Psilocybin-Induced Mystical-Type Experiences are Related to Persisting Positive Effects: A Quantitative and Qualitative Report

In this open-label study (n=28), participants were administered medium-high doses of psilocybin (12-30mg) and reported the intensity of their experience using the Mystical Experience Questionnaire (MEQ). The Persisting Effects Questionnaire (PEQ) was administered 3-months after psilocybin administration. It was found that the total MEQ score was positively correlated with the later emergence of positive PEQ effects. Using natural language pre-processing, participants’ qualitative reports of their experience were analysed to provide descriptions of the “Complete Mystical Experience.”

Abstract

“Psychedelic drugs such as psilocybin have shown substantial promise for the treatment of several psychiatric conditions including mood and addictive disorders. They also have the remarkable property of producing persisting positive psychological changes in healthy volunteers for at least several months. In this study (NCT03289949), 35 medium-high doses of psilocybin were administered to 28 healthy volunteers (12 females). By the end of the dosing day, participants reported the intensity of their acute experience using the 30-item Mystical Experience Questionnaire (MEQ) and an open-form qualitative report from home. Persisting psychological effects attributed to the psilocybin experience were measured using the Persisting Effects Questionnaire (PEQ) 3-months after administration. Using a linear latent-variable model we show that the MEQ total score is positively associated with the later emergence of positive PEQ effects (p = 3 × 10⁻⁵). Moreover, the MEQ subscales “Positive Mood” (p_corr = 4.1 × 10⁻⁴) and “Mysticality” (p_corr = 2.0 × 10⁻⁴) are associated with positive PEQ whereas the subscales “Transcendence of Time and Space” (p_corr = 0.38) and “Ineffability” (p_corr = 0.45) are not. Using natural language pre-processing, we provide the first qualitative descriptions of the “Complete Mystical Experience” induced by orally administered psilocybin in healthy volunteers, revealing themes such as a sense of connection with the Universe, familial love, and the experience of profound beauty. Combining qualitative and quantitative methods, this paper expands understanding of the acute psilocybin induced experience in healthy volunteers and suggests an importance of the type of experience in predicting lasting positive effects.”

Authors: Drummond E-W. McCulloch, Maria Z. Grzywacz, Martin K. Madsen, Peter S. Jensen, Brice Ozenne, Sophia Armand, Gitte M. Knudsen, Patrick M. Fisher & Dea S. Stenbæk

Summary

INTRODUCTION

Psilocybin, a prodrug to the 5-HT2A agonist psilocin, has been associated with long-lasting positive psychological effects in healthy individuals and patients, while no association with persisting effects on cognition has been observed.

Subjective psychedelic effects vary between individuals and are substantially affected by dose, CYP2D6 phenotype, and non-pharmacological factors like emotional “set” and environmental “setting”. The typical experience induced by a medium-high dose of psilocybin has a plateau of maximum subjective intensity. Despite extensive quantitative characterisation, no papers so far have described the subjective experience of orally administered psilocybin in healthy volunteers.

At maximum intensity, psychedelic experiences can share many similarities with traditional “mystical-type” or “peak” experiences, which have a potential for psychological transformation. A subset of these experiences, known as “Complete Mystical Experiences”, are hypothesised to be instrumental in the lasting positive effects of psychedelics.

Qualitative research suggests that psychedelic therapy may have lasting effects on aesthetic appreciation, connection with senses, self, others and the world, and emotional acceptance. In terminally ill patients, reconciliation with death and reconnection with life are also important themes.

In this study, we examined whether the intensity of the mystical-type experience is associated with persisting effects reported 3 months later in healthy volunteers. We also provided NLP of qualitative reports to differentiate participants who have a CME compared to those who do not.

Participants Recruitment

We recruited 28 healthy participants from a list of individuals that expressed interest in participating in a psilocybin neuroscience study. The participants took part in three sub-projects and received 35 psilocybin administrations.

All participants underwent screening for somatic illness, including a medical examination, an ECG, blood screening for somatic disease, and screening for psychiatric disorders using the Mini International Neuropsychiatric Interview, Danish translation version 6.0.0.

Ethics

Written informed consent was obtained from all participants before inclusion, and the study was approved by the ethics committee and the Danish Medicines Agency.

Psilocybin Intervention

All participants attended a preparatory consultation with the study psychologists who would assist them on the intervention day, and were administered psilocybin orally in 3 mg capsules with a glass of water. Interpersonal support was provided throughout the interventions by the same leading psychologist.

