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Acta Psychiatr Scand 2018: 138: 368–378 © 2018 The Authors.

he Authors. Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.
All rights reserved ACTA PSYCHIATRICA SCANDINAVICA
DOI: 10.1111/acps.12904

Effects of psilocybin therapy on personality


structure
Erritzoe D, Roseman L, Nour MM, MacLean K, Kaelen M, Nutt DJ, D. Erritzoe1 , L. Roseman1,
Carhart-Harris RL. Effects of psilocybin therapy on personality M. M. Nour2,3, K. MacLean4,
structure. M. Kaelen1, D. J. Nutt1,
R. L. Carhart-Harris1
Objective: To explore whether psilocybin with psychological support 1
Centre for Neuropsychopharmacology, Division of Brain
modulates personality parameters in patients suffering from treatment- Sciences, Faculty of Medicine, Imperial College London,
resistant depression (TRD). London, UK, 2South London and Maudsley NHS
Method: Twenty patients with moderate or severe, unipolar, TRD Foundation Trust, London, UK, 3The Institute of
received oral psilocybin (10 and 25 mg, one week apart) in a supportive Psychiatry, Psychology and Neuroscience, Kings College
setting. Personality was assessed at baseline and at 3-month follow-up London, London, UK and 4Sherman, CT, USA
using the Revised NEO Personality Inventory (NEO-PI-R), the
subjective psilocybin experience with Altered State of Consciousness
(ASC) scale, and depressive symptoms with QIDS-SR16. This is an open access article under the terms of the
Results: Neuroticism scores significantly decreased while Extraversion Creative Commons Attribution License, which permits
increased following psilocybin therapy. These changes were in the use, distribution and reproduction in any medium,
direction of the normative NEO-PI-R data and were both predicted, in provided the original work is properly cited.
an exploratory analysis, by the degree of insightfulness experienced Key words: depression; personality; NEO-PI-R;
during the psilocybin session. Openness scores also significantly Openness; psilocybin; psychedelic
increased following psilocybin, whereas Conscientiousness showed
David Erritzoe, Centre for Neuropsychopharmacology,
trend-level increases, and Agreeableness did not change. Division of Brain Sciences, Department of Medicine,
Conclusion: Our observation of changes in personality measures after Imperial College London, Burlington Danes Building,
psilocybin therapy was mostly consistent with reports of personality Hammersmith Campus, 160 Du Cane Road, London W12
change in relation to conventional antidepressant treatment, although 0NN, UK.
the pronounced increases in Extraversion and Openness might constitute E-mail: d.erritzoe@imperial.ac.uk
an effect more specific to psychedelic therapy. This needs further
exploration in future controlled studies, as do the brain mechanisms of
postpsychedelic personality change. Accepted for publication May 2, 2018

Significant outcomes
• Personality trait Neuroticism decreased, while traits Extraversion, Conscientiousness (trend-level), and
Openness all increased from baseline to the 3-month follow-up after psilocybin-facilitated therapy for
treatment-resistant depression.
• An exploratory analysis revealed that the degree of insightfulness during the psychedelic experience
predicted changes in Neuroticism and Extraversion.
• Where changes in Neuroticism and Conscientiousness are consistent with what has been observed pre-
viously among patients responding to antidepressant treatment, the pronounced increases in
Extraversion and Openness might constitute an effect more specific to therapy with a psychedelic.

Limitations
• Relatively small sample size of 20 patients suffering treatment-resistant depression.
• Open-label design and absence of a control condition.
• Two-thirds of the patients in this study were men, limiting extrapolation to the general population
where rates of treatment-resistant depression are marginally higher in women than in men.

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Effects of psilocybin therapy on personality structure

