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The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects

This perspective paper (2020) argues that the subjective experience of psychedelics is necessary for enduring therapeutic outcomes.

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Authors

Roland Griffiths
David Yaden

Published

December 11, 2020

ACS Pharmacology and Translational Science

meta Study

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Abstract

Classic psychedelics produce altered states of consciousness that individuals often interpret as meaningful experiences. Across a number of human studies, when the participant-rated intensity of the overall drug effects are statistically controlled for, certain subjective effects predict therapeutic and other desirable outcomes. Underlying neurobiological mechanisms are likely necessary but not sufficient to confer full and enduring beneficial effects. We propose that the subjective effects of psychedelics are necessary for their enduring beneficial effects and that these subjective effects account for the majority of their benefit.

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Research Summary of 'The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects'

Introduction

Classic psychedelics are a chemically diverse group of compounds that act as partial agonists at 5-HT2A serotonin receptors and elicit distinctive subjective effects. The authors note that substances such as psilocybin, DMT (as in ayahuasca), mescaline and LSD have low toxicity and limited abuse liability, and that several recent clinical studies have reported favourable outcomes when these drugs are given under supportive conditions. A central unresolved question is the mechanism of therapeutic action: whether underlying neurobiological changes (for example, enhanced neural plasticity or brain network reorganisation) are sufficient, or whether the first-person subjective experiences engendered by moderate-to-high doses are necessary to produce enduring benefit in humans. Yaden and colleagues set out to argue that certain acute subjective effects are necessary for the full and lasting therapeutic and otherwise beneficial outcomes of psychedelics in humans. They frame this position against an alternative view that regards subjective effects as epiphenomena, summarise psychometric and clinical evidence bearing on the question, and propose a critical experimental test (a thought experiment involving administration under deep anaesthesia) to adjudicate whether subjective experience is essential for durable therapeutic benefit.

References (23)

Papers cited by this study that are also in Blossom

Psychedelics

Nichols, D. E. · Pharmacological Reviews (2016)

Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action

Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)

Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function

Johnson, M. W., Hendricks, P. S., Barrett, F. S. et al. · Pharmacology and Therapeutics (2019)

Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study

Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer

Results

Yaden and colleagues review experimental, clinical and survey data linking specific subjective features of psychedelic experiences to longer-term positive outcomes. They highlight the development and use of psychometric instruments, notably the Mystical Experience Questionnaire (MEQ), which operationalises mystical-type experiences across subscales such as unity/connectedness, positively valenced affect, alterations in time and space, and ineffability. Laboratory and clinical studies repeatedly show associations between higher scores on mystical-type or related subjective measures and later benefit. In a double-blind study at Johns Hopkins, 61% of 36 psychedelic-naïve participants met prespecified criteria for a “complete” mystical experience after psilocybin compared with 11% after methylphenidate; follow-up ratings at two months showed greater positive changes attributed to the psilocybin session, and an immediate post-session MEQ score correlated with long-term ratings of personal meaning (r = 0.61) after controlling for three measures of overall drug intensity. A dose–response replication in 18 healthy participants similarly found that mystical experience scores and positive follow-up ratings increased with psilocybin dose. In a randomised double-blind study examining psilocybin combined with meditation, 50 participants received moderate–high doses on two occasions and 25 received low placebo-like doses; 61% of the moderate–high group had complete mystical experiences versus 4% of the low-dose group. Hierarchical regression indicated that MEQ scores on session days substantially improved prediction of a composite measure of positive outcomes (attitudes, mood and behaviour) at six months, increasing the model r-square by 0.54. Clinical trials in patients with life-threatening cancer also linked mystical-type experiences to reductions in anxiety and depression. In one crossover study, mean MEQ percentage of maximum possible score was 64% after a moderate psilocybin dose versus 27% after a low dose; session-day MEQ scores correlated with enduring therapeutic changes at five weeks, and mediation analyses suggested mystical experience partly mediated treatment response. The second crossover study produced similar results. Open-label and dependence treatment studies provide convergent findings. In a smoking cessation trial, 9 of 15 participants (60%) reported a complete mystical experience during at least one psilocybin session; mean session-day MEQ scores correlated with reductions in craving (r = -0.65) and urine cotinine (r = -0.56) at six months, and stronger mystical experiences were associated with biologically verified abstinence. In treatment-resistant depression and major depressive disorder samples, measures related to oceanic boundlessness or peak mystical ratings correlated with reductions in depressive symptoms (for example, r = -0.41 in one MDD study), whereas challenging experience ratings did not show such correlations. Beyond mystical-type experiences, the authors summarise evidence that psychological insight and ‘‘emotional breakthrough’’ are also predictive of positive outcomes. A double-blind comparison of psilocybin and dextromethorphan found psychological or personal insight increased with psilocybin dose and was associated with motivation to use psilocybin. Cross-sectional path analyses and prospective naturalistic surveys suggest that insightful experiences and mystical-type experiences can independently mediate improvements in depression, anxiety and substance use. One open-label psilocybin depression study (N = 24) found a correlation of r = 0.60 between ratings of psychological insight the day after dosing and decreases in depression four weeks later. Across many of these reports, associations between specific subjective features and later benefit remain when statistical controls for overall intensity of the drug effect are applied, and some studies present mediation analyses indicating subjective experiences mediate therapeutic response. The authors acknowledge that non-subjective neurobiological mechanisms observed in animal models (for example, plasticity-related changes) could account for some effects, but they argue these findings do not rule out an essential mediating role for subjective experience in humans.

