Effects of psilocybin therapy on personality... — Research Summary & Context

Effects of psilocybin therapy on personality... — Research Summary & Context | Blossom

Abstract

Objective

To explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment‐resistant depression (TRD).

Method

Twenty patients with moderate or severe, unipolar, TRD received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. Personality was assessed at baseline and at 3‐month follow‐up 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.

Results

Neuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO‐PI‐R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend‐level increases, and Agreeableness did not change.

Conclusion

Our observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy. This needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.

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Research Summary of 'Effects of psilocybin therapy on personality structure'

Introduction

Major depressive disorder is common, causes substantial individual and societal burden, and a sizeable fraction of cases are treatment-resistant (treatment-resistant depression, TRD), defined here as poor response to two adequate trials of different antidepressant classes. Given TRD’s poor prognosis and high cost, alternative therapeutic strategies have been sought. Interest in classic serotonergic psychedelics such as psilocybin has re-emerged, and small pilot studies suggest psychedelic-assisted therapy can produce durable clinical benefits across conditions including addiction, obsessive–compulsive disorder, end-of-life distress, major depression, and TRD. One intriguing observation from prior work is that therapeutic effects often outlast the acute pharmacological presence of the compounds, and that psychedelic-occasioned ‘‘peak’’ or ‘‘mystical-type’’ experiences—characterised by ego-dissolution, unity, insight and connectedness—may be linked to longer-term change. Mm and colleagues set out to examine whether psilocybin with psychological support modulates personality structure in patients with TRD, whether any personality changes relate to the subjective quality of the psychedelic experience, and whether such changes might help explain the durability of psychedelic-assisted therapy. The study therefore investigated pre-to post-treatment change in the five NEO-PI-R personality domains and their facets, and explored associations between personality change, clinical response, and measures of the acute psilocybin experience.

Methods

This was an open-label feasibility study conducted with regulatory and ethics approvals in the UK. Twenty patients meeting criteria for unipolar major depression of at least moderate severity (HAM-D ≥17) and having failed at least two pharmacologically distinct antidepressant trials in the current episode were enrolled. Key exclusions included a current or past psychotic disorder or a first-degree relative with psychosis. Five participants reported prior psychedelic use; most participants had previously received psychological therapy. After telephone prescreening and an in-person screening with medical and psychiatric assessment (including MINI-5), baseline measures were obtained including the NEO-PI-R personality inventory and the QIDS-SR16 for depressive symptoms. Eligible participants attended a preparation visit and then two dosing sessions one week apart: 10 mg psilocybin in the first session and 25 mg in the second. During dosing, participants lay with eyes closed listening to a music playlist while two therapists provided a non-directive, supportive presence. Integration visits occurred one day and one week after the 25 mg session; personality was reassessed at 3 months. Primary personality outcomes were the five NEO-PI-R domains (Neuroticism, Extraversion, Openness, Conscientiousness, Agreeableness) and their facets, scored as T-scores (M = 50, SD = 10). The acute subjective experience was measured with the altered states of consciousness questionnaire (ASC), whose subfactors include insightfulness, blissful state, experience of unity, and spiritual experience. Depression severity was measured with the QIDS-SR16. Analyses compared baseline to 3-month NEO-PI-R scores with two-tailed paired t-tests and applied false discovery rate correction (FDR) at 0.05. Cohen’s d effect sizes were calculated from raw scores. Treatment response was defined as ≥50% reduction in QIDS from baseline; exploratory Pearson bivariate correlations tested associations among ASC subfactors, personality change, and depressive symptom change. Correlation analyses were not corrected for multiple comparisons and are presented as exploratory.

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RESULTS

Out of the 20 patients included in the trial, 18 met criteria for severe or very severe depression at baseline (QIDS-16 score of ≥16), and the remaining two suffered 'moderate' depression (QIDS-16 score ≥11, <16). As described in, one patient decided not to complete most follow-up measures, including NEO-PI-R at 3-month follow-up, therefore leaving 19 complete datasets (6 females and 13 males; mean age = 44.7 AE 10.9; 27-64).