Introduction unknown. There appears to be a relationship


between the therapeutic outcome and the subjec-
Major depression is a commonly occurring disor-
tive experiences during the psychedelic sessions
der associated with high morbidity, socio-eco-
(18, 27, 35–38). Moreover, psilocybin and LSD
nomic burden, and rates of completed suicide (1,
may increase the NEO-PI-R (39) personality trait
2). It affects 10–15% of the general population (2–
Openness to Experience (or simply ‘Openness’) in
4) and has been ranked by The World Health
healthy volunteers after a single dose (40, 41).
Organization (WHO) as the fourth leading con-
Interestingly, and constituting a possible link
tributor to the global burden of disease (5), with a
between the quality of the experience and the
forecast of becoming number one by 2030 (6).
impact on personality, in the subgroup of partici-
Almost half of the cost and disease burden caused
pants who had mystical experiences during their
by depression has been attributed to treatment-
psilocybin session, Openness remained significantly
resistant depression (TRD) (7, 8), typically defined
higher than baseline more than 1 year after the ses-
as ‘a poor response to two adequate trials of differ-
sion (40).
ent classes of antidepressants’ (9). TRD is associ-
Openness is considered to be one of the five
ated with longer duration and higher severity of
major dimensions of personality and is linked to
the disease, more protracted functional impair-
Openness to new ideas and values, imagination,
ment, and poses a significant personal and public
aesthetic appreciation, novelty-seeking, non-con-
health problem (8). TRD affects about 30% of
formity, and creativity (39). In major depression,
patients with major depression and up to 60% if
effective treatment with antidepressants has been
TRD is defined as absence of remission (7, 10).
shown not only to increase Openness scores but
The poor prognosis and socio-economic burden
also to significantly affect three of the remaining
associated with TRD give ground for research
four NEO-PI-R personality domains; decreasing
focusing on therapeutic interventions with alterna-
Neuroticism, increasing Extraversion and Conscien-
tive strategies to conventional pharmaceutical and
tiousness, with Agreeableness remaining unchanged
therapeutic approaches.
(42).
Beginning in the 1990s (11, 12), neurobiological
The aim of the present study was to explore
and psychiatric interest in classic serotonergic psy-
whether psilocybin with psychological support
chedelic compounds, such as psilocybin, N,N-
modulates personality parameters in patients suf-
dimethyltryptamine (DMT), and lysergic acid
fering from treatment-resistant depression, to
diethylamide (LSD), gradually re-emerged after
investigate whether these changes relate to the
decades of being suppressed (13, 14). Recent pilot
quality of the psychedelic experience and to inves-
studies point to the potential of psychedelic-
tigate whether such modulations could potentially
assisted therapy to treat conditions including
help us understand the long-lasting nature of psy-
tobacco (15) and alcohol (16) addiction, obsessive-
chedelic-assisted therapy.
compulsive disorder (17), end of life anxiety/de-
pression (18–20), major depression (21), and TRD
(22, 23) – (see Carhart-Harris & Goodwin, 2017
Methods
for a review (24)). Intriguingly, the treatment effect
in these trials appears to last for several months – The study was approved by the National Research
much longer than the pharmacological presence of Ethics Service (NRES) London – West London,
the actual compounds (25, 26). sponsored and approved by Imperial College Lon-
Typically, psychedelic-assisted therapy involves don’s Joint Research and Complication Organisa-
only one or two sessions in which a moderate to tion (JRCO), adopted by the National Institute of
high dose of a psychedelic compound is given in a Health Research (NIHR) Clinical Research Net-
supportive environment (27, 28) with the intention work (CRN), and reviewed and approved by
of evoking ‘peak’ (29) or ‘mystical-type’ (30, 31) Medicines and Healthcare products Regulatory
experiences, characterized by disintegration of ego Agency (MHRA).
boundaries and an accompanying sense of con-
nectedness (32, 33), oneness, or unity (34). This
Participants
treatment paradigm differs from the approach of
long-term daily pharmacological intervention asso- Twenty patients suffering treatment-resistant
ciated with conventional antidepressant medica- depression were enrolled in this open-label feasibil-
tion. ity study. The main inclusion criteria were: unipo-
The mechanisms underlying the long-lasting lar major depression of at least moderate severity
therapeutic effects of psychedelic therapy remain (17+ on the 21-item HAM-D) and no improvement

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Erritzoe et al.

