Psychedelics, Mystical Experience, and Therapeutic Efficacy: A Systematic Review

This systematic review (s=12, 2022) finds a significant association between the mystical experience (MEQ) and psychedelic-assisted therapy (psilocybin, ketamine, ayahuasca) outcomes in ten of the 12 studies. Although promising, half of the studies were open-label and all with small sample sizes.

Abstract

“The mystical experience is a potential psychological mechanism to influence outcome in psychedelic therapy. It includes features such as oceanic boundlessness, ego dissolution, and universal interconnectedness, which have been closely linked to both symptom reduction and improved quality of life. In this review, 12 studies of psychedelic therapy utilizing psilocybin, ayahuasca, or ketamine were analyzed for association between mystical experience and symptom reduction, in areas as diverse as cancer-related distress, substance use disorder, and depressive disorders to include treatment-resistant. Ten of the twelve established a significant association of correlation, mediation, and/or prediction. A majority of the studies are limited, however, by their small sample size and lack of diversity (gender, ethnic, racial, educational, and socioeconomic), common in this newly re-emerging field. Further, 6 out of 12 studies were open-label in design and therefore susceptible to bias. Future studies of this nature should consider a larger sample size with greater diversity and thus representation by use of randomized design. More in-depth exploration into the nature of mystical experience is needed, including predictors of intensity, in order to maximize its positive effects on treatment outcome benefits and minimize concomitant anxiety.”

Authors: Kwonmok Ko, Gemma Knight, James J. Rucker & Anthony J. Cleare

Summary

INTRODUCTION

Psychedelic therapy is being studied for a range of psychiatric illnesses, including depression, anxiety, PTSD, addiction, end-of-life distress, and possibly others. Studies indicate not only effectiveness but also safety, with fewer potential side effects than other forms of medication.

Psychedelics have been shown to have neurobiological and psychological effects, including emotional breakthrough, increased psychological flexibility, and mystical experience, including oceanic boundlessness, universal interconnectedness, ego dissolution, and transcendence of time and space.

Psychedelics and mystical experience may both elicit personally meaningful insight, which is a primary goal of psychotherapy. Psychological flexibility is a fundamental psychotherapeutic mechanism of psychedelics, which is further explored in the context of Acceptance and Commitment Therapy.

Psychedelic drugs are commonly used for therapeutic purposes, including lysergic acid diethylamide [LSD], psilocybin, mescaline, and ayahuasca. MDMA and ketamine are also being studied for similar purposes.

Mystical experience may have a relationship to psychedelic therapy outcome as it is often identified as a phenomenon related to acute psychedelic experience, which is defined as a range of subjective effects including visual alteration, acute anxiety, and insightfulness, among others.

Several instruments have been designed to measure the intensity of mystical experience, including the MEQ, HMS, HRS, and 5D-ASC. OBN, one of five subdimensions of 5D-ASC, has a Pearson correlation of 0.93 with MEQ.

Sanders and Zijlmans dismiss the concept of mysticism in psychedelic research as non-empirical, while Breeksema and van Elk argue that mysticism is clinically valid and has been rigorously studied with multiple well-established instruments.

Olson (39) has suggested that subjective experience may not be necessary for the therapeutic outcome, but the synergy between subjective experience and neurobiological mechanisms may maximize outcome.

This review explores the relationship between the intensity of a mystical psychedelic experience and therapeutic efficacy.

Although mystical experience was incidentally included in a systematic review by Romeo et al. (40), this review has as its primary objective the relationship of mystical experience to therapeutic efficacy.

Searches and Study Selection

The study protocol was developed and agreed prior to the review. A literature search was conducted in Embase, MEDLINE, and PsychINFO to include publication dates from January 1990 to August 2021.

The Multidisciplinary Association for Psychedelic Studies [MAPS] online bibliography was searched, and studies were selected that included adult subjects with psychiatric and/or addictive disorders who received psychedelic dosing either in laboratory or clinical setting, and subjectively reported data regarding mystical experience and treatment response.

Quality Assessment

Open-label uncontrolled studies were assessed using the Newcastle Ottawa Quality Modified Scale (43) and randomized trials were assessed using the Revised Cochrane Risk of Bias Tool for Randomized Trials (44).

Data Extraction

Data were extracted from each study individually, and the results were analyzed for correlation, mediation, and/or prediction between intensity of mystical psychedelic experience and symptomatology decrease.

Study Categorization

Twelve studies were selected based on the inclusion criteria, 6 of which were randomized and the other 6 open-label. Five studies investigated substance use disorder, two investigated alcohol use disorder, two examined tobacco smokers and one inspected cocaine dependency.

Eight studies used psilocybin, six used ketamine, and three used ayahuasca. Doses ranged from 10 to 30 mg dependent on body mass, and two studies used 10 and 25 mg doses 7 days apart, irrespective of body mass.