CONCLUSION

In this open-label study of psilocybin therapy for treat-resistant major depression, clinical improvement among patients was found to be accompanied by significant changes in personality measures. Thus, from baseline to 3-month followup, the NEO-PI-R 'Big Five' score of Neuroticism significantly decreased, Extraversion and Openness scores significantly increased, Conscientiousness showed a trend-level increase, and no changes were seen in Agreeableness. A total of 11 of the 30 NEO_PI-R facets also significantly changed, with 10 of these surviving multiple comparisons correction. To our knowledge, this is the first time personality measures have been reported to change among patients undergoing psychedelic therapy for depression. These results expand on the findings of psilocybin-induced changes of personality traits in healthy volunteers. Overall, the detected pre-to post-treatment changes in both trait and facet scores in our trial corresponded well with observations from a study of patients who successfully underwent pharmacotherapy, mostly with selective serotonin reuptake inhibitors (SSRIs), for major depression. More specifically, the same four of 'the Big Five' traits changed in the two trials and in the same directionthat is toward the personality profile of healthy populations (although Conscientiousness only at trend-level in our study). Also several of the facet changes we saw here overlapped with those reported by Costa et al.. More specifically, patients in both trials displayed decreases on the Neuroticism facets of depression, vulnerability, self-consciousness, and anxiety. Increases in Extraversion included the facets of warmth and positive emotions. Increases in Conscientiousness included the facets of competence and self-discipline. Means and standard deviations of NEO-PI-R scores were not reported by Costa et al., hindering calculation of effect sizes for direct comparison with our findings (listed in Table). Pre-to post-treatment changes in Neuroticism, a known vulnerability marker for affective disorders, and increases in Extraversion, a trait associated with general positive affect, have previously been found to be significantly correlated with SSRI/SNRI-induced reduction in depression severity. In accord with this, QIDS decreases in our study were associated with decreases in Neuroticism and increases in Extraversion, albeit at only trend-level significance. In contrast, increased Openness did not correlate with treatment response and neither was it different between responders and non-responders. This is consistent with the principle that Openness to Experience is orthogonal to anxiety or depression symptoms (46)although there are also some findings to suggest there is a moderate relationship between Openness and psychological wellbeing. Support for the change in Openness score potentially being an addition to, rather than a direct effect of, improved affective symptoms can be taken from a recent naturalistic survey among more than 200 individuals for whom symptomatology and personality measures were assessed online, of a psychedelic experience conducted by our team. Here, Openness changed equally for depressed and non-depressed, whereas changes in Neuroticism were only observed among depressed individuals (manuscript in prep, data not shown). In addition, an extensive meta-analysis of personality changes after therapeutic interventions revealed that trait Openness was the only one among the 'Big Five' traits that did not robustly change. For a more direct comparison of our NEO-PI-R domain changes to previous treatment studies in depression, we identified 5 patient samples from 3 different trials in major depression where NEO-PI-R changes were reported after treatment with antidepressant medicationalthough, in one of these studies, only Neuroticism scores were reported. Across these trials, SSRIs (citalopram, paroxetine, sertraline, and fluoxetine), a norepinephrine-dopamine reuptake inhibitor (bupropion), a serotonin-norepinephrine reuptake inhibitor (venlafaxine), a reversible inhibitor of monoamine oxidase A (moclobemide), a non-selective irreversible monoamine oxidase inhibitor (phenelzine), and a norepinephrine reuptake blocker (desipramine)were used in relevant clinical doses over 8-20 weeks to treat a total number of 469 patients suffering major depression. The pre-and post-treatment NEO-PI-R domain score data presented in these publications allowed for calculation