despite two courses of pharmacologically distinct T-scores (M = 50, SD = 10) using the combined-
antidepressant medications for an adequate dura- sex norms reported in the NEO-PI-R manual.
tion (6 weeks minimum) within the current epi- Cohen’s d effect size was also calculated from raw
sode. Main exclusion criteria were: a current or scores: (Mean-scorebaseline mean-score3-months)/
previously diagnosed psychotic disorder or an ((SDbaseline)2 + (SD3-months)2)0.5. The subjective
immediate family member with a diagnosed psy- experience under psilocybin was assessed using the
chotic disorder. Five patients had previously tried altered state of consciousness questionnaire (ASC)
a psychedelic drug; in four of five cases, this had (43). This self-rated instrument captures the acute
occurred in recreational contexts in early adult- quality of the psychedelic experience and covers
hood. All but three had undergone psychological factors such as insightfulness, blissfulness, experi-
therapy/counseling (23). ence of unity, and spirituality. The 16-item Quick
Inventory of Depressive Symptoms, (QIDS-SR16)
was employed to assess depressive symptoms at
Study procedure
baseline and at selected time points. Change in
Full details of study procedures have been pub- severity of depressive symptoms, as assessed with
lished previously (22, 23). Briefly, the first phase of different measures, from baseline to follow-up time
screening involved a scripted telephone interview, points have been published separately (23).
which was used to prescreen for the major inclu-
sion/exclusion criteria. Suited candidates were
Analysis
invited for a screening visit at the Imperial Clinical
Research Facility (ICRF) at the Hammersmith Baseline vs. 3-month follow-up NEO-PI-R scores
hospital where informed consent was taken. A were compared using two-tailed paired t-tests, and
detailed history of both physical and mental (using false discovery rate (FDR) method with a thresh-
MINI-5) health, routine blood tests, ECG, urine old of 0.05 applied. Results are reported as
test for drugs of abuse and pregnancy where rele- mean  SD. A standard threshold for defining
vant, breathalyzer, and a number of baseline treatment response (≥50% reduction in QIDS
assessments, including the NEO-PI-R, were score from baseline) was used to separate patients
acquired during this visit. Eligible patients into responders and non-responders. Bivariate cor-
attended a preparation visit, followed by two dos- relations were tested using Pearson’s correlation
ing sessions, separated by one week. In the first ses- coefficient; to test whether any of 4 ASC subfactors
sion, patients received 10 mg psilocybin, and in the related to the ‘peak’ experience, insightfulness,
second, 25 mg. The second session was the focus blissful state, ‘experience of unity’, and spiritual
of the therapeutic process, as only this dose was experience (37) were related to changes in any of
predicted to induce lasting therapeutic effects. the NEO-PI-R trait scores (baseline vs. 3-month
After capsule ingestion, patients laid with their follow-up), and to test associations between
eyes closed while listening to a music playlist (27). changes in NEO-PI-R scores (trait and facet
Two therapists adopted a non-directive, supportive scores) and QIDS scores. These correlation analy-
approach, allowing the patient to experience a ses were uncorrected for multiple comparisons and
mostly uninterrupted introspection. Patients came should be regarded as explorative in nature.
back one day and again one week after the 25 mg
session for integration of the experience.
Results
Out of the 20 patients included in the trial, 18 met
Measures
criteria for severe or very severe depression at base-
Personality was assessed using the NEO-PI-R line (QIDS-16 score of ≥16), and the remaining
instrument (39), which covers 5 domains, Neuroti- two suffered ‘moderate’ depression (QIDS-16 score
cism (anxious, insecure, emotional), Extraversion ≥11, <16). As described in (23), one patient decided
(sociable, optimistic, talkative), Openness to Expe- not to complete most follow-up measures, includ-
rience (or short: Openness) (curious, imaginative, ing NEO-PI-R at 3-month follow-up, therefore
creative), Conscientiousness (hard-working, ambi- leaving 19 complete datasets (6 females and 13
tious, persistent), and Agreeableness (good-nat- males; mean age = 44.7  10.9; 27–64).
ured, cooperative, helpful). Each domain has six
facets, each of which contains eight items that are
Personality changes from baseline to 3-month follow-up
rated by respondents using a 5-point Likert-type
scale ranging from strongly disagree to strongly As listed in Table 1 and illustrated in Fig. 1, three
agree. NEO-PI-R raw scores were standardized as out of the five NEO-PI-R domain scores

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Effects of psilocybin therapy on personality structure

