Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression

This open-label study (n=20) found that the quality of the psychedelic experience (10-25mg psilocybin, measured with the ASC – specifically oceanic boundlessness) predicted therapeutic effect (lower depression scores).

Abstract

“Introduction: It is a basic principle of the “psychedelic” treatment model that the quality of the acute experience mediates long-term improvements in mental health. In the present paper, we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence and magnitude of Oceanic Boundlessness (OBN) (sharing features with mystical-type experience) and Dread of Ego Dissolution (DED) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would have negligible predictive value.

Materials and Methods: Twenty patients with treatment-resistant depression underwent treatment with psilocybin (two separate sessions: 10 and 25 mg psilocybin). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality of experiences in the 25 mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-type and challenging experiences, respectively. The Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) at 5 weeks served as the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments, thus confounding inferences. In a repeated measure ANOVA, Time was the within-subject factor (independent variable), with QIDS-SR as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. OBN and DED were independent variables. OBN-by-Time and DED-by-Time interactions were the primary outcomes of interest.

Results: For the interaction of OBN and DED with Time (QIDS-SR as dependent variable), the main effect and the effects at each time point compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our main hypothesis. Furthermore, Pearson’s correlation of OBN with QIDS-SR (5 weeks) was specific compared to perceptual dimensions of the ASC (p < 0.05).

Discussion: This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. Future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety.”

Authors: Leor Roseman, David J. Nutt & Robin L. Carhart-Harris

Notes

This paper is included in our ‘Top 10 Articles on Psychedelics in the Treatment of Depression‘

The participants from this study are the same as in Carhart-Harris et al. (2016), an open-label, feasibility study for treatment-resistant depression (TRD). As did the 6-month follow-up in Carhart-Harris et al. (2017).

This study was funded by an MRC clinical development scheme grant (MR/J00460X/1), the Alex Mosley Charitable Trust (G30444), the COMPASS group (I30006), and the Beckley Foundation.

“The so-called “mystical” experience has been a classic problem area for mainstream psychology—if not science more generally.”

“Perhaps the most widely used subjective measure of altered states of consciousness, and particularly the psychedelic state, is the altered states of consciousness questionnaire (ASC) (Dittrich, 1998). We chose this scale over the MEQ as it measures a broader range of subjective phenomena, not just the “mystical-type experience.” Crucially, this enabled us to test the specificity of the relationship between mystical-type experiences (vs. e.g., perceptual changes) and subsequent therapeutic outcomes. “

This study tried to step away from parts of the controversy of the word mystical (which has many more meanings attached to it than implied by the MEQ). And therefore use the ASC, and specifically looked at ‘oceanic boundlessness’ (OBN). The other side of that term/coin is ‘dread of ego dissolution’ (DED).

“Consistent with our prior hypothesis, psilocybin-induced high OBN (sharing features with mystical-type experience) and low DED (similar to anxiety) predicted positive long-term clinical outcomes in a clinical trial of psilocybin for TRD.”

“It remains possible that as yet unmeasured and therefore unaccounted for components of psychedelic therapy play important roles in mediating long-term outcomes. There are several candidate factors in this regard, and the following should not be considered an exhaustive list: emotional insight/breakthrough or catharsis; priming and suggestibility; reliving of trauma/defining life events; insights about the self and relationships; the patients relationship to music heard; his/her success at “letting go”; the quality of therapeutic relationship; and the degree of “closure” attained during post-drug integration work.”

This remains an open question to this day, and something to keep on studying.

Summary

INTRODUCTION

Psychedelic therapy involves high-dose psychedelic dosing sessions flanked by psychological preparation and integration. The dosing sessions take place in a welcoming environment, with dim lighting, eye-shades, calming and emotionally-directing music, and empathic support provided by trained therapists.

Psychedelic psychotherapy involves high doses of drugs that produce profound psychological experiences. These experiences are rated among the most “meaningful” of a person’s life. Regardless of the terms used to describe them, profound psychological experiences can be predictive of subsequent psychological health. Furthermore, recent ketamine for depression studies have also found an association between the quality of acute experience and subsequent positive clinical outcomes.

The so-called “mystical” experience has been a classic problem area for mainstream psychology, as it suggests associations with the supernatural. However, this text uses the term “mystical” only to refer to the phenomenology of the experience.

William Richards and Walter Pahnke developed a measure of “mystical-type” experience in the late 1960s that was inspired by the work of Stace (1960). The MEQ and M scale have been found to be predictive of long-term positive therapeutic outcomes in trials of psilocybin for cancer-related distress, tobacco smoking and alcohol dependence.

