Personality change in a trial of psilocybin... — Research Summary & Context

Personality change in a trial of psilocybin... — Research Summary & Context | Blossom

Abstract

Background

Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action.

Methods

In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up.

Results

PT was associated with decreases in neuroticism (B= −0.63), introversion (B= −0.38), disagreeableness (B= −0.47), impulsivity (B= −0.40), and increases in absorption (B= 0.32), conscientiousness (B= 0.30), and openness (B= 0.23) at week 6, with neuroticism (B= −0.47) and disagreeableness (B= −0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (B= −0.38), disagreeableness (B= −0.26), impulsivity (B= −0.35), and increases in openness (B= 0.28) at week 6, with neuroticism (B= −0.46) remaining decreased at month 6. No significant between-condition differences were observed.

Conclusions

Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v.ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.

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Research Summary of 'Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression'

Introduction

Depression is a leading contributor to global disease burden, and recent clinical research has examined psychedelic-assisted therapies as potential interventions. Earlier trials have reported promising antidepressant effects of psilocybin therapy (PT), and one double-dummy, double-blind trial directly compared PT with escitalopram treatment (ET), finding PT superior on many secondary outcomes but not on the primary outcome. Personality traits, as captured by the Five-Factor Model (FFM), overlap with symptom dimensions of psychopathology and could therefore serve as complementary signals for understanding therapeutic mechanisms and broader functional outcomes beyond symptom change. Weiss and colleagues set out to compare the effects of PT versus ET on personality domains in a Phase II, randomized, double-blind, active-comparator trial of patients with moderate-to-severe major depressive disorder. Primary aims included testing within-condition personality change from baseline to six weeks and to six months, assessing between-condition differences in personality change, and examining moderators of personality change such as pre-trial treatment expectancy and acute psychological experiences during dosing. The study preregistered hypotheses that neuroticism, introversion, disagreeableness and impulsivity would decrease in both arms, and that openness would increase selectively in the PT arm; changes in absorption were treated as exploratory given limited prior data.

Methods

The trial used a randomized, double-blind, two-arm repeated-measures design. Fifty-nine patients meeting criteria for major depressive disorder were randomised to PT (N = 30) or ET (N = 29). Dosing comprised two supervised psilocybin sessions spaced three weeks apart: the PT arm received two 25 mg doses of synthetic psilocybin (COMP360) plus placebo capsules, whereas the ET arm received two 1 mg psilocybin doses (intended as active comparator masking) plus daily escitalopram capsules (initially 10 mg, increased to 20 mg after the first three weeks). Psychological support using an Accept/Connect/Embody (ACE) model was provided across 11 sessions beginning at screening and continuing to three weeks after the second dosing day. Assessments occurred at Baseline, Week 6 (end of the six-week core trial period) and Month 6; Month 6 follow-up responses were available for 25 PT and 21 ET participants. The extracted text does not include full details of inclusion/exclusion criteria or some protocol specifics, which are referenced as available in the original article. Personality outcomes comprised the Big Five Inventory (BFI) domains—Neuroticism, Extraversion (reverse-scored as Introversion for clinical relevance), Openness, Agreeableness (reverse-scored as Disagreeableness), and Conscientiousness—as well as two Openness aspects from the Big Five Aspects Scale (Intellect and Aesthetic Openness). Trait absorption was measured with the Modified-Tellegen Absorption Scale (MODTAS) and impulsivity with the Barrett Impulsivity Scale–Brief (BIS-B). Several items were excluded from BFI and BFAS follow-up scoring due to administrator error; the authors adjusted scores accordingly and report internal consistencies for scales at each timepoint. Acute experience measures collected after each dosing day included the Mystical Experience Questionnaire (MEQ) subscales, the Emotional Breakthrough Inventory (EBI), single-item emotional insight and intensity ratings; the maximum value across dosing days was used for each acute measure. Pre-trial treatment expectancy for psilocybin and escitalopram were each measured on a 0–100 scale the day before the first dosing day (expectancy data available for 55 participants). Analytically, two datasets were used: dataset A (N = 59; Baseline and Week 6) and dataset B (N = 46; Baseline, Week 6, Month 6). The authors set a significance threshold of p < 0.05 for preregistered (hypothesised) outcomes and p < 0.01 for non-hypothesised outcomes, and applied False Discovery Rate adjustment where appropriate. Moderation analyses tested whether pre-trial expectancy, baseline characteristics (e.g. prior psychedelic use, demographics, baseline personality), and acute factors moderated within-condition personality change. Further analytic details and supplementary tables are reported in online materials referenced in the extract but not reproduced here.