Table 1. NEO-PI-R domain and facet scores pre- and post-psilocybin

Baseline 3 months
Domains and facets T-score T-score Change P-value Cohen’s d

Neuroticism (N) 76.6 70.9 5.7 0.002 0.571


Extraversion (E) 31.1 37.6 6.5 0.000 0.716
Openness to Experience (O) 52.7 57.6 4.9 0.012 0.437
Agreeableness (A) 46.8 46.7 0.1 0.953 0.006
Conscientiousness (C) 29.9 33.1 3.2 0.086 0.273
Anxiety (N1) 70.3 66.6 3.7 0.037 0.403
Angry-Hostility (N2) 67.6 65.4 2.2 0.222 0.277
Depression (N3) 77.8 71.2 6.6 0.006 0.661
Self-consciousness (N4) 68.1 63.6 4.5 0.016 0.366
Impulsiveness (N5) 57.8 56.3 1.4 0.446 0.184
Vulnerability (N6) 78.6 71.3 7.3 0.004 0.706 Fig. 1. Trait T-scores scores at baseline (solid thick line) and
Warmth (E1) 34.7 41.8 7.1 0.001 0.604 at 3-month follow-up (dotted line). T-scores calculated with
Gregariousness (E2) 37.7 42.2 4.5 0.011 0.503 the use of means and standard deviations from a combined
Assertiveness (E3) 43.9 45.9 2.0 0.152 0.304 sample of 500 healthy women and 500 healthy men (NEO-PI-
Activity (E4) 35.2 38.3 3.1 0.071 0.442 R manual). The normative data (solid thin line) are repre-
Excitement seeking (E5) 43.1 44.9 1.8 0.279 0.171 sented by normalized scores of 50.
Positive emotions (E6) 27.8 36.1 8.3 0.000 0.740
Openness to Fantasy (O1) 58.9 57.2 1.7 0.415 0.193
Openness to 53.2 56.2 3.0 0.157 0.244
Personality changes vs. changes in depression scores
Aesthetics (O2)
When dividing patients into clinical responders
Openness to Feelings (O3) 52.7 54.0 1.3 0.589 0.111
Openness to Actions (O4) 41.2 48.8 7.5 0.002 0.783 (n = 7) vs. non-responders (n = 12) at 3 months, a
Openness to Ideas (O5) 51.5 55.2 3.7 0.077 0.324 group comparison revealed that among respon-
Openness to Values (O6) 50.0 56.3 6.3 0.001 0.692 ders, Neuroticism score had decreased more from
Trust (A1) 36.8 40.0 3.3 0.085 0.372
Straightforwardness (A2) 47.8 46.6 1.2 0.478 0.120
baseline to 3-month follow-up than among non-
Altruism (A3) 44.8 43.2 1.7 0.318 0.177 responders ( 23  17 vs. 6  8 respectively,
Compliance (A4) 43.8 43.0 0.8 0.685 0.069 P = 0.038), whereas Conscientiousness score had
Modesty (A5) 58.3 55.9 2.4 0.163 0.199 increased more among responders than among
Tender-mindedness (A6) 56.2 58.9 2.7 0.274 0.215
Competence (C1) 26.7 33.0 6.3 0.011 0.743
non-responders over the same period (15  11 vs.
Order (C2) 42.4 40.5 1.9 0.376 0.138 0  12 respectively, P = 0.017). Responders did
Dutifulness (C3) 38.2 41.3 3.1 0.191 0.250 not differ significantly from non-responders with
Achievement striving 33.1 36.4 3.3 0.110 0.294 regard to personality changes within the 3 other
(C4)
Self-discipline (C5) 22.9 27.6 4.7 0.010 0.465
domains (Openness: 11  21 vs. 7  6, P = 0.623;
Deliberation (C6) 47.2 46.6 0.6 0.662 0.080 Agreeableness: 1  7 vs. 1  8, P = 0.577;
Extraversion: 17  10 vs. 9  11, P = 0.105). In
Domains and facets in bold represent scores that showed significant difference
an exploratory analysis none of the 5 NEO-PI-R
between baseline and 3-month follow-up with Student’s paired t-tests and that sur-
vived FDR correction for multiple comparisons. Thus, facet anxiety is the only of the domain changes from baseline to 3-month follow-
11 significantly changed facet scores not to survive the FDR correction. Cohen’s d up significantly correlated with change in either
effect sizes were calculated from the raw mean and SD scores at baseline and 3- QIDS or BDI depression scores at 3 months.
month follow-up. There were positive associations between decreases
in Neuroticism and decreases in QIDS scores
(r = 0.41, P = 0.080), and a negative association
between increases in Extraversion and decreases in
significantly changed from baseline to 3-month QIDS (r = 0.42, P = 0.071). These relationships,
postpsilocybin treatment: Neuroticism scores however, did not reach statistical significance.
decreased (T-score change: 5.7, P = 0.002),
whereas both Extraversion and Openness increased
(T-score changes: 6.5, P < 0.001, and 4.9, Relationship between Peak Experience and personality changes
P = 0.012, respectively). An increase in T-score of The degree of insightfulness experienced during the
3.2 in Conscientiousness was only borderline signif- focal 25 mg psilocybin session was significantly
icant (P = 0.086). Eleven NEO-PI-R facet scores, associated with a reduction in Neuroticism score
all arising from these four domains, changed sig- (r = 0.47, P = 0.043), as well as with an increase
nificantly from baseline to 3-month follow-up, ten in Extraversion score (r = 0.54, P = 0.017). Also,
of these changes surviving FDR correction (these spiritual experience was significantly positively cor-
are listed in Table 1 and Fig. 2). Cohen’s d effect related with increased Extraversion from baseline
sizes calculated from the raw scores are listed in to 3-month follow-up (r = 0.47, P = 0.048),
Table 1. whereas positive relationships between

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Erritzoe et al.