of Cohen's d effect sizes. Interestingly, changes in Neuroticism, Agreeableness, and Conscientiousness scores were very similar to what was seen in our study (sample sizeweighted average Cohen's d; À0.59, 0.04, and 0.18 respectively, vs. À0.57, À0.01, and 0.27 in our study). In contrast, Cohen's d effect sizes for Openness in our trial were more than 3 times larger (0.44 vs. an average of 0.13) and more than 2 times larger for Extraversion (0.72 vs. 0.32) than the average effect sizes from the comparison trials. Of note, the lack of full consistency regarding followup (ranging from 8 to 20 weeks) means that interpretations of direct Cohen's d comparisons across studies should be made cautiously. From the present data, it is hard to infer that the NEO-PI-R changes, and in particular changes in Neuroticism and Extraversion, represent trait and not state changes. However, a 3-month enduring change might suggest that it might not just be a state artifacta notion also supported by the long-lasting psilocybin-induced increases in Openness observed in healthy individuals. Whereas the facet scores were not reported in these studies, none of the Openness facets were found to be significantly changed after successful antidepressant treatment in the study by Costa et al.. In contrast, the facets Openness to actions and to values significantly increased in our study. The facet Openness to Actions pertains to not being set in one's way, and instead, being ready to try and do new things. Openness to Values is about valuing permissiveness, open-mindedness, and tolerance. These two facets therefore reflect an active approach on the part of the individual to try new ways of doing things and consider other peoples' values and/or worldviews. Thus, treatmentinduced modification of Openness and its facets following psilocybin treatment might be an outcome separate and additional to the changes that have previously been seen with antidepressant treatment for example. Whether the pattern of change in personality measures, in particular with regard to Openness, is different between psychedelic therapy and conventional pharmacotherapy (e.g., with SSRIs) should be tested in the future. In our laboratory, we are currently setting up a treatment study in major depression where the effects of such treatment models can be compared directly. Studies investigating the relationship between psychedelics and personality among non-depressed individuals are worth considering in this regard. Follow-up evaluations of work from the 1950-60s have suggested the possibility of long-lasting effects on personality, resulting from the use of psychedelics, and this has since been confirmed in a series of modern, controlled studies. For example, a single high dose of psilocybin with psychological support was found to facilitate longlasting increases in trait Openness in psychedelic-na€ ıve healthy individuals. Similarly, administration of LSD in a brain imaging setting led to discrete increases in Openness scores in healthy volunteers assessed at 2 weeks after the LSD session (41) although this was not replicated in a recent LSD study with longer postsession follow-up time points (1 month and 12 months). Recently, administration of the entactogen, 3,4-methylenedioxy-methamphetamine (MDMA), in conjunction with psychotherapy has been shown to lead to increases in Openness, as well as decreases in Neuroticism, in patients being treated for post-traumatic stress disorder. Regular ceremonial use of the psychedelic brew, ayahuasca, was associated with higher Openness scores when compared with matched non-ayahuasca using controls (57) and self-reported lifetime recreational psychedelic use correlated positively with Openness scores in a large online survey, as well as in a separate brain imaging trial (D. Erritzoe, under review). Interestingly, in the latter trial, it was the Openness to Actions and Openness to Values subfactors that correlated with lifetime psychedelic use (D. Erritzoe, under review). It is well established that trait Openness correlates reliably with liberal political perspective. Given that psychedelics have been found to modulate Openness and other work has shown that Openness and liberal political perspectives are related, it is reasonable to surmise that psychedelics may modulate political perspective also. Indeed, work in the past has found associations between psychedelic use and attitudes of 'personal liberty' and 'foreign