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INTRODUCTION

Depression has been ranked by The World Health Organization (WHO) as the fourth leading contributor to the global burden of disease, with a forecast of becoming number one by 2030. In recent years, psychedelic therapy has been increasingly studied as a psychiatric intervention, with ten published clinical trials demonstrating promising efficacy for depressive symptoms (e.g.. In one recent trial involving an active comparator and 'double-dummy' and double-blind procedures, psilocybin therapy (PT) showed efficacy superior to escitalopram treatment (ET) across most depression outcomes measuredbut not the primary outcome. ET was a combination of escitalopram pharmacotherapy, a selective serotonin reuptake inhibitor (SSRI), psychological support, and two dosing days of low dose (1 mg) psilocybin, whereas PT was a combination of moderate-to-high dose (25 mg) psilocybin, psychological support, and placebo escitalopram capsules. PT's comparable efficacy to ET on the primary outcome was notable given escitalopram and SSRI medication's demonstrated efficacy in the treatment of depression, and the even greater efficacy of combined SSRI pharmacotherapy and psychotherapy, which converges more closely with ET in the present study. The purpose of the present study was to extend investigation of PT's treatment effects using the Five-Factor model (FFM;of personality within thesample. This purpose is considered important for three reasons. First, we agree with others that personality domains bear relevance to mental illness, and measuring personality could yield new insights on therapeutic mechanisms and psychiatric targets of treatment. Second, personality provides a useful taxonomy for probing with a different, complementary framework, the nature of PT's v. ET's influence on depression. Third, relative standing on personality domains have been linked to important life outcomes including relationship satisfaction, occupational attainment, and longevity, and as such represent useful outcomes with relevance for treatment evaluation.

PERSONALITY AS A SIGNAL OF RELEVANT TREATMENT TARGETS

The FFM model of personality is a widely-used and well-validated framework for characterizing individual differences in the human population. The FFM was used in the present study because it contains normal-range dimensions that show strong overlap with most symptom dimensions of psychopathology. Such evidence has persuaded many scientists that normal-range personality and psychopathology likely share a common underlying dimensional structure, while occupying different locations along each dimension. The following normal-range traits, pathological personality symptom dimensions [from the Alternative Model of Personality Disorder instantiated in DSM-5 (AMPD), containing personality disorders], and psychopathological spectra [from the Hierarchical Taxonomy of psychopathology (HiTOP) model, containing DSM-5 clinical and personality disorders] are considered to share the same dimensions (neuroticism <> negative affectivity <> internalizing; extraversion <> introversion <> detachment; openness <> psychoticism <> thought disorder; agreeableness <> antagonism <> antagonistic externalizing; conscientiousness <> disinhibition <> disinhibitory externalizing). †1 Given this overlap, examining the effects of emerging treatments on personality domains holds potential for signaling clinically relevant targets that are often overlooked in favor of a singular target (e.g. major depression). Such examinations could provide preliminary evidence supporting clinical applications for additional spectra of psychopathology.

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Study Details

Study Type
individual
Population
humans
Characteristics
randomizedparallel group
Journal
Psychological Medicine
Compound
Psilocybin
Topics
Anxiety Disorders Depressive Disorders Major Depressive Disorder (MDD)Personality & Trait Factors