Discussion

The authors interpret the reviewed evidence as making a compelling case that certain acute subjective effects occasioned by moderate-to-high doses of classic psychedelics play a key role in enduring therapeutic and other beneficial outcomes. They contend that neurobiological mechanisms are almost certainly necessary but are likely not sufficient to produce the full magnitude and durability of benefit seen in human studies. Much of their argument rests on the repeated finding that measures of mystical-type experience, psychological insight or emotional breakthrough predict longer-term positive change even after controlling for overall intensity of drug effects, and on mediation analyses in several trials. To provide a decisive test of the relevance of subjective effects, Yaden and colleagues propose a critical experiment: administration of a psychedelic while rendering participants fully unconscious (for example, via deep anaesthesia) so they retain no memory of a psychedelic-like subjective experience. They argue that if full and lasting therapeutic efficacy persisted under those conditions, it would refute the necessity of subjective effects; conversely, if efficacy were reduced in magnitude or more transient, that would support their position. The authors describe this as unlikely but logically definitive. They position their view relative to earlier research by acknowledging animal and neurobiological studies that demonstrate plausible mechanisms independent of subjective report, while emphasising that such mechanisms do not negate a mediating role for first-person experience in humans. Limitations acknowledged in the paper include that much of the evidence is preliminary and correlational, and that causality is imperfectly established outside of mediation analyses. The authors do not report conducting new empirical work themselves in this paper; rather, they synthesise existing experimental, clinical and survey findings to support their proposal. In terms of implications, the authors suggest that preserving or facilitating the salient subjective experiences may be important to achieving enduring therapeutic benefit in clinical applications, and they imply that future research should aim to test the proposed anaesthesia-style experiment or otherwise disentangle subjective and neurobiological contributions. They also note that an alternative perspective is available in a companion Viewpoint in the same issue.

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■ INTRODUCTION

The classic psychedelics are a structurally diverse group of compounds that are partial agonists at 5-HT2A serotonin receptors and produce a unique profile of subjective effects.These compounds include tryptamines such as psilocybin (the main psychoactive constituent in psychedelic mushrooms), N,N-dimethyltryptamine (DMT, an ingredient of the plant admixture ayahuasca), phenethlyamines such as mescaline (from peyote and other cacti), and the ergotamines (such as lysergic acid diethylamide, LSD). Pharmacological blocking of the 5-HT2A receptor blocks many subjective and other major effects of psychedelics in humans and infrahuman animals.These classic psychedelics have low toxicity and limited abuse liability,and several recent studies have investigated their treatment potential for mood and substance use disorders.While favorable outcomes have been observed when psychedelics are taken under supportive conditions, questions remain regarding their mechanisms of action. Here we argue that some subjective effects occasioned by moderate to high doses of psychedelics in humans are necessary for their full and enduring therapeutic and otherwise beneficial outcomes. In this article, subjective effects refer to first-person experience, which is empirically measured by self-report data. Our view is neatly captured by the thought experiment (which we elaborate on later in this piece): would psychedelics confer their therapeutic benefits if they were administrated to someone who was under heavy sedation? We suspect the answer is no. Our position contrasts the idea that subjective effects of psychedelics may be irrelevant to their therapeutic effects. The position that subjective effects are irrelevant to therapeutic effects is probably true of many pharmacological treatments. Suggestive evidence supporting this position include studies in which psychedelics have been shown to produce positive effects in a rodent model of depression.Although we cannot completely discount the possibility of subjective drug effects in rodents, it seems unlikely that rodents would have experiences similar to those to which humans attribute deep personal meaning and positive, therapeutically relevant mood and behavioral change after taking a psychedelic. From this perspective, the subjective experiences elicited by psychedelic substances are merely epiphenomena of the underlying neurobiological mechanisms which convey the beneficial effects. For example, psychedelics promote structural and functional neural plasticity in the prefrontal cortex through 5-HT2A receptor-mediated mechanisms,or, to cite another example of a neurobiological model that may not require subjective experience, it is observed that the antidepressant effects of psychedelics are associated with brain network reorganization.While these and other neurobiological mechanisms could plausibly account for some of the therapeutic actions of psychedelics, none rule out an essential mediating role of subjective effects in humans.