Data Collection and Outcome Measures Baseline Psychometrics

We collected data on depressive symptoms, perceived stress and sleep quality using the Major Depression Inventory, Cohen’s Perceived Stress Scale and Pittsburgh Sleep Quality Index.

Mystical Experience Questionnaire

The Mystical Experience Questionnaire (MEQ) is a validated questionnaire that captures the essential elements of a mystical-type experience relating to a single, discrete event (e.g., one psilocybin administration). A score of >60% on all sub-scales was used to divide data into CME and non-CME.

Mandala Drawing

Participants were asked to draw a mandala of their psilocybin experience using coloured pencils following completion of the MEQ.

Qualitative Experience Report

Participants completed a qualitative report describing their experience of psilocybin using a secured online survey system before going to sleep.

Persisting Effects Questionnaire

Approximately 3 months following the psilocybin sessions, participants completed the Persisting Effects Questionnaire (PEQ), which is a non-validated self-report questionnaire used to measure long-lasting positive and negative effects attributed directly to the psychedelic experience. The PEQ comprises 145 questions about how the participants perceive changes in their life that they feel are “due to the experiences during your last session [of psilocybin] and your contemplation of those experiences”. It has 12 subscale-themes, namely a positive and a negative change in.

Plasma Psilocin Levels

Plasma samples were drawn before, 40, 80, 110, 160, 190, and 340 min post-psilocybin administration, and psilocin levels were evaluated.

Statistical Analyses Descriptive Analyses

Differences in baseline measures were observed between participants who experienced a CME and those who did not experience a CME. Sex differences were also observed, as were associations between the highest PPL value and MEQ total score and PPELV.

Association Between MEQ and PEQ

The association between the MEQ and the PEQ was investigated using linear latent variable models (LVMs), which relax the assumption of constant correlation between measurements. We used the modelsearch function from the lava package to evaluate latent-variable models and calculated the associations between the MEQ total and Positive Persisting Effects (PPELV). We also calculated the potential direct and indirect mediation effects of the co-variates Age, Sex, Dose, Project 2 and Project 3. The total MEQ score was evaluated first, and the relation between the total score and PPELV was investigated using the subscales.

Language Analyses Lemmatisation

All evaluations were performed on the untranslated Danish text, and words were lemmatised using the python package “lemmy” v 2.1.0. This was accurate in all instances, and the first lemma for each word was selected and others discarded.

Tf-idf Analyses

In this paper we attempt to control for investigator-narrative bias by identifying distinguishing themes in the text prior to qualitative analysis. We did this by using term-frequency inverse document frequency (tf-idf) to identify terms within CME and non-CME documents.

Post-hoc Qualitative Analyses

We manually searched through all reports and extracted quotes that included each of the five highest tf-idf terms.

Mandala Assignment

To further illustrate our qualitative findings, five participants’ mandala drawings were selected and their perceptions of the themes represented were verified.

Descriptive Analyses

35 reports from 28 participants were recorded, and the mean age was 31.7 years. 15 were from female subjects, and one participant had missing PEQ data at 3-month follow-up.

There was no significant difference in baseline psychometric measures between groups (sex, age, weight, naivety to psychedelics, dose, and psilocybin session), and no relation between peak PPL and MEQ total score or PPELV.

Association Between MEQ and PEQ Latent-Variable Model Construction

The latent variable PPELV was loaded onto all six positive subscales of the PEQ, and no additional covariances were modelled in the main analysis evaluating MEQ total.

Association Between PEQ and MEQ

The MEQ total score showed a statistically significant positive association with PPELV, and the MEQ subscales Positive Mood and Mysticality showed significant positive associations with PPELV, but no significant associations were observed for Transcendence of Time and Space or Ineffability.

Language Differences in Mystical and Non-Mystical Experiences Natural Language Processing

21 out of 35 reports met the criteria for a CME, and the words with the highest tf-idf score from CME Qualitative Experience Reports were “universe”, “dad”, “MR”, “beautiful”, “simultaneous”, “infinite”, “purple”, “in relation to”, “ray”, “happy” and “brother”.

Qualitative Reports of the Complete Mystical Experience

The word with the highest tf-idf score from the CME reports was “Universe”. It appears to relate to feelings of unity and connectedness, as well as wonderment around the complexity of conscious experience.

Report 31, male, CME, MEQ total 4.2

The word that next-best distinguished the CME was “dad”. The participants described feelings of gratitude, love and respect for their fathers, and a desire to share this experience with their fathers specifically.