Results

Descriptive comparisons showed the depressed sample scored higher than normative samples on personality domains typically associated with depression (higher Neuroticism, Introversion, Disagreeableness, Impulsivity; lower Conscientiousness). Analyses of within-condition change from Baseline to Week 6 (dataset A) found that PT was associated with several statistically significant adaptive personality changes: reductions in Neuroticism (B = -0.63), Introversion (B = -0.38), Disagreeableness (B = -0.47), and Impulsivity (B = -0.40), and increases in Openness (B = 0.23) and Absorption (B = 0.32). In the ET condition, significant Week 6 changes included reductions in Neuroticism (B = -0.38), Disagreeableness (B = -0.26), and Impulsivity (B = -0.35), and an increase in Openness (B = 0.28); Introversion and Absorption did not change significantly in ET. Longer-term analyses using dataset B examined Baseline, Week 6 and Month 6. The extracted text reports that Neuroticism remained decreased at Month 6 in the ET condition (F (2, 40) = 2.42, p = 0.001; post-hoc B = -0.46). The extraction also contains statements elsewhere that Neuroticism (B = -0.47) and Agreeableness (B = 0.41) remained decreased at Month 6 following PT, but the Month 6 results section in the provided extraction does not clearly report PT month-6 statistics; therefore the persistence of specific PT month-6 estimates is reported ambiguously in the extract. Direct between-condition tests showed no statistically significant differences in personality change. A trend-level between-condition difference appeared for Absorption (B = 0.23, 95% CI 0.04–0.43, p = 0.037), which met conventional p < 0.05 but did not meet the study's more conservative threshold for non-hypothesised outcomes (p < 0.01). Effect sizes for between-condition differences did not exceed Cohen's d = 0.20. Moderation analyses indicated that pre-trial positive expectancy for escitalopram significantly moderated Week 6 personality change within the ET arm: each one-unit increase in escitalopram expectancy (on a 0–100 scale) was associated with an incremental 0.01 unit decrease in Neuroticism (p = 0.002) and a 0.01 unit increase in Conscientiousness (p = 0.004). A counterfactual model suggested the observed Neuroticism and Conscientiousness changes in ET would be non-significant if escitalopram expectancy had been zero. By contrast, psilocybin expectancy did not significantly moderate personality change in the PT arm. Additional tests of moderation by baseline characteristics and acute factors produced three instances of moderation, but the authors caution regression-to-the-mean effects could not be ruled out and did not interpret these findings further. Attrition reduced Month 6 responders to 25 PT and 21 ET participants. The extracted text does not provide a detailed adverse-event profile in the sections provided.

Discussion

Weiss and colleagues interpret the observed pattern of personality change as broadly consistent with adaptive, clinically relevant effects of both treatments. PT produced reductions in Neuroticism, Introversion, Disagreeableness and Impulsivity and increases in Openness and Absorption at Week 6, changes that align with traits most closely linked to depressive symptomatology (e.g. neuroticism with negative affectivity; introversion with anhedonia and withdrawal). The authors note that impulsivity showed a particularly large standardised decrease post-PT (reported as a Cohen's d of about -0.77). ET showed parallel effects on Neuroticism, Disagreeableness and Impulsivity and also increased Openness; the latter finding raises the possibility that the psychotherapeutic support provided in both arms contributed to openness increases rather than drug-specific effects. Although PT appeared to effect broader changes in facets of openness (aesthetic openness, intellect) and absorption—suggesting enhanced cognitive exploration and engagement with sensory and imagined phenomena—the study found no compelling statistically significant between-condition differences. The authors caution that limited statistical power, and a selective expectancy effect that amplified apparent change in the ET arm, complicate between-arm comparisons. Specifically, positive pre-trial expectancy for escitalopram moderated reductions in Neuroticism and increases in Conscientiousness within ET, and a counterfactual analysis suggested those changes might not have been significant absent expectancy. By contrast, expectancy did not moderate PT outcomes, a pattern the investigators suggest may reflect disruption of expectancy effects by the salient acute psilocybin experience, though they present this as speculative. The discussion weighs possible clinical implications conservatively: PT may offer a time-limited alternative to chronic SSRI administration with effects on personality domains relevant to functioning, but larger trials are required before drawing firm conclusions. The authors also highlight both potential benefits and theoretical risks associated with increased trait absorption—greater imaginative engagement and creativity on one hand, and weakly supported links to apophenia, schizotypal traits and impaired reality-testing on the other—calling for further study of absorption's role and safety. Key limitations are acknowledged, including small sample size and limited power to detect between-condition differences, expectancy measurement constrained to depression-related improvement, incomplete long-term assessment for some measures (absorption and impulsivity), and potential confounders affecting Month 6 outcomes. Recommended next steps include replication in larger samples, more frequent assessment of expectancy and blinding, expectancy measures tailored to personality domains, intensive longitudinal personality measurement, targeted clinical trials for phenotypes suggested by these findings (e.g. disorders involving impulsivity and disagreeableness), and investigation of neurobiological mechanisms linking PT to personality and symptom change.

