Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing

This prospective survey study (n=81) found that expectancy effects were mostly predictive of microdosing outcomes on reductions in state anxiety, depressive symptoms (at 4-week endpoint), and positive outcomes (e.g. psychological resilience, -connectedness, -flexibility).

Abstract

“Psychedelic microdosing describes the ingestion of near-threshold perceptible doses of classic psychedelic substances. Anecdotal reports and observational studies suggest that microdosing may promote positive mood and well-being, but recent placebo-controlled studies failed to find compelling evidence for this. The present study collected web-based mental health and related data using a prospective (before, during and after) design. Individuals planning a weekly microdosing regimen completed surveys at strategic timepoints, spanning a core four-week test period. Eighty-one participants completed the primary study endpoint. Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological flexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a significant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value.”

Authors: Laura S. Kaertner, Michael B. Steinborn, Hannes Kettner, Meg J. Spriggs, Leor Roseman, Tobias Buchborn, Maria Balaet, Chris Timmermann, David Erritzoe & Robin L. Carhart-Harris

Notes

“The current study provides the first prospective exploration of microdosing in naturalistic settings and is, to our knowledge, the first to highlight the role of positive expectations in predicting pertinent psychological outcomes linked to psychedelic drug use.”

The study found that expectancy effects (at the start) were significantly associated with changes in well-being, depressive symptoms, and anxiety scores.

Unfortunately, there weren’t enough participants at the six- and twelve-month post-microdosing moment to provide enough data to also say something about the long-term effects of microdosing.

“In the specific context of microdosing (but also more generally), we would hypothesise that expectations of impending drug effects may sensitise people to perceived changes in their conscious experience (whether ‘real’ or imagined).”

The authors also note that microdosing may function as active placebos, amplifying (positive) expectations by increasing (brain) plasticity. The authors also note that the pharmacological effects of microdoses are really doing something (vs being too low to actually have influence). Still, this may not be the main way through which they serve as (active) placebos.

Future studies on microdosing psychedelics could: “[include] appropriate active placebos that successfully maintain the integrity of study blinds … Combining subjective measures with objective physiological ones, using a multi-method approach … Venturing into clinical populations rather than using samples of healthy volunteers, where there may be comparatively less scope for meaningful psychological change, is another worthy consideration.”

Summary

Classic tryptamine psychedelics induce their distinct psychological and physiological effects mainly through agonism of the 5-HT2A receptor. Microdosing is a popular practice that involves taking a psychedelic every third or fourth day over a period of a few weeks.

Microdosing is a phenomenon that has been brought into prominence by James Fadiman (2011), followed by expanding internet community interest9,10. It is a way of mitigating some of the perceived psychological challenges and risks associated with higher doses of psychedelics.

Observational studies and open-label studies have found that microdosing psychedelics can have positive effects on psychological functioning and well-being. However, placebo-controlled studies have failed to find compelling evidence for beneficial effects of microdoses on cognition or mood.

Placebo effects can be important in psychedelic microdosing studies, as they can affect various outcomes. Positive media coverage of the topic may also contribute to a positive bias in expectations about a treatment.

The present study did not include a placebo control condition, but instead employed a prospective, naturalistic design to track time-dependent changes in well-being, anxiety and depressive symptom scores, neuroticism and emotional stability, and other secondary psychological outcomes.

The study was approved by the Imperial College Research Ethics Committee and conducted in accordance with the framework of Good Clinical Practice.

A cohort of volunteers planned to start microdosing psilocybin, LSD, ayahuasca, DMT/5-MeO-DMT, salvia divinorum, mescaline, or iboga in the near future were surveyed using web-based surveys at different time-points.

Materials and method

Participants were recruited online by disseminating advertisements on several drug-related online-platforms, in social media online communities, and via word of mouth. They received e-mails with links to the relevant questionnaires based on their indicated start date.

In this study, participants completed at least five surveys at different time points, including one week before, once weekly throughout the four-week period, and at six- and twelve-months post start date.

This survey collected demographic information and aimed to assess a potential sample bias by asking participants to specify their relationship to psychedelic substances.

Participants were asked to specify their plans for their upcoming microdosing protocol, including the substance they planned to use, the number of dosing days per week, the planned dose, and the duration.

At baseline, participants’ expectancies were assessed using four VAS items derived from the credibility/expectancy questionnaire48: how confident are they that the upcoming microdosing experience will have a long-lasting positive effect?, how logical does the microdosing experience seem to you?, and how successfully will it improve their overall well-being?

The 14-item Warwick-Edinburgh Mental Well-being Scale was used to measure positive mental health and well-being during the microdosing process.

The TIPI, MODTAS, SSS, BEAQ, BRS and PDI were used to measure personality domains, trait absorption, connectedness to self, others and nature, as well as psychological flexibility, connection to nature and delusional ideation.

Two measures were used to assess the intensity of low dose psychedelic drug effects: the 11-Dimensional Altered States of Consciousness Rating Scale and the Ego Dissolution Inventory.