policy liberalism' (53), as well as concern for others, irrespective of culture of origin. Moreover, a series of recent studies have further endorsed a general relationship between psychedelic use and greater pro-environmental behaviorand nature-relatedness, as well as liberaland antiauthoritarian perspectives. The apparent link between Openness and a generally liberal worldview may be attributed to the notion that people who are more open to new experiences are also less personally constrained by convention and that this freedom of attitude extends into every aspect of a person's life, including their political orientation. It is worth noting that the Openness score among patients entering our trial was already slightly higher at baseline (2.7 T-score points higher, illustrated in Fig.) than the normative scores reported in the NEO-PI-R manualand increased another 4.9 T-score points following the intervention. Openness therefore differed from the other three personality traits in that it changed from an already higher than average baseline to an even higher level 3 months later. In contrast, the other traits all changed in the direction of normative data (see Fig.), for example, Neuroticism decreased from an abnormally high level at baseline, whereas Conscientiousness (trend-level) and Extraversion both increased from an abnormally low baseline, and thus toward the values of healthy non-depressed individuals (66). The explanation for Openness being relatively high at baseline may be found in the nature of the trial; people who are less Open to Experience are probably less likely to volunteer for a novel treatment involving a psychedelic drug. In support of this interpretation, healthy volunteers who took part in an invasive PET brain imaging study specifically had significantly higher Openness scores when compared to Danish NEO-PI-R norm data. The observation that a single profound psychedelic experience can lead to lasting changes in personality is intriguing, especially when considering the relative stability of personality once adulthood is reached. Longitudinal studies have shown that personality changes after age 30 are typically subtle and/or gradual, that is around 1-2 T-score points per decade, with a subtle drop in Openness and Extraversion scores and a slight increase Agreeableness in older age. However, as longitudinal studies of personality are typically conducted with very long intervals between sampling of personality traits, the personality literature overall provides limited evidence for how fast or slow personality trait change can occur. Thus, our observation of relatively marked changes in personality within a short time span challenges the assumption that personality can only change slowly, gradually, and subtly. A systematic review of more than 200 studies concluded that enduring and large changes in personality are obtainable through a range of therapeutic interventionsbut to our knowledge, none so rapidly or as marked as with psychedelics. The phenomenon of psychological 'quantum change' may be relevant in this regard, where one's outlook and behavior rapidly and profoundly changessuch as with sudden religious conversion experiences. Of the acute experience factors that most related to personality change, greater insightfulness during the 25 mg experience was found to be correlated with decreased Neuroticism as well as increased Extraversion at 3 months. Also, greater spiritual experience was correlated with increased Extraversion. Borderline relationships were seen between increased Extraversion and higher blissful state and Experience of unity scores. The observation that the long-lasting impact of psychedelic therapyin this case on measures of Extraversion and Neuroticismmay depend on their ability to occasion profound insights and 'peak'or mystical-typeexperiences is supported by a number of modern clinical trials, where the magnitude of such peak or mystical experience is often predictive of positive clinical outcome. Problems related to the potentially non-secular meaning of 'mystical experience' have recently been raisedbut if the construct has predictive value, then it at least forces us to ask 'why'? With the exception of spiritual Experience, blissful state, and unity predicting increased Extroversion, the major personality changes observed here were not strongly predicted by factors relevant to 'mystical experience'. It is interesting that the somewhat more concrete notion