EVIDENCE FOR PERSONALITY CHANGE ACCOMPANYING PT AND SSRI THERAPIES

Measuring change in personality traits to evaluate the nature of therapeutic action has a long-standing history in clinical psychology. This stream of research incorporates personality trait measures to test the effectiveness of various forms of therapeutic interventions on clinical outcomes, such as depression and anxiety. For example, the efficacy of antidepressant pharmacotherapies containing SSRIs in remediating depression and anxiety may in part be related to reduced neuroticism, introversion, and disagreeableness, and increased conscientiousness. In a large meta-analysis of 81 studies examining pharmacotherapeutic effects on personality,observed a large reduction in neuroticism, and smallsized decreases in introversion and disagreeableness and increases in conscientiousness; whereas openness was not observed to exhibit change after performing corrections for small study bias. By comparison, research examining the effect of psychedelic therapy on personality is scarce, with just one open-label depression trial making this a focus. The authors observed decreases in neuroticism and introversion, and increases in openness. They interpreted these findings as suggesting that PT may be uniquely advantageous for depressed patients in producing increased extraversion and openness, given that these traits are less sensitive to change with other conventional psychiatric interventions. The present study enables an enhanced test of these findings by comparing PT's effects on personality to those of ET. Adaptive changes in neuroticism, introversion, and openness are additionally supported by other areas of psychedelic research. For example, despite lacking formal therapeutic interventions, controlled laboratory studies, involving supportive monitoring from clinicians, have observed increases in openness in healthy subjects. More mixed findings of increased conscientiousness and agreeableness have additionally been reported. The ceremonial use of psychedelics may also inform hypotheses about PT efficacy, as ceremony-goers typically show a higher prevalence of psychopathology (40% endorsed a lifetime psychiatric disorder diagnosis;, and shamans and facilitators tend to hold a healing-oriented focus. Consistent with, studies examining personality in these 'naturalistic' contexts have found substantive increases in openness and decreases in neuroticism, alongside increases in agreeableness and substantial increases in extraversion (though only captured by self-report, not informant-report data). In sum, there is growing evidence from therapeutic contexts that † The notes appear after the main text.

SECTION

Brandon Weiss et al. psychedelic therapy may result primarily in adaptive changes to neuroticism, extraversion, and openness. Direct comparisons between antidepressant pharmacotherapy and PT are difficult to form given differences in the effect size formulas used, but evidence is suggestive that PT-induced changes in extraversion and openness may exceed those of SSRI therapy (e.g.. Introversion has shown particular relevance to depression given its relations to amotivation, anhedonia, social integration, and may be particularly relevant to clinical impairment in relationships, work, and leisure, as e.g., increased extraversion may confer greater energy for interpersonal engagement. Relative to other personality traits, openness bears comparatively lower relevance to psychological dysfunction) (exception: substance use) and may accordingly be less related to depressive symptomology. Nevertheless, openness alongside extraversion has been linked to the dopaminergic neurotransmitter system (DeYoung, 2013), and therefore may be relevant to depression through enhancing motivation and reward-seeking. Scholars have proposed that trait openness is related to elevated cognitive exploration following from the propensity to derive greater incentive value from information and uncertainty in artistic and/or intellectual domains. Openness may also be relevant to depression given its association with creative and flexible problem-solving, which could aid in the application of new therapeutic strategies or create opportunities for reward. Openness has also been linked to mystical, transcendental, and transpersonal experiencesand to forgivenessand inspiration, all domains of experience that may be sensitive to psychedelics. Related to openness is the trait construct of absorption. Absorption has been theorized to describe a cognitive disposition toward immersion in one's internal mental landscape, which can include being engrossed in interior objects of imagination or exterior objects of awareness (e.g. finding meaning in a sunset, experiencing a movie as being real). Individuals with high absorption tend to hold paranormal beliefs, report more vivid spiritual and religious experiences, and are more likely to report extraordinary experiences under a sham 'god helmet' condition. Asobserve, 'absorption…seems to allow the individual to become caught up in their imagination like a daydream and to experience something immaterial as present and real.' In the context of psychedelics, trait absorption is among the most robust predictors of mystical experience, and relates to genetic variation in serotonin 2A receptor functioning. One important and relatively unexplored question is whether psychedelics produce changes in absorption, and what the health implications of such changes may be.