Support models included nondirective support during treatment, Motivation Enhancement Therapy, Cognitive Behavioral Therapy, and therapeutic rapport with allocated psychiatrists.

Cancer-Related Distress Studies

In two randomized controlled trials, multiple significant correlations were observed between intensity of mystical experience and symptomatology reduction.

Griffiths et al. (46) reported that 18 out of 20 self-rated primary outcome measures had significant correlation with mystical experience. Symptom reduction was indicated by negative correlations in instruments for depression and/or anxiety, and improvement in quality of life was indicated by positive correlations regarding meaningfulness and spiritual significance.

A crossover design was used in this study to assess the relationship between persisting effects, meaningful existence, quality of life, coherence, death acceptance, purpose in life, and death transcendence.

In both studies, the correlation between mystical experience and 4 out of 6 primary outcome measures was significant.

Agin-Liebes et al. (45) conducted a long-term follow-up of Ross et al. and found no statistically significant correlation between mystical experience and anxiety or depression.

Treatment-Resistant Depression

Roseman et al. (14) and Carhart-Harris et al. (16) used the same population data from an open-label feasibility study (51) to determine the predictors of clinical outcome following psilocybin administration.

Roseman et al. found that psilocybin-induced oceanic boundlessness and dread of ego dissolution predicted decrease in depressive symptoms. Additionally, those who experienced more intense or “complete” OBN demonstrated improved clinical outcomes.

Carhart-Harris et al. (16) found that the experience of unity, spiritual experience, blissful state, and insightfulness were related to changes in QIDS-SR16 scores at the fifth week.

A clinical trial utilizing ayahuasca for TRD showed no significant correlation between Hallucinogen Rating Scale and changes in Montgomery-Asberg Depression Rating Scale. The MEQ-30 sub-dimension of transcendence of time and space correlated with therapeutic outcome.

Major Depressive Disorder

In an uncontrolled open-label ketamine study of adult inpatients with MDD, DED was significantly higher among those who did not respond to treatment, but the other 10 dimensions of the 11D-ASC showed no significant difference among responders and non-responders.

Alcohol Use Disorder

In the Bogenschutz et al. (49) study, data from HRS and MEQ were correlated significantly with 4 measures of symptomatology decrease, including Penn Alcohol Craving Scale, Alcohol Abstinence Self-Efficacy Confidence score, change in percent of drinking days, and percent of heavy drinking days.

Rothberg et al. (23) observed a significant negative correlation between HMS and number of heavy drinking days, and symptomatology decrease for ineffability, positive affect, and average number of daily drinks post-infusion.

Tobacco Addiction

Garcia-Romeu et al. (34) and Johnson et al. (50) analyzed long-term treatment effects of psilocybin on smoking cessation, and found that higher scores on the States of Consciousness Questionnaire, spiritual significance, impact on wellbeing, and personal meaning were significant predictors.

Garcia-Romeu et al. (34) measured complete mystical experience in 42 out of 60 participants, and found that complete mystical experience was induced at higher rates than in previous healthy volunteer studies.

Cocaine Dependence

One randomized controlled trial utilizing ketamine infusion was conducted with 18 cocaine-dependent healthy subjects who expressed disinterest in treatment or abstinence. The study found that ketamine increased mystical experience, dissociation, and near-death experience phenomena, but did not decrease cocaine use or craving.

DISCUSSION

In this systematic review of 12 studies, the association between mystical experience and therapeutic outcome in psychedelic therapy was indicated by most clinical studies. The association between mystical experience and long-term outcomes was not significant due to the nature of long-term studies.

The factor of ineffability was significantly correlated with symptom reduction in two related substance use disorders studies, at long-term followup of 6 months and 12 months.

If mystical experience predicts therapeutic outcome, it is important to factor in the elements that affect the phenomenon. For example, acute anxiety induced by psychedelics can compromise outcome, and openness to experience is negatively correlated with acute anxiety.

Psychedelics can induce near-death experience, which can lead to increased personal insight and therefore, symptom reduction. However, causality of psilocybin as a catalyst for neural plasticity cannot be established in human trials.

This review found that there are relatively few studies on mystical experience as a therapeutic predictor, and that the phenomena is non-observable and self-reported. Two common limitations of these studies were small sample size and lack of ethnic, racial, gender, educational, and/or socioeconomic diversity.

In future studies, the limitations of the sample size and lack of diversity among subjects could be addressed by addressing the funding issues, legal restrictions, and the nature of psychedelics which requires a rigorous screening process.

This review indicates a relationship between mystical experience and therapeutic efficacy. Further studies are needed to assess and possibly establish causality, and to explore ways to increase intensity of said experience.

If causality is established, then study into psychological and/or clinical markers that predispose people to mystical experience should be conducted.