■ SUBJECTIVE EFFECTS OF PSYCHEDELICS

Naturally occurring psychedelics have been used for millennia in some cultures in religious and healing rituals, with an emphasis on the subjective experiences that they produce.The importance of acute subjective effects in therapeutic outcomes has been also been documented in qualitative interview studies of patients treated with psychedelics in contemporary settings.There is a great deal of historical, anecdotal, and qualitative data supporting the value of the subjective effects of psychedelics. The meaning and significance attributed to psychedelic experiences has been well established in laboratory settings. Psilocybin administration studies have repeatedly shown that participants frequently rate their psychedelic experiences as among the most meaningful of their entire livesand they are sometimes compared to the birth of a first-born child or death of a parent. Due to their salience, such experiences may serve as narrative "inflection points" in one's life that could provide an impetus for changing one's identification with certain patterns of thoughts, feelings, and behaviors. Several subjective features of psychedelic experiences are measurable through psychometric survey instruments. Building on the foundational scholarship of William James, Walter Stace, Walter Pahnke, and others,the Mystical Experience Questionnaire (MEQ) was developed and subsequently revised and psychometrically validated to provide a self-report measure of the acute effects of psilocybin.This scale includes four subscales: 1, an authoritative sense of unity or connectedness accompanied by feelings of reverence; 2, positively valenced feelings such as love or peace; 3, alterations to the sense of both time and space; and 4, difficulty with putting the experience into words. The MEQ likely taps several different cognitive and affective processes that ongoing psychometric studies are further delineating. Scores on questionnaires assessing mystical-type experiences are predictive of beneficial outcomes from psychedelics administered in experimental contexts (Figure). An initial double-blind study from Johns Hopkins showed that 61% of 36 psychedelic naıve participants met a priori criteria for having a "complete" mystical experience at the end of the psilocybin session day compared to 11% after methylphenidate.Two months after sessions, participants attributed significantly greater positive changes in attitudes about life and self, positive mood, positive behaviors, and positive social effects to experiences during the psilocybin than methylphenidate sessions. Importantly, correlation and regression analyses indicated a central role of the mystical experience assessed on the session day, but not the intensity of the psilocybin experience, in predicting the high ratings of personal meaning assessed at 14 months.For instance, r-values of 0.61 were found between mystical experience scores immediately after psilocybin sessions and the follow-up ratings of the personal meaning of the experience after controlling for three different measures of the intensity of the drug effect. A systematic replication of the first study in 18 healthy participants showed that mystical experience on session days and positive ratings on follow-up increased as an orderly function of psilocybin dose.A further extension of this research explored the role of psilocybin-occasioned mystical experience in combination with meditation on enduring changes in trait measures of prosocial attitudes and behaviors.In that randomized double-blind study, 50 participants received moderate-high doses of psilocybin on each of two sessions while 25 received a low placebo-like dose on both sessions. Overall, 61% of those receiving moderate-high doses of psilocybin had complete mystical experiences in contrast to 4% for those receiving the low placebo-like dose with the same levels of psychological support. Hierarchical regression analysis showed that mystical experience (MEQ scores) on session days contributed significantly (improving the r-square of a model that included only spiritual practices by 0.54) to predicting a composite measure of positive outcomes such as positive attitudes about life, self, mood, and behavior at 6 months. Mystical-type experience scores on psilocybin session days are also predictive of treatment success at long-term follow-up in clinical studies (see Figure). Two double-blind crossover studies showed that psilocybin produced substantial and enduring decreases in symptoms of anxiety and depression among patients with a life-threatening cancer diagnosis.In the first of these studies, 5 mean percentage of maximum total possible score on the MEQ was significantly higher immediately after a moderate psilocybin dose (64%) than after a low placebo-like dose (27%). These scores after the first session were significantly correlated with most of the enduring changes in therapeutic outcome measured 5 weeks later. For most measures, this relationship continued to be significant when the intensity of overall psilocybin effect was controlled for in a partial correlation analysis, suggesting