Fig. 2. Facet T-scores scores at baseline (solid thick line) and at 3-month follow-up (dotted line), with normative data normalised to
50 (solid think line).

Extraversion and scores of blissful state and Expe- responders on any of the 5 domain scores at base-
rience of unity only reached borderline significance line.
levels (r = 0.41, P = 0.081, and r = 0.42,
P = 0.075, respectively). None of the Peak Experi-
Discussion
ence-related ASC scores were associated with
changes in Openness or Conscientiousness. In this open-label study of psilocybin therapy for
treat-resistant major depression, clinical improve-
ment among patients was found to be accompa-
Baseline personality scores as predictors of Peak Experience
nied by significant changes in personality
Among the 5 NEO-PI-R domains assessed at base- measures. Thus, from baseline to 3-month follow-
line, only Openness showed a borderline significant up, the NEO-PI-R ‘Big Five’ score of Neuroticism
association with any of the ratings of Peak Experi- significantly decreased, Extraversion and Openness
ence-related ASC subdimensions, assessed in rela- scores significantly increased, Conscientiousness
tion to the focal 25 mg psilocybin session; thus, a showed a trend-level increase, and no changes were
positive association between baseline Openness and seen in Agreeableness. A total of 11 of the 30
blissful state reached borderline significance NEO_PI-R facets also significantly changed, with
(r = 0.43, P = 0.063). In an exploratory analysis, 10 of these surviving multiple comparisons correc-
we tested whether individual variation in Openness tion. To our knowledge, this is the first time per-
scores at baseline correlated with the Peak Experi- sonality measures have been reported to change
ence. Correlation analysis revealed that two facets among patients undergoing psychedelic therapy
of this personality domain, Openness to Fantasy for depression. These results expand on the find-
(r = 0.50, P = 0.030) and Openness to Aesthetics ings of psilocybin-induced changes of personality
(trend-level; r = 0.45, P = 0.054) were positively traits in healthy volunteers (40).
associated with blissful state experienced during Overall, the detected pre- to post-treatment
the psychedelic experience. There were also trend- changes in both trait and facet scores in our trial
level positive associations between Openness to corresponded well with observations from a study
Fantasy at baseline and both Experience of unity of patients who successfully underwent pharma-
and spiritual experience during the experience cotherapy, mostly with selective serotonin reup-
(r = 0.41, P = 0.080, and r = 0.43, P = 0.069, take inhibitors (SSRIs), for major depression (42).
respectively). More specifically, the same four of ‘the Big Five’
traits changed in the two trials and in the same
direction – that is toward the personality profile of
Baseline personality scores as predictors of treatment response
healthy populations (although Conscientiousness
Neuroticism scores at baseline showed a negative only at trend-level in our study). Also several of
correlation with improvement in depression scores the facet changes we saw here overlapped with
at 3 months at trend level (r = 0.42, P = 0.075), those reported by Costa et al. (42). More specifi-
such that patients with higher Neuroticism scores cally, patients in both trials displayed decreases on
at baseline showed reduced clinical improvement the Neuroticism facets of depression, vulnerability,
after psilocybin. Treatment responders after self-consciousness, and anxiety. Increases in
3 months did not significantly differ from non- Extraversion included the facets of warmth and

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Effects of psilocybin therapy on personality structure