STUDY DESIGN AND PARTICIPANTS

Information regarding trial ethics, patient characteristics, inclusion/exclusion criteria, and study design details can be found in the originalarticle. Briefly, 59 patients with diagnoses of MDD were randomized to either the PT arm (N = 30) or the ET arm (N = 29). At visit 1 (baseline), all patients completed self-report questionnaires and clinicianrated interviews. At visit 2 (one day after visit 1), the patients in the PT arm received 25 mg of Compass Pathways' investigational, proprietary, synthetic, psilocybin formulation, i.e., COMP360, and those in the ET arm received 1 mg of psilocybin. All investigators and medication-administering staff were unaware of trial-group assignment. Measures of acute experience were completed after psychedelic effects had subsided. At the end of visit 2, patients received a bottle of capsules and were instructed to take one capsule each morning until their next scheduled day of psilocybin dosing. The capsules contained either microcrystalline cellulose (placebo), which were given to the patients who received the 25 mg dose of psilocybin, or 10 mg of escitalopram, which were given to patients who received the 1 mg dose of psilocybin. Three weeks after the first dosing session (visit 2), patients received their second dose of 25 mg psilocybin or 1 mg psilocybin. Patients again completed measures of acute experience, and were instructed to take two capsules each morning (either placebo in PT arm or an increased dose of 20 mg of escitalopram in the ET arm) for the next three weeks. Following three weeks, the patients returned to complete self-report questionnaires and clinician-rated interviews. We refer to this assessment as Week 6, corresponding to the end of patients' use of escitalopram in Psychological Medicine the ET condition and three weeks following the last 25 mg psilocybin dosing session for patients in the psilocybin condition. This intervention procedure is presented in Fig.. Psychological support including psychoeducation, therapeuticalliance-building, and a form of Acceptance and Commitment Therapy, namely the Accept/Connect/Embody (ACE) modelwas administered over the course of 11 sessions beginning at screening and ending three weeks after the second dosing day (DD2). A preset music playlist was played to patients during their 4-6 h psychedelic experience. Six months following this assessment, patients were emailed survey links with additional self-report questionnaires. We refer to this assessment as Month 6. Only 21 patients from the ET condition and 25 patients from the PT condition responded at Month 6 follow-up. Groups tended not to differ in their usage of medication, psychedelics, and therapy during the follow-up period (online Supplementary Fig.).

PERSONALITY OUTCOMES

Big Five Personality Domains. The Big Five Inventory (BFI)) is a self-report scale designed to measure personality domains including Neuroticism, Extraversion, Openness (to experience), Agreeableness and Conscientiousness. Forty-four items are scored using a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). FFM domains have shown adequate test-retest reliability across an average interval of 4 weeks. Tests of internal consistency revealed a low correlation between BFI item 4 (depression) and the remaining items at baseline (r drop = -0.06). BFI item 4 was accordingly excluded from the Neuroticism domain score. Internal consistency ranged from 0.72 (Agreeableness -Baseline) to 0.88 (Extraversion -Week 6). The BFI was also assessed at Month 6. However, seven of 44 items failed to be assessed due to administrator error. Missing items included item 39 (Neuroticism), items 40, 41, and 44 (Openness), and item 42 (Agreeableness), and items 38 and 43 (Conscientiousness). For all follow-up analyses (aim 2), FFM domain scores were computed without these items (and BFI item 4 for the above reasons) for baseline, Week 6, and Month 6 timepoints. Internal consistency ranged from 0.72 (Agreeableness -Baseline) to 0.90 (Extraversion -Month 6). Due to the present study's clinical context, Extraversion and Agreeableness were reverse-scored and will heretofore be referred to as Introversion and Disagreeableness, respectively. Big Five Aspects Aesthetic Openness and Intellect. The Big Five Aspects Scale (BFAS)was used to measure two components of FFM Openness at an intermediate level of the personality hierarchy. Aspects Intellect and Aesthetic Openness were each measured by 10 items using a 5-point Likert scale (1 = Strongly disagree, 5 = Strongly agree). Internal consistency ranged from 0.82 (Aesthetic Openness Baseline) to 0.88 (Intellect Month 6). The BFAS was also assessed at Month 6. However, two of 20 items failed to be assessed due to administrator error. Missing items included Intellect item 10 and Aesthetic Openness item 6. For all follow-up analyses (aim 2), Intellect and Aesthetic Openness scores were computed without these items for baseline, Week 6, and Month 6 timepoints. Internal consistency ranged from 0.77 (Aesthetic Openness -Month 6) to 0.86 (Intellect -Week 6). Absorption. The Modified-Tellegen Absorption Scale (MODTAS)) is a self-report trait measure. Only the 25 scored items were included in this survey. Participants rated each Absorption item on a 5-point Likert-scale (1 = Never, 5 = Very often). Internal consistency was 0.92 (Baseline) and 0.95 (Week 6). Impulsivity. Barrett Impulsivity Scale-Brief (BIS-B)) is an 8-item self-report measure used to index lack of premeditation, a facet of impulsivity that overlaps with (low) FFM Conscientiousness. The BIS-B was used in lieu of the full BIS-11 in view of psychometric problems with the original scale involving low internal consistency and multidimensionality. Participants rated items using a Likert-scale (1 = Rarely/Never, 4 = Always). Internal consistency ranged from 0.70 to 0.75 across timepoints.