The third highest tf-idf score was assigned to the word “MR” referring to the MRI scanner. Some participants felt that the environment played a positive role in the experience.

The word with the fourth highest score was “beauty”. Participants described the beauty of the closed eye visual effects and their interactions with them, as well as the beauty of the world and Universe around them.

The fifth highest tf-idf word was “simultaneous”. Participants reported feeling several emotions at the same time.

Qualitative Reports of the Non-Complete Mystical Experience

Many words used in non-CME reports had high tf-idf values, but were only used by one or two reports. Thus, they did not reflect the themes within the non-CME.

Summary

This study investigated how the self-reported “mystical” nature of the experience was associated with the persistent positive effects of psilocybin in healthy volunteers. The results showed that the intensity and character of mystical-type experiences were associated with the persistent positive effects.

Relation Between MEQ and PEQ

Previous research suggests that the mystical-type experience is qualitatively linked to positive patient outcomes and quantitatively linked to positive persisting effects in healthy volunteers and patients. In this study, healthy Danish individuals who had ecstatic or connectedness experiences had lasting positive effects. However, if the experiences were described as beyond typical comprehension of space and time, or difficult to describe, there were no lasting positive effects. Although previous studies have shown a relation between psilocybin use and positive outcomes, this study is the first to show a relation between MEQ total score and persisting positive effects.

Given the above findings, we may consider how to optimise conditions that permit mystical-type experiences to unfold safely and allow patients to surrender to the experience. This may be modulated by parameters such as dose, choice of psychedelic compound, or “set” and “setting”.

Qualitative Findings

In this paper, we describe the subjective experience of healthy volunteers given medium-high doses of oral psilocybin in a modern research environment. The themes revealed by tf-idf analyses were connection with the Universe, sense of infinity, and wonderment/ beauty. Several themes emerged in the CME open-ended reports that are not described in the MEQ, including familial love, gratitude, and the simultaneous presence of contradictory feelings. None of these themes have connotations of the “challenging” or “dysphoric” experiences reported in the qualitative literature of patient experiences.

Ineffability

Even those who had non-CME had an average MEQ subscale Ineffability score of 3.9 out of 5, and every participant surpassed the threshold of 3 for CME relating to Ineffability. Yet, describing psychedelic phenomena as ineffable can be considered scientifically pessimistic. It has been argued that the ineffability of psychedelic experiences reflects the novel nature of the experience to individuals without indicating any epistemic truth about the experience.

Scientific Inquiry Into the “Mystical-Type Experience”

The focus of this paper is the investigation of the mystical-type experience, which is an area of inquiry with which some researchers have taken issue. The framework of “mystical-type experiences” is a useful one for describing a cluster of co-occurring experiences, independent of ontological judgement of their content.

Limitations

We controlled the type-1 error at the nominal level and accounted for individuals who took part in two projects using robust standard error, but the type-1 error may still be inflated by the sample size.

This study had a small sample size, was not blinded, and did not account for expectancy effects. Further work should aim to replicate these findings with larger samples and evaluate the role of expectancy in the intensity and character of mystical-type experiences induced by psilocybin.

The psychological effects of PET scanning are similar to those reported by a group in Basel, Switzerland for a comparable dose of LSD, but are far lower than those reported following similar doses of psilocybin.

We did not feel that the terms within the corpus of non-CME reports were sufficient to provide a qualitative characterisation of non-CME.

We attempted to control for bias in the qualitative analysis by manually searching to ensure each word described was used in multiple reports. However, tf-idf was still susceptible to bias and the results represent the most frequently used terms that only appear in the CME reports.

Conclusion

We show that the intensity of the psilocybin-induced mystical-type experience is related to lasting positive psychological effects, and provide the first extensive qualitative descriptions of orally administered psilocybin in healthy volunteers.

AUTHOR CONTRIBUTIONS

DM collected data, MG performed analyses, MM and SA provided feedback on the manuscript, BO provided statistical consultation, PJ managed data and PF provided feedback on the manuscript.

FUNDING

This paper was supported by Innovation Fund Denmark, Independent Research Fund Denmark, Ester M. og Konrad Kristian Sigurdssons Dyrevrnsfond, the Lundbeck Foundation, and COMPASS Pathways Ltd.

ACKNOWLEDGMENTS

Psilocybin was kindly supplied by the Czech National Institute of Mental Health and the Forensic Laboratory of Biologically Active Compounds.