positive emotions. Increases in Conscientiousness over 8–20 weeks to treat a total number of 469
included the facets of competence and self-disci- patients suffering major depression. The pre- and
pline. Means and standard deviations of NEO-PI- post-treatment NEO-PI-R domain score data pre-
R scores were not reported by Costa et al., hinder- sented in these publications allowed for calculation
ing calculation of effect sizes for direct comparison of Cohen’s d effect sizes.
with our findings (listed in Table 1). Interestingly, changes in Neuroticism, Agreeable-
Pre- to post-treatment changes in Neuroticism, a ness, and Conscientiousness scores were very simi-
known vulnerability marker for affective disorders lar to what was seen in our study (sample size-
(44, 45), and increases in Extraversion, a trait asso- weighted average Cohen’s d; 0.59, 0.04, and 0.18
ciated with general positive affect (46), have previ- respectively, vs. 0.57, 0.01, and 0.27 in our
ously been found to be significantly correlated with study). In contrast, Cohen’s d effect sizes for Open-
SSRI/SNRI-induced reduction in depression sever- ness in our trial were more than 3 times larger
ity (47). In accord with this, QIDS decreases in our (0.44 vs. an average of 0.13) and more than 2 times
study were associated with decreases in Neuroti- larger for Extraversion (0.72 vs. 0.32) than the
cism and increases in Extraversion, albeit at only average effect sizes from the comparison trials. Of
trend-level significance. In contrast, increased note, the lack of full consistency regarding follow-
Openness did not correlate with treatment response up (ranging from 8 to 20 weeks) means that inter-
and neither was it different between responders pretations of direct Cohen’s d comparisons across
and non-responders. This is consistent with the studies should be made cautiously.
principle that Openness to Experience is orthogonal From the present data, it is hard to infer that the
to anxiety or depression symptoms (46) – although NEO-PI-R changes, and in particular changes in
there are also some findings to suggest there is a Neuroticism and Extraversion, represent trait and
moderate relationship between Openness and psy- not state changes. However, a 3-month enduring
chological wellbeing (48, 49). Support for the change might suggest that it might not just be a
change in Openness score potentially being an state artifact – a notion also supported by the
addition to, rather than a direct effect of, improved long-lasting psilocybin-induced increases in Open-
affective symptoms can be taken from a recent nat- ness observed in healthy individuals (40).
uralistic survey among more than 200 individuals Whereas the facet scores were not reported in
for whom symptomatology and personality mea- these studies, none of the Openness facets were
sures were assessed online, of a psychedelic experi- found to be significantly changed after successful
ence conducted by our team. Here, Openness antidepressant treatment in the study by Costa
changed equally for depressed and non-depressed, et al. (42). In contrast, the facets Openness to
whereas changes in Neuroticism were only actions and to values significantly increased in our
observed among depressed individuals (manuscript study. The facet Openness to Actions pertains to
in prep, data not shown). not being set in one’s way, and instead, being ready
In addition, an extensive meta-analysis of per- to try and do new things. Openness to Values is
sonality changes after therapeutic interventions about valuing permissiveness, open-mindedness,
revealed that trait Openness was the only one and tolerance. These two facets therefore reflect an
among the ‘Big Five’ traits that did not robustly active approach on the part of the individual to try
change (50). For a more direct comparison of our new ways of doing things and consider other peo-
NEO-PI-R domain changes to previous treatment ples’ values and/or worldviews. Thus, treatment-
studies in depression, we identified 5 patient sam- induced modification of Openness and its facets
ples from 3 different trials in major depression following psilocybin treatment might be an out-
where NEO-PI-R changes were reported after come separate and additional to the changes that
treatment with antidepressant medication (47, 51, have previously been seen with antidepressant
52) – although, in one of these studies, only Neu- treatment for example (50). Whether the pattern of
roticism scores were reported (51). Across these tri- change in personality measures, in particular with
als, SSRIs (citalopram, paroxetine, sertraline, and regard to Openness, is different between psychede-
fluoxetine) (47, 51, 52), a norepinephrine-dopa- lic therapy and conventional pharmacotherapy
mine reuptake inhibitor (bupropion) (51, 52), a (e.g., with SSRIs) should be tested in the future. In
serotonin–norepinephrine reuptake inhibitor (ven- our laboratory, we are currently setting up a treat-
lafaxine) (52), a reversible inhibitor of monoamine ment study in major depression where the effects
oxidase A (moclobemide) (51), a non-selective irre- of such treatment models can be compared
versible monoamine oxidase inhibitor (phenelzine) directly.
(52), and a norepinephrine reuptake blocker (de- Studies investigating the relationship between
sipramine) (47) were used in relevant clinical doses psychedelics and personality among non-depressed

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Erritzoe et al.