of insightfulness showed more compelling relationships with the personality changes in the present study. Importantly, correlation analyses in this paper were not corrected for multiple comparisons and should therefore be considered exploratory in nature. In addition, it should here be noted that the sample size of the present study is modest, in particular when dividing it further into subgroups of responders and non-responders. This limits our statistical power to detect small effect sizes that may be of clinical importance, and future randomized and placebocontrolled trials with larger sample sizes will be important to further substantiate the findings from the present study. These present findings are somewhat inconsistent with those of MacLean et al. who found that individuals who had a 'mystical-type' experience were more likely to show sustained increases in Openness several months later. This may be explained by differences in the study populations, differences in the questionnaires that were used to assess subjective psilocybin experience, attitudes, and philosophy of support provided by the research staff (e.g., relative emphasis on mystical experience during preparation), or by the time delay at which personality was assessed (i.e., 3 months in the present study and over 12 in the MacLean study). The neurobiological correlates of personality change after psychedelics have yet to be investigated. However, positron emission tomography (PET) imaging has revealed that brain serotonin 2A receptor levels, the key initiator of psychedelics' signature psychological and neurophysiological effects (71) are positively associated with Neuroticism scores. In fact, the same Neuroticism facet scores that were found to decrease the most after psilocybin therapy in the present study (vulnerability anxiety, depression, and self-consciousness) were also the facets most strongly correlated with serotonin 2A receptor binding in a sample of 83 healthy volunteers. Also, the trait 'dysfunctional attitude', which is associated with pessimistic beliefs, has been associated with elevated serotonin 2A receptor levels in both depressed patientsand individuals recovered from depression. It has been suggested that serotonin 2A receptor upregulation is secondary to deficient stimulation with serotonin, which is consistent with the observation that downregulation of 2A receptors is associated with treatment with antidepressant drugs that elevate synaptic serotonin (Muguruza et al., 2014). To our knowledge, although Openness has not been directly associated with serotonin 2A receptor regulation, and 2A receptor levels did not appear to mediate an association between lifetime recreational use of psychedelics and elevated Openness scores (D. Erritzoe, J. Smith, P. M. Fisher, R. Carhart-Harris, V. G. Frokjaer, G. M. Knudsen, under review), it is possible that serotonin 2A receptor function is linked to Openness. Evidence from rodents suggests that cognitive flexibility is in part mediated via the 2A receptor, and, as discussed previously, a variety of 2A receptor agonists, such as psilocybin, DMT, and LSD, are associated with increased Openness, as well as increased cognitive flexibility and creative thinking. Indeed, serotonin and more specifically, serotonin 2A receptor stimulation has been associated with a relaxing of prior assumptions (80)which would fit with the qualities of open-mindedness that characterize the Openness dimension. More investigations into the role of serotonin 2A receptors in mediating changes in Openness are therefore clearly warranted. In summary, our study detected changes in personality measures from baseline to 3 months post psilocybin therapy in patients suffering major depression. Decreases in Neuroticism and (trendlevel) increases in Conscientiousness were consistent with what has been found previously among patients responding to antidepressant treatment, whereas pronounced increases in Extraversion and, in particular, in Openness, might constitute an effect more specific to therapy with a psychedelic than with other antidepressant interventions. This hypothesis needs to be explored further in future controlled studies, however, as do the brain mechanisms of postpsychedelic personality change. Finally, some preliminary evidence was found that certain changes in personality were predicted by the nature of the acute experience under psilocybin, with acute Insight being particularly implicated.

