-administer at least five doses per block.

We recruited 75 participants, 63 completed the baseline measures, 68 completed session 1 (S1), 61 completed session 2 (S2), 59 completed session 3 (S3) and 56 completed session 4 (S4). We excluded participants who did not comply with the behavioural guidelines and who consumed other psychoactive substances during the study.

Procedure

We recruited and screened participants to attend one of three consecutive microdosing workshops, and provided them with written consent, the DASS-21, and psilocybin microdoses. They were instructed to consume one bag of doses over the subsequent 3-week period, then take a 2-week break, and finally consume the second bag.

Participants signed up for four lab sessions, two sessions per block, 1.5 h after self-administering a dose of psilocin. The tests took place within the first 15 min of each session, and 20 min of each session.

Doses

The participants created their own psilocybin microdoses and received a bag containing seven psilocybin capsules. A member of PSN randomly labelled half of the bags with number ‘1’ and the other half with number ‘2’, corresponding to the 3-week block at which the doses in this bag should be consumed.

Instruments and scales

The DASS-21 is a shortened version of the DASS that consists of 21 items pertaining to the severity/frequency of depression, anxiety and stress over the past week. It has strong convergent validity with the original DASS, the Hospital Anxiety and Depression Scale and the Beck Depression Inventory-II.

In the emotional go/no-go task, participants were instructed to respond to a ‘Go’ stimulus as fast as possible and not to respond to a ‘No-Go’ stimulus. The stimuli were pictures of emotional faces.

The task consisted of eight trial blocks of go/no-go emotional face category pairs, in which participants responded by pressing the keyboard space bar. The blocks were randomized across participants and consisted of 30 trials, with 20 go stimuli and 10 no-go stimuli.

Participants were required to respond within 1000 ms to pictures presented on the screen. Their RTs were automatically registered with respect to stimulus-onset when they pressed the space bar during a block.

The MAIA is a 32-item self-report questionnaire used to assess eight constructs of interoceptive body awareness. It is suitable for a repeated-measures design and measures the acute microdose effect on four subscales: noticing, emotional awareness, self-regulation and body listening.

Participants answered questions at the start of each lab session to assess their adherence to the behavioural guidelines, and were also asked to guess their condition after each dosing block.

Data processing and analyses

We split the data per condition (psilocybin/placebo), per session (baseline/first block/second block) and per subscale (depression/anxiety/stress) and analysed them using Bayesian and frequentist repeated-measures analysis of variance (rmANOVA) with condition (psilocybin or placebo) as the within-subject factors.

We analysed 40 participants’ responses to an emotional go/no-go task using a Bayesian and frequentist rmANOVA. We expected more evidence for the alternative hypothesis, reflected in a BF10 > 7 and a Condition / Emotion interaction effect below the p = 0.05 threshold of probability.

We summed the scores per subscale and analysed them separately using Bayesian and frequentist rmANOVA with condition as the within-subject factor.

Participants who complied with the behavioural guidelines could accurately identify their condition in block 1 and block 2.

Doses

A sample of dried psilocybin-containing truffles was analysed to determine the potency, which was 1.5 mg per 0.7 g dried truffle dose administered by our participants.

Descriptive statistics

The Cronbach’s alpha for anxiety was 0.69 in block 1 and 0.49 in block 2, and for depression it was 0.79 in block 1 and 0.79 in block 2.

Confirmatory analyses

The comparison between placebo and psilocybin conditions with depression and anxiety scores as the outcome variables did not reveal an effect of condition, and further subscale-specific analyses did not find an effect of condition on stress scores.

We added block-order to the rmANOVA, but failed to find an interaction between block-order and condition. Bayesian statistics support the null hypothesis that block-order did not affect our experimental manipulation.

The results revealed that there was a main effect of emotion, but no main effect of condition. In addition, the Emotion – Condition interaction analysis did not reveal an effect, suggesting stronger evidence for the null hypothesis that RTs did not differ between condition when emotional valences are taken into account.

Exploratory analyses

A post hoc power analysis indicated that our study only achieved a power of 0.12 to detect a condition with emotion interaction effect, but based on hypotheses that psilocybin would increase RTs for negative stimuli and a 10% increase in RTs for neutral stimuli, a power of 0.96 would be needed.

We used frequentist and Bayesian rmANOVA to compare psilocybin condition scores with placebo scores per subscale, but found no differences. However, there was a significant main effect of block-order for nearly all subscales, including emotional awareness, body listening, self-regulation and noticing.

There were significant differences between conditions in block 1 for emotional awareness and self-regulation, but not for the body listening and noticing subscales. There was a trend towards higher scores in the placebo condition in block 1 than in the psilocybin condition in block 2.

We explored the data obtained from 40 participants that attended all sessions and adequately followed the behavioural guidelines regarding depression, anxiety and stress subscale scores. We failed to find a difference between psilocybin and placebo conditions in the stress subscale.