ACUTE FACTORS

Immediately following two dosing sessions, spaced three weeks apart, patients reported on properties of their acute experience. For each acute variable described below, the maximum value was selected from the two dosing sessions to serve as each patient's score. Mystical experience. The Mystical Experience Questionnaire (MEQ)) is a 30-item scale that measures mystical aspects of participants' experiences. The MEQ's items were originally represented on the Pahnke-Richards MEQ. In line with psychometric work, four subscales were assessed: Mystical (15-item; e.g. 'Experience of the fusion of your personal self into a larger whole'), Positive mood (6-item; e.g. 'Sense of awe or awesomeness'), Transcendence of time and space (6-item; e.g. 'Loss of your usual sense of space'), and Ineffability (3-item; e.g. 'Sense that the experience cannot be described adequately in words'). Participants rated each item on a 6-point Likert scale (1 = None, Not at all; 6 = Extreme, more than any other time in your life and stronger than 5). Internal consistency (α) ranged from 0.86 (Ineffable dosing day 1) to 0.98 (Mystical dosing day 1). Emotional Breakthrough. The Emotional Breakthrough Inventory (EBI)is a 6-item scale that measures productive engagement with emotional problems (e.g. 'I felt able to explore challenging emotions and memories'). Participants rated each item on a visual analog scale ranging from 0 (No, not more than usually) to 100 (Yes, entirely or completely). Internal consistency (α) was 0.95 (dosing day 1) and 0.97 (dosing day 2). Emotional Insight. One item using a visual analog scale (0-100) was used to capture psilocybin patients' ratings of emotional insightfulness during their dosing sessions ('Please rate how emotionally insightful the experience was overall'). Intensity. One item using a visual analog scale (0-100) was used to capture psilocybin patients' ratings of intensity during their dosing sessions ('Please rate the overall intensity of the drug effects when the effects were at their most intense'). Intensity is regarded to approximate the broad psychoactive and somatic effects of the drug, beyond particular psychological properties such as mystical experience or emotional breakthrough.

EXAMINING MODERATION OF PERSONALITY CHANGE

These analyses used dataset A to examine moderation of personality change (within each condition separately) by three sets of variables: response expectancy to control for possible positive pretrial expectancy effects under conditions of imperfect blinding (psilocybin expectancy was used for the PT condition; escitalopram expectancy was used for the ET condition), baseline characteristics (including personality, gender, age, unemployment status, education level, previous psychedelic use), and acute factors (including MEQ subscales, Emotional Breakthrough, Emotional Insight, Intensity). For expectancy-related analyses, moderation was tested only for personality outcomes that showed significant within-condition change. First, expectancies of treatment response in depression were examined as potential moderators of within-condition personality change. Full results are provided in online Supplementary Table. Contrary to recent critiques hypothesizing an important role for expectancy in biasing response to PT, expectancy for PT was not found to moderate prev. post-PT personality change in this study. Rather, positive expectancy for escitalopram did show evidence of significantly moderating Neuroticism and Conscientiousness in the ET condition, such that being higher in positive expectancy by one unit (on a 100 unit scale) was associated with an incremental decrease in Neuroticism of 0.01 units (p = 0.002) and increase in Conscientiousness of 0.01 units (p = 0.004). Furthermore, we tested a counterfactual model to address the question of whether change in Neuroticism and Conscientiousness following at Week 6 would remain significant if escitalopram expectancy was set to zero. Results indicated that change in Neuroticism and Conscientiousness would be non-significant if there had been no positive expectancy for ET. Second, baseline characteristics and acute factors were examined as moderators of personality change within each condition separately. Three instances of moderation were observed, but a regression to the mean effect could not be ruled out, and thus these results are not interpreted. For detailed results, see online Supplementary Materials III.

