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

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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The Subjective Effects of Psychedelics Are Necessary for Their
Enduring Therapeutic Effects
David B. Yaden and Roland R. Griffiths*
Cite This: https://dx.doi.org/10.1021/acsptsci.0c00194
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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.
■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.
1
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.
2
These classic psychedelics have low toxicity and limited
abuse liability,
3
and several recent studies have investigated
their treatment potential for mood and substance use
disorders.
4−9
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.
10
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,
11
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.
12
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.
Special Issue: Psychedelics
Received: November 12, 2020
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■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.
13
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.
14,15
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 lives
5,6,8,16−19
and
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,
20
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.
21
This scale includes
four subscales: 1, an authoritative sense of unity or connected-
ness 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
arepredictiveofbeneficial outcomes from psychedelics
administered in experimental contexts (Figure 1). An initial
double-blind study from Johns Hopkins showed that 61% of 36
psychedelic naı
̈
ve participants met a priori criteria for having a
“complete”mystical experience at the end of the psilocybin
session day compared to 11% after methylphenidate.
16
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.
17
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.
18
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.
19
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
Figure 1. Left panel shows data from a study (N= 15) of psilocybin on cigarette smoking cessation (replotted from Garcia et al.
22
). Smoking
craving data are change scores from pretreatment to the 6-month follow-up. Mystical experience data for each participant are the mean total score
on the 43-item version of the Mystical Experience Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of
each of 2 or 3 psilocybin sessions. The middle panel shows data from a study (N= 24) of psilocybin on depression (adapted from Davis et al.
9
).
Depression was measured with GRID-Hamilton Depression Rating Scale and expressed as change scores from pretreatment to 4 weeks after the
second psilocybin session. Mystical experience data for each participant are the highest of two total scores on the 30-item Mystical Experience
Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of each of two psilocybin sessions. The right panel
shows data from a study of (N= 50) of individuals with a life-threatening cancer diagnosis who received either a very low dose or a moderately high
dose of psilocybin (Griffiths et al.
5
). Mystical experience data for each participant are the total score on the 30-item Mystical Experience
Questionnaire (expressed as a percentage of the maximum possible score) assessed at the end of the first psilocybin session. Anxiety was measured
with the Hamilton Anxiety Rating Scale and expressed as a change score from baseline to 5 weeks postsession. More details regarding these images
can be found in the citations above describing the original studies.
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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 1). 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.
5,6
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 mystical-
type 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 studies
6
were 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 ses-
sion(s).
22
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.
23
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 suggest-
ing some specificity to mystical-type experiences.
9
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 treat-
ment, participants reported gaining vivid insights into self-
identity and reasons for smoking along with strengthened
belief that they had the ability remain abstinent.
8,15
In a
double-blind study comparing psilocybin and dextromethor-
phan, 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.
24
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 therapeu-
tic outcomes on depression, anxiety, and substance use after
psychedelics.
25−27
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.
23
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
thesubjectivepsychedeliceffect 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.
28
■AUTHOR INFORMATION
Corresponding Author
Roland R. Griffiths −Department of Psychiatry and
Behavioral Sciences, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205, United States; Center
for Psychedelic and Consciousness Research and Department
of Neuroscience, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21224, United States;
Phone: 410-550-0034; Email: rgriff@jhmi.edu
Author
David B. Yaden −Department of Psychiatry and Behavioral
Sciences, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205, United States; Center for
Psychedelic and Consciousness Research, Johns Hopkins
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University School of Medicine, Baltimore, Maryland 21224,
United States; orcid.org/0000-0002-9604-6227
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsptsci.0c00194
Notes
Dr. Griffiths reports grants from the Riverstyx Foundation, a
crowdsourced funding campaign organized by Tim Ferris, and
National Institute on Drug Abuse (grant R01DA03889) for
research support outside of submitted the work; personal fees
from the Heffter Research Institute (HRI) to cover travel costs
as member of the board of directors of HRI outside the
submitted work; and is site principal investigator for a multisite
trial of psilocybin-facilitated treatment of major depressive
disorder, which is sponsored by the Usona Institute.
The authors declare no competing financial interest(s).
■ACKNOWLEDGMENTS
We thank Chris Letheby (University of Western Australia),
Albert Garcia-Romeu (Johns Hopkins University School of
Medicine), Brian D. Earp (Yale University), Derek E.
Anderson (Boston University), and Chaz Firestone (Johns
Hopkins University) for their helpful comments and
suggestions. Support for Drs. D. Yaden and Griffiths through
the Johns Hopkins Center for Psychedelic and Consciousness
Research was provided by Tim Ferriss, Matt Mullenweg, Blake
Mycoskie, Craig Nerenberg, and the Steven and Alexandra
Cohen Foundation.
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