The altered states of consciousness questionnaire (ASC) is a widely used subjective measure of altered states of consciousness, and particularly the psychedelic state. It contains a factor named “oceanic boundlessness” (OBN), which is closely related to the mystical experience described by Stace (1960).

We recently completed an open-label clinical trial treating 20 patients with treatment-resistant depression with psilocybin. The present study sought to assess whether the quality of the acute psychedelic experience was predictive of longer-term clinical outcomes.

MATERIALS AND METHODS

This trial was approved by several agencies and was sponsored by Imperial College London. All participants provided written informed consent after receiving a complete description of the study.

Design

Twenty patients with major depression were treated with psilocybin, one week apart, using a low-dose (10 mg) and a high-dose (25 mg). Eight more patients were added to the study since publication of the initial 12 in Carhart-Harris et al. (2016a).

Clinical Outcomes

Post-treatment ratings of relevant symptomatology were compared against those collected at baseline (before therapy). A 50% reduction in self-rated 16-item Quick Inventory of Depressive Symptoms (QIDS-SR16) scores was observed at 5 weeks, and a 47% response rate was observed at 6 months.

Measures of Acute Psilocybin Session

The altered state of consciousness questionnaire (ASC) was used to measure the acute subjective experience of psilocybin use. It can be divided into 5 dimensions: experience of unity, dread of ego-dissolution, visionary restructuralization, auditory alterations, and vigilance reduction.

We hypothesized that OBN and DED would predict clinical outcome up to 5 weeks. We tested the relationship between OBN and depression changes using repeated measure ANOVA and found that patients who had a “complete” OBN had a better clinical outcome.

We also issued participants a 29-item “psychedelic questionnaire” (PQ) which was completed at the same time as the ASC. A correlation analysis was done on all items of the PQ and the ASC.

Prediction of QIDS-SR up to 5 Weeks

This study found that the 5 dimensions of the 11D ASC predict 1QIDS-SR (5 weeks) and that the interactions of Time X OBN and Time X DED are significant (p 0.05). The responders (n = 9) and non-responders (n = 10) in the 11D ASC scores are presented for descriptive purposes.

Prediction of Secondary Clinical Measures

The results show that patients with “complete” OBN had better outcomes than those with “non-complete” OBN on a number of different measures and at different time points.

In further exploratory analyses, correlations between the ASC and 1QIDS-SR were calculated, and items related to OBN correlated most strongly with positive clinical outcomes.

DISCUSSION

Consistent with our prior hypothesis, high OBN and low DED experienced during a psilocybin session predicted positive long-term clinical outcomes in a clinical trial of psilocybin for TRD. This result replicates previous studies showing that psychedelic-induced peak or mystical-type experiences are predictive of positive long-term clinical outcomes.

One may naturally infer that OBN or mystical-type experience mediates long-term positive clinical outcomes, but one must exercise caution in assuming too much. There are several candidate factors in this regard, including emotional insight/breakthrough or catharsis, priming and suggestibility, reliving of trauma/defining life events, insights about the self and relationships.

Psychological factors may exert influence before, during and after the acute experience itself, and may also be more or less dependent on particular psychological frameworks and their relevant vocabularies. The development of subjective, behavioral and biological measures relevant to these constructs would represent an important advance.

A study of psychedelic therapy found that anxiety negatively correlated with clinical outcome, yet no patient showed a worsening of clinical symptoms at 5 weeks. Less anxiety combined with high OBN predicted 54% of the variance of clinical change at 5 weeks.

Psychoanalytic theory suggests that emotional breakthrough and insight are required for the occurrence of mystical-type/peak experiences, and that loss of self is one of their basic pre-requisites. Recent work has sought to develop a measure that is sensitive to difficult or challenging psychedelic experiences.

Improved subjective measures of high-level human experiences such as the mystical-type/peak experience will enhance our understanding of their psychology and underlying neural substrates. Furthermore, enhanced sensitivity to context may be an important function of 5-HT2A receptor signaling.

A psychedelic state is characterized by increased cortical entropy, which is related to high-level subjective experiences such as “ego-dissolution” and increased “openness”. This increased sensitivity to perturbation may account for the special sensitivity to “environment” that is characteristic of the psychedelic state.

Understanding the neurobiological mechanisms of OBN, mystical-type or peak experiences should help to demystify them and enable a better conversation about them with mainstream psychology. This may help to explain why their integration into western society has proved so difficult.

A high OBN and low DED under psilocybin predicted positive clinical outcomes in a trial of psilocybin for TRD. The quality of the experience may be the critical determinant of therapeutic success.