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Study Details

Study Type
individual
Population
humans
Characteristics
open labelfollow up
Journal
Acta Psychiatrica Scandinavica
Compound
Psilocybin
Topics
Depressive Disorders Major Depressive Disorder (MDD)Treatment-Resistant Depression (TRD)Obsessive-Compulsive Disorder (OCD)

Results

Of 20 enrolled patients, 19 provided complete follow-up personality data (6 females, 13 males; mean age 44.7 ± 10.9 years, range 27–64). At baseline, 18 participants met criteria for severe or very severe depression (QIDS-16 ≥16), and two were in the moderate range. Comparing baseline to 3-month follow-up, three of the five NEO-PI-R domains changed significantly. Neuroticism decreased (T-score change −5.7, P = 0.002), while Extraversion increased (T-score change +6.5, P < 0.001) and Openness increased (T-score change +4.9, P = 0.012). Conscientiousness showed a borderline increase (+3.2 T-score points, P = 0.086) and Agreeableness did not change. Eleven facet scores changed significantly, ten of which survived FDR correction. Cohen’s d effect sizes were reported in the paper’s tables (not fully reproduced in the extracted text). When participants were divided by clinical response at 3 months (responders n = 7; non-responders n = 12), responders showed a larger reduction in Neuroticism (mean change −23 ± 17 vs −6 ± 8; P = 0.038) and a larger increase in Conscientiousness (15 ± 11 vs 0 ± 12; P = 0.017) than non-responders. Responders and non-responders did not differ significantly in changes in Openness (11 ± 21 vs 7 ± 6, P = 0.623), Agreeableness (−1 ± 7 vs 1 ± 8, P = 0.577) or Extraversion (17 ± 10 vs 9 ± 11, P = 0.105). In exploratory correlation analyses, none of the five domain changes correlated significantly with change in QIDS or BDI scores at 3 months; there were trend-level associations between decreases in Neuroticism and QIDS decreases (r = 0.41, P = 0.080) and between increases in Extraversion and QIDS decreases (r = −0.42, P = 0.071), but these did not reach conventional significance. Analyses relating the acute experience to personality change found that higher insightfulness during the 25 mg session correlated with greater reduction in Neuroticism (r = −0.47, P = 0.043) and a greater increase in Extraversion (r = 0.54, P = 0.017). Spiritual experience correlated positively with increased Extraversion (r = 0.47, P = 0.048). Baseline Openness showed a borderline association with blissful state (r = 0.43, P = 0.063); at the facet level, Openness to Fantasy correlated with blissful state (r = 0.50, P = 0.030) and Openness to Aesthetics showed a trend (r = 0.45, P = 0.054). Several other facet-level associations with aspects of the peak experience were at trend level. Baseline Neuroticism correlated negatively with improvement in depression at trend level (r = −0.42, P = 0.075), indicating higher baseline Neuroticism tended to predict smaller clinical gains, although responders and non-responders did not differ on baseline domain scores.

Discussion

Mm and colleagues interpret their findings as evidence that psilocybin therapy for treatment-resistant depression is accompanied by measurable changes in personality structure at 3 months: decreases in Neuroticism, increases in Extraversion and Openness, and a trend-level increase in Conscientiousness, with no change in Agreeableness. Ten facet-level changes survived correction for multiple comparisons. The authors note this is the first report of personality change following psychedelic-assisted therapy in a clinical depressed sample and that the pattern of change overlaps substantially with personality shifts reported after conventional antidepressant treatment, in particular reductions in Neuroticism and increases in Extraversion and Conscientiousness. Where the present results differ, the researchers highlight larger effect sizes for Openness and Extraversion in this psilocybin-treated sample compared with pooled effect sizes from several antidepressant trials, a finding they suggest could indicate an effect more specific to psychedelic therapy. They caution, however, that differences in follow-up timing across studies and limited sample size make direct comparisons tentative. The authors also discuss the possibility that the observed changes are not merely transient state effects: durability at 3 months and prior reports of long-lasting increases in Openness after single-dose psilocybin in healthy volunteers argue that at least some changes may reflect enduring trait modification. Associations between acute experience and personality change were reported chiefly for insightfulness predicting decreased Neuroticism and increased Extraversion, and spiritual experience predicting increased Extraversion. The authors emphasise these correlation analyses were exploratory and uncorrected for multiple comparisons. They acknowledge important limitations: the open-label design, small sample size (especially for subgroup analyses), lack of a placebo or active comparator, and the resulting limited statistical power. These constraints prevent strong causal inference and mandate replication in larger, randomised, controlled trials. Neurobiological mechanisms remain speculative; the paper discusses serotonin 2A receptor links to Neuroticism and proposes further work to probe receptor-level and other neural correlates of personality change. In conclusion, the study reports that psilocybin-assisted therapy was associated with several personality changes at 3 months in patients with TRD, that some of these changes aligned with clinical improvement while others (notably increased Openness) appeared independent of symptom change, and that facets of the acute psychedelic experience—particularly insight—may help predict which personality domains change. The authors call for future controlled trials and mechanistic studies to confirm and extend these observations.

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