that mysticaltype experience per se has an important role apart from overall intensity of drug effect. Furthermore, a statistical mediation analysis suggested that mystical-type experience was a mediator in positive therapeutic response. The results of the second of these studieswere very similar, with correlation analysis controlling for the intensity of drug effect and a mediation analysis suggesting that mystical experience was a mediator of therapeutic effects. Open-label pilot studies of psilocybin in the treatment of substance dependence and depression have reported data consistent with these findings. In a smoking cessation study, 9 of 15 participants (60%) had a "complete" mystical experience during one or more psilocybin session(s).Results showed significant correlations between mean MEQ total scores assessed on session days and change from baseline in smoking craving scores (r = -0.65) and urine cotinine (r = -0.56) at the 6-month follow-up. Further, those participants who showed stronger mystical experiences on psilocybin sessions were more likely to be successful in biologically assessed smoking abstinence. In a psilocybin study in 20 patients with treatment-resistant depression, a measure assessing oceanic boundlessness (a construct related to mystical experience) on session days correlated with reductions in depression and was a significantly better predictor than subjective measures assessing visual or auditory alterations.Finally, in a psilocybin study in 24 patients with major depressive disorder there was a moderate correlation (r = -0.41) between peak postsession mystical experience ratings and decreases in depression, but no such correlation with postsession challenging experience ratings, thus again suggesting some specificity to mystical-type experiences.In addition to mystical-type experiences, meaningful insights and belief changes are also frequently cited as fundamentally important to enduring positive outcomes in anecdotal descriptions of psychedelic treatments. For example, in a study of successful smoking cessation after psilocybin treatment, participants reported gaining vivid insights into selfidentity and reasons for smoking along with strengthened belief that they had the ability remain abstinent.In a double-blind study comparing psilocybin and dextromethorphan, psychological or personal insight rated after sessions increased as a function of psilocybin dose and was identified as an important domain associated with motivation to use psilocybin.Although experiences of insight may sometimes overlap with mystical-type experience, a statistical path analysis of cross-sectional survey data suggests that insightful and mystical experiences independently mediate positive therapeutic outcomes on depression, anxiety, and substance use after psychedelics.A prospective survey study that assessed respondents before and after taking a psychedelic in a noncontrolled, naturalistic manner showed that a measure of "emotional breakthrough," likely related to psychological insight, predicted well-being 2 weeks later after controlling for mystical and challenging types of experiences.A recent open label study of psilocybin in depression (N = 24) showed a strong correlation (r = 0.60) between ratings of psychological insight the day after the session and decreases in depression 4 weeks later. 9 ■ PROPOSAL FOR A CRITICAL TEST OF THE RELEVANCE OF SUBJECTIVE EFFECTS Although preliminary, the foregoing experimental observations make a case that some subjective effects occasioned by moderate to high doses of psychedelics play a key role in their enduring beneficial effects. It is our contention that the only definitive study to disprove the importance of such subjective effects would be one in which a psychedelic was administered to individuals who were rendered fully unconscious (e.g., via deep anesthesia) and who subsequently reported no memory for a psychedelic-like experience. Although we think it to be highly unlikely, if full and lasting therapeutic efficacy remained under these conditions, we would concede that the subjective effects are irrelevant.

■ CONCLUSION

Based on the results from experimental studies of moderate to high dose psychedelics we believe that the case for subjective effects playing a major role in enduring beneficial effects is compelling. Across a number of studies, when the intensity of the subjective psychedelic effect is controlled, certain subjective effects predict desirable outcomes. Underlying neurobiological-based mechanisms are undoubtedly necessary but likely not sufficient to confer full beneficial effects. In the nonsubjective anesthesia test that we describe, we would not be surprised to see some therapeutic effects but that they would be of lower magnitude and/or more transient. We suspect that the proportion of the long-term beneficial outcomes that are mediated through subjective effects is substantial, accounting for the majority of the lasting beneficial effects of psychedelics. For an alternative perspective, please see a companion Viewpoint in this issue.

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