individuals are worth considering in this regard. It is worth noting that the Openness score among
Follow-up evaluations of work from the 1950–60s patients entering our trial was already slightly
have suggested the possibility of long-lasting higher at baseline (2.7 T-score points higher, illus-
effects on personality, resulting from the use of trated in Fig. 1) than the normative scores
psychedelics (53, 54), and this has since been con- reported in the NEO-PI-R manual (66) and
firmed in a series of modern, controlled studies. increased another 4.9 T-score points following the
For example, a single high dose of psilocybin with intervention. Openness therefore differed from the
psychological support was found to facilitate long- other three personality traits in that it changed
lasting increases in trait Openness in psychedelic- from an already higher than average baseline to an
na€ıve healthy individuals (40). Similarly, adminis- even higher level 3 months later. In contrast, the
tration of LSD in a brain imaging setting led to other traits all changed in the direction of norma-
discrete increases in Openness scores in healthy vol- tive data (see Fig. 1), for example, Neuroticism
unteers assessed at 2 weeks after the LSD session decreased from an abnormally high level at base-
(41) although this was not replicated in a recent line, whereas Conscientiousness (trend-level) and
LSD study with longer postsession follow-up time Extraversion both increased from an abnormally
points (1 month and 12 months) (55). Recently, low baseline, and thus toward the values of healthy
administration of the entactogen, 3,4-methylene- non-depressed individuals (66). The explanation
dioxy-methamphetamine (MDMA), in conjunc- for Openness being relatively high at baseline may
tion with psychotherapy has been shown to lead to be found in the nature of the trial; people who are
increases in Openness, as well as decreases in Neu- less Open to Experience are probably less likely to
roticism, in patients being treated for post-trau- volunteer for a novel treatment involving a psyche-
matic stress disorder (56). Regular ceremonial use delic drug. In support of this interpretation,
of the psychedelic brew, ayahuasca, was associated healthy volunteers who took part in an invasive
with higher Openness scores when compared with PET brain imaging study specifically had signifi-
matched non-ayahuasca using controls (57) and cantly higher Openness scores when compared to
self-reported lifetime recreational psychedelic use Danish NEO-PI-R norm data (67).
correlated positively with Openness scores in a The observation that a single profound psyche-
large online survey (58), as well as in a separate delic experience can lead to lasting changes in per-
brain imaging trial (D. Erritzoe, under review). sonality is intriguing, especially when considering
Interestingly, in the latter trial, it was the Openness the relative stability of personality once adulthood
to Actions and Openness to Values subfactors that is reached. Longitudinal studies have shown that
correlated with lifetime psychedelic use (D. Errit- personality changes after age 30 are typically sub-
zoe, under review). tle and/or gradual, that is around 1–2 T-score
It is well established that trait Openness corre- points per decade, with a subtle drop in Openness
lates reliably with liberal political perspective (58– and Extraversion scores and a slight increase
61). Given that psychedelics have been found to Agreeableness in older age (68). However, as longi-
modulate Openness and other work has shown that tudinal studies of personality are typically con-
Openness and liberal political perspectives are ducted with very long intervals between sampling
related, it is reasonable to surmise that psychede- of personality traits, the personality literature
lics may modulate political perspective also. overall provides limited evidence for how fast or
Indeed, work in the past has found associations slow personality trait change can occur (50). Thus,
between psychedelic use and attitudes of ‘personal our observation of relatively marked changes in
liberty’ and ‘foreign policy liberalism’ (53), as well personality within a short time span challenges the
as concern for others, irrespective of culture of ori- assumption that personality can only change
gin (62). Moreover, a series of recent studies have slowly, gradually, and subtly. A systematic review
further endorsed a general relationship between of more than 200 studies concluded that enduring
psychedelic use and greater pro-environmental and large changes in personality are obtainable
behavior (63) and nature-relatedness (58, 63, 64), through a range of therapeutic interventions (50)
as well as liberal (60) and antiauthoritarian per- but to our knowledge, none so rapidly or as
spectives (58, 64). The apparent link between marked as with psychedelics. The phenomenon of
Openness and a generally liberal worldview may be psychological ‘quantum change’ may be relevant
attributed to the notion that people who are more in this regard (69), where one’s outlook and behav-
open to new experiences are also less personally ior rapidly and profoundly changes – such as with
constrained by convention and that this freedom sudden religious conversion experiences.
of attitude extends into every aspect of a person’s Of the acute experience factors that most related
life, including their political orientation (65). to personality change, greater insightfulness during

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Effects of psilocybin therapy on personality structure