Participants specified the microdosing particulars (drug type, number of dosing days during the last week, doses on each dosing day) and rated the average intensity of the subjective effects of the preceding week on a 6-point rating scale.

Statistical analysis was conducted to evaluate time-dependent changes in the main outcome measures over all five timepoints. Expectancy scores were tested for effects on changes in the primary outcome measures.

Two-tailed dependent samples t-tests were applied to test for changes in the remaining outcome variables measured at baseline and endpoint. A mixed between-within ANOVA was employed to assess changes in depressive symptomatology in a clinically relevant subsample.

Demographic & participant information can be found in Supplementary Table S1. The mean age of the sample was 35.47( 11.87) years and was predominantly male (60.5%).

117 participants reported having one or more psychiatric disorders, with major depressive disorder and anxiety disorder being the most prevalent, followed by ADHD and PTSD.

Results

Most participants were experienced psychedelic drug users, and most had experimented with microdosing prior to the study. The sample was positively biased towards psychedelic drug use in general and also towards therapeutic use of psychedelics.

At baseline, the majority of participants planned to use Magic Mushrooms/Psilocybin, LSD, or LSD analogues. Seventeen participants planned to mix those two substances, and 0.8% planned to use DMT/5-MeO-DMT.

Psychological well-being increased over time, reaching asymptote at week 2, and then decreasing at week 3. The planned contrast analysis showed significant differences between well-being scores at baseline and all successive timepoints.

Results revealed a significant decrease in depressive symptoms over time, reaching asymptote at week 4. The planned contrast analysis showed a significant difference between depressive symptoms scores at baseline and all subsequent time-points.

Results revealed a significant decrease in state anxiety over time, which reached asymptote at week 4. The planned contrast analysis revealed a significant difference between baseline state anxiety scores and all subsequent time-points.

Table 1 shows that the mean, SD and skewness of the self-report data of main outcome variables over five time-points were higher for individuals who completed all five time-points on the Warwick-Edinburgh Mental Well-being Scale, the Quick Inventory of depressive Symptomatology and the Spielberger State-Trait Anxiety Inventory.

The effects of baseline expectations on endpoint change scores were investigated for well-being, depressive symptoms and anxiety. The results indicated that baseline expectations were predictive of mental health change.

Results revealed a significant increase in the personality facet emotional stability (p 0.001, d = 0.40) in the total sample who completed all timepoints.

Discussion

The current study provides the first prospective exploration of microdosing in naturalistic settings and highlights the role of positive expectations in predicting pertinent psychological outcomes linked to psychedelic drug use.

The present findings could be viewed as another endorsement of the positive claims about microdosing, but the relationship between baseline positive expectations and subsequent outcomes is not unique to psychedelics, and it highlights the importance of including a placebo arm in future research.

Participants in the present study reported 2 – 3 dosing days per week and followed the so-called ‘Fadiman’ protocol, which suggests the ingestion of a microdose once every three days, for several weeks.

Observational research has its strengths, but also has weaknesses. In the present study, uncertainties were introduced by using ‘LSD equivalent dosages’ to calibrate dosage estimates, and inconsistent drug purity and potencies.

The present study was limited by its observational design and lack of a control group. However, the results suggest that microdosing may increase social connectedness, nature-relatedness, brief resilience scale, and brief experiential avoidance questionnaire.

The high rates of attrition might have created a systematic bias favouring those who experienced positive effects, but early side-effects such as an increase in anxiety were not a significant predictor of drop-out.

The present study found that prior positive forecasts about the mental health benefits of microdosing were strongly correlated with the benefits that were subsequently reported. This finding suggests that prior experience with psychedelics may contribute to the relationship between prior expectations and subsequent mental health outcomes.

It seems plausible that microdoses of psychedelics function as active placebos, amplifying expectations due to the plasticity-promoting nature of the drug effects themselves. However, it remains to be determined whether the effects of repeated administration of psychedelic microdoses are different to those associated with a given active placebo.

Table 2 shows the descriptive statistics and results of dependent samples t-tests for remaining outcome variables measured at baseline and key-endpoint. Significant effects are denoted in bold, p-values and effect sizes (Cohen’s d) are shown.

The present study did not adequately address the possibility that non-pharmacological contextual factors influence microdosing outcomes. Further research should consider including appropriate active placebos and combining subjective measures with objective physiological ones.

Almost 50% of the participants reported to have been diagnosed with one or more psychiatric disorders. The severity of self-reported depression and anxiety symptom scores approximated the normal/ healthy range within the first week of microdosing, indicating a clinically meaningful, and quite rapid, improvement.

In conclusion, the present study provides the first demonstration of the role of positive expectancy in mediating positive mental health outcomes associated with psychedelic microdosing.

Acknowledgements

The authors thank several people for their support of the Centre for Psychedelic Research, Imperial College London, and would like to thank Allan Blemings for statistical advice and informal discussisons on study methods.

Author contributions

L.K., M.B.S., H.S.K., M.J.S., L.R., C.T., T.B. and M.B. contributed to the methodology, data collection, analysis, figures and tables, and main manuscript text, and all authors reviewed and approved the final version for submission.

Additional information

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