We found significant differences in the scores of depression, anxiety and stress between the baseline and psilocybin conditions, but not between the baseline and placebo conditions. This suggests that the effect of condition may be driven by baseline scores.

Paired-samples t tests revealed significant differences in depression and stress subscale scores between baseline and block 1, regardless of condition, but not in anxiety subscale scores.

We failed to find an interaction of sex with condition for the DASS-21 or the MAIA, nor any other effect of sex.

Participants could not accurately identify their condition following block 1, but could identify their condition following block 2. This means that participants broke blind during the second block.

We found a significant between-subject effect of expected condition per block and per subscale score of the DASS-21 and MAIA, but this effect was not strongly supported by Bayesian statistics.

We found no significant differences between expected drug conditions nor effects of perceived drug strength for any of the DASS-21 nor MAIA subscales.

We asked participants to report subjective effects that led them to guess their condition. We listed these effects per condition and per block.

Discussion

We hypothesized that repeated psilocybin microdosing would reduce symptoms of anxiety and depression, increase the processing time needed to identify negative emotions and increase interoceptive awareness. However, the results suggest that interoceptive awareness did not change with repeated psilocybin microdosing.

The repeated microdosing of psilocybin did not affect emotion processing, anxiety, depression and stress symptoms, and did not differ from placebo. This finding contradicts previous survey studies that reported marked reductions in negative emotionality following the repeated microdosing of psychedelic substances.

Although our participants’ baseline DASS-21 scores were in the same range as those of Polito and Stevenson (2019), we did not see additional improvements in depression scores after microdosing. However, we did see significant reductions in stress and depression subscales in block 1.

Previous studies on psilocybin have not found a significant effect on emotion processing nor on negative emotionality. Our study focused on specifically psilocybin, and we had little control over the specific amount of psilocybin that participants consumed.

Our participants consumed the microdoses for a shorter duration (3 weeks) compared with those in the research by Polito and Stevenson (2019; 6 weeks), and likely in the research by Johnstad (2018) and Anderson et al. (2019), although here the specific duration of microdosing was not reported.

Cameron et al. (2019) administered DMT to rats every third day for 7 weeks and found no markers of increased neural plasticity. In fact, the researchers found a decrease in dendritic spine density in PFC of female rats.

Previous findings regarding the effects of psilocybin microdosing may be due to participants’ expectations rather than the chemical components of the doses. In our study, participants experienced a decrease in depression and stress scores from baseline to block 1, irrespective of the condition that they were assigned to.

We found no difference between psilocybin and placebo conditions in our outcome measures in either block, which indicates that explicit expectations likely did not influence our results. We propose two possible reasons for this lack of effect: either the measures were not sensitive enough, or the placebo effect was guided by other processes.

We need to consider the possibility that microdosing does not affect depression and anxiety at all, as previous reports suggest.

Limitations

We note five key limitations of our study: the sample suffers from selection bias, the doses were made by the participants using dried psilocybin truffles, and several participants dropped out during the project.

We used a combined field and lab-based study to assess the effects of microdose psilocybin on psychological outcomes. However, due to the small sample size and selection bias, our study may have been underpowered to detect true effects.

Conclusion and suggestions for future research

The study did not find an effect of psilocybin microdosing on interoceptive awareness, emotion processing, or symptoms of anxiety and depression.

Study details

Compounds studied
Psilocybin

Topics studied
Microdosing

Study characteristics
Placebo-Controlled Double-Blind Within-Subject

Participants
75 Humans

Authors

Authors associated with this publication with profiles on Blossom

Michiel van Elk
Michiel van Elk is an Assistant Professor at the unit Cognitive Psychology of the Institute of Psychology, at Leiden University.

George Fejer
George Fejer is a Research Assistant at the Religion Cognition & Behavior Lab, investigating the placebo effects of psychedelics related to prior expectations, personality traits, and the set and setting. He is also working as a team coordinator of ALIUS, an interdisciplinary collaborative network of researchers, involving neuroscientists, psychologists, philosophers of mind, psychiatrists, and anthropologists, who are dedicated to the development of a systematic and scientific model of consciousness supported by both theoretical work and experimental studies.

Compound Details

The psychedelics given at which dose and how many times

Psilocybin 0.7 g

Linked Research Papers

Notable research papers that build on or are influenced by this paper

Effects of psilocybin microdosing on awe and aesthetic experiences: a preregistered field and lab-based study
This double-blind placebo-controlled study (n=30) found that microdosing psychedelics (psilocybin; 1.5mg; 5-7 doses) increased awe but not aesthetic experiences (e.g. viewing art). Many participants knew which group (receiving placebo or psilocybin in which timeframe) they were in ('breaking blind') and the researcher presume that expectancy-effects may explain the effects found.

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