the 25 mg experience was found to be correlated (PET) imaging has revealed that brain serotonin
with decreased Neuroticism as well as increased 2A receptor levels, the key initiator of psychede-
Extraversion at 3 months. Also, greater spiritual lics’ signature psychological and neurophysiologi-
experience was correlated with increased Extraver- cal effects (71) are positively associated with
sion. Borderline relationships were seen between Neuroticism scores (67). In fact, the same Neuroti-
increased Extraversion and higher blissful state and cism facet scores that were found to decrease the
Experience of unity scores. The observation that most after psilocybin therapy in the present study
the long-lasting impact of psychedelic therapy – in (vulnerability anxiety, depression, and self-con-
this case on measures of Extraversion and Neuroti- sciousness) were also the facets most strongly cor-
cism – may depend on their ability to occasion pro- related with serotonin 2A receptor binding in a
found insights and ‘peak’ (29) or mystical-type (70) sample of 83 healthy volunteers (67). Also, the trait
experiences is supported by a number of modern ‘dysfunctional attitude’, which is associated with
clinical trials, where the magnitude of such peak or pessimistic beliefs, has been associated with ele-
mystical experience is often predictive of positive vated serotonin 2A receptor levels in both
clinical outcome (16, 18, 20, 35, 37). Problems depressed patients (72) and individuals recovered
related to the potentially non-secular meaning of from depression (73). It has been suggested that
‘mystical experience’ have recently been raised (24) serotonin 2A receptor upregulation is secondary to
but if the construct has predictive value, then it at deficient stimulation with serotonin (72), which is
least forces us to ask ‘why’? With the exception of consistent with the observation that downregula-
spiritual Experience, blissful state, and unity pre- tion of 2A receptors is associated with treatment
dicting increased Extroversion, the major personal- with antidepressant drugs that elevate synaptic
ity changes observed here were not strongly serotonin (Muguruza et al., 2014).
predicted by factors relevant to ‘mystical experi- To our knowledge, although Openness has not
ence’. It is interesting that the somewhat more con- been directly associated with serotonin 2A receptor
crete notion of insightfulness showed more regulation, and 2A receptor levels did not appear
compelling relationships with the personality to mediate an association between lifetime recre-
changes in the present study. Importantly, correla- ational use of psychedelics and elevated Openness
tion analyses in this paper were not corrected for scores (D. Erritzoe, J. Smith, P. M. Fisher, R. Car-
multiple comparisons and should therefore be con- hart-Harris, V. G. Frokjaer, G. M. Knudsen,
sidered exploratory in nature. In addition, it under review), it is possible that serotonin 2A
should here be noted that the sample size of the receptor function is linked to Openness. Evidence
present study is modest, in particular when divid- from rodents suggests that cognitive flexibility is in
ing it further into subgroups of responders and part mediated via the 2A receptor (74), and, as dis-
non-responders. This limits our statistical power to cussed previously, a variety of 2A receptor ago-
detect small effect sizes that may be of clinical nists, such as psilocybin, DMT, and LSD, are
importance, and future randomized and placebo- associated with increased Openness, as well as
controlled trials with larger sample sizes will be increased cognitive flexibility and creative thinking
important to further substantiate the findings from (75–79). Indeed, serotonin and more specifically,
the present study. serotonin 2A receptor stimulation has been associ-
These present findings are somewhat inconsis- ated with a relaxing of prior assumptions (80) –
tent with those of MacLean et al. who found that which would fit with the qualities of open-minded-
individuals who had a ‘mystical-type’ experience ness that characterize the Openness dimension.
were more likely to show sustained increases in More investigations into the role of serotonin 2A
Openness several months later (40). This may be receptors in mediating changes in Openness are
explained by differences in the study populations, therefore clearly warranted.
differences in the questionnaires that were used to In summary, our study detected changes in per-
assess subjective psilocybin experience, attitudes, sonality measures from baseline to 3 months post
and philosophy of support provided by the psilocybin therapy in patients suffering major
research staff (e.g., relative emphasis on mystical depression. Decreases in Neuroticism and (trend-
experience during preparation), or by the time level) increases in Conscientiousness were consis-
delay at which personality was assessed (i.e., tent with what has been found previously among
3 months in the present study and over 12 in the patients responding to antidepressant treatment,
MacLean study). whereas pronounced increases in Extraversion and,
The neurobiological correlates of personality in particular, in Openness, might constitute an
change after psychedelics have yet to be investi- effect more specific to therapy with a psychedelic
gated. However, positron emission tomography than with other antidepressant interventions. This

375
Erritzoe et al.

hypothesis needs to be explored further in future autonomic, and cardiovascular effects. Arch Gen Psychia-
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RR. Pilot study of the 5-HT2AR agonist psilocybin in the
The research was carried out at the NIHR/Wellcome Trust treatment of tobacco addiction. J Psychopharmacol
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the Medical Research Council (MRC), Beckley Foundation, 16. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE,
Compass Pathways, and the Alexander Mosley Charitable Barbosa PC, Strassman RJ. Psilocybin-assisted treatment
Trust. We are also thankful to Luke Williams for kindly shar- for alcohol dependence: a proof-of-concept study. J Psy-
ing his expertise with regard to NEO-PI-R data, as well as Vic- chopharmacol 2015;29(3):289–299.
toria Amalie Nygart and Lis Marie Pommerencke for their 17. Moreno FA, Wiegand CB, Taitano EK, Delgado PL.
great work on the psychedelic survey data used in the discus- Safety, tolerability, and efficacy of psilocybin in 9 patients
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Declaration of interests produces substantial and sustained decreases in depression
and anxiety in patients with life-threatening cancer: a ran-
None. domized double-blind trial. J Psychopharmacol 2016;30
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