DISCUSSION

PT was associated with decreases in neuroticism, introversion, disagreeableness, and impulsivity, and increases in openness and absorption at study endpoint, whereas ET was associated with decreasesin neuroticism, impulsivity, and disagreeableness, and increases in openness. The pattern of personality changes within the PT arm are consistent with a robust antidepressant response based on empirical associations between personality and depression. Neuroticism converges quite closely with the cognitive-emotional core of depression, and can be understood as reflecting the shared variance of internalizing disorders. High introversion, or detachment, converges strongly with psychological symptoms of depression including anhedonia, amotivation, and low attention-seeking, and behavioral symptoms of depression including withdrawal and interpersonal passivity. Non-planning impulsivity, indexed by the measure of impulsivity used in this study, has been psychologicallyand neurobiologicallylinked to depression, and could in part contribute to work-related and cognitive dysfunction observed in depression. Notably, impulsivity showed the strongest standardized effect size change in an adaptive directioni.e., decreasing by 0.77 standard deviations (in terms of Cohen's d ) post-PT. Disagreeableness has shown a more peripheral relationship to depression, but there is evidence that disagreeable traits are sometimes expressed in the form of distrust and frustration, and experience-sampling data has revealed the centrality of angerbearing a substantial relation to disagreeableness)as a symptom of depression. As such, our results were suggestive that most of the personality domains principally associated with depression showed evidence of being impacted by PT therapy. Furthermore, adaptive alterations in personality showed evidence of being impressively maintained in the follow-up period following PT. Neuroticism remained lower up to six months following PT intervention, and, unlike in the only previous examination of PT-induced personality change, an open-label trial, we observed a moderately-sized decrease in disagreeableness three weeks post-intervention that appeared to persist six months later. In addition to examining domains related to depression, the present study expanded upon the open-label trial in observing increases in aesthetic openness, intellect, and absorption. Whereas changes in openness in the open-label trial were restricted to facets of openness to actions (indexing preference for variety and creativity) and values (indexing liberalism v. conservatism), the present study observed increases in a broader array of aspects and facets. Our results were suggestive that PT enhances cognitive exploration in both esthetic and intellectual domains, and leads to increased cognitive engagement with sensory and imagined phenomena (absorption). Such changes may covary with increases in facets of depression involving anhedonia and amotivation as openness has been linked to dopaminergic systems of wanting and reward. Greater cognitive exploration may also support psychotherapeutic processes of change involving deeper introspective engagement and motivation, phenomena that have been linked with psychedelic experience in previous work. In addition to assessing the effect of PT on personality domains, the study also aimed to identify potential differences between PT and ET in personality change. Interaction tests however found no compelling evidence for such differences. A few considerations are nonetheless worth noting. First, although there were no pre-registered hypotheses on absorption change, moderation-based tests were tentatively suggestive of a greater change in this domain with PT than ET. Second, pre-trial positive expectancy was observed to amplify neuroticism reductions in the ET condition, but not the PT condition, suggesting that placebo response localized to the ET condition may have limited our ability to detect a between-condition difference in neuroticism change. Finally, relatively poor statistical power (see Supplementary Materials IV) limited the study's ability to detect between-condition differences. However, differences between conditions did not exceed d = 0.20 across outcomes. Finally, our results contribute evidence for the effect of SSRI pharmacotherapy + psychological support on personality. Parallel to PT and consistent with previous evidence, ET was associated with decreases in neuroticism and impulsivity, and an increase in agreeableness. However, ET was not related to decreased introversion or increased conscientiousness immediately following therapy. Notably, patients reported increased openness, which is not empirically associated with SSRI pharmacotherapy. This result may be suggestive that the psychotherapeutic component of the trial exerted effects on openness, irrespective of drug effect, and raises questions regarding the true source of increased openness in the PT condition.

ADDITIONAL TREATMENT APPLICATIONS OF PT

Our results may also guide inferences about latent targets for PT that extend beyond the construct of depression. Implications include the possible utility of PT for treating disorders characterized by antagonistic externalizing (linked to disagreeableness, e.g. antisocial personality disorder, criminal antisocial acts, violations of rules of conduct) and detachment (linked to introversion, e.g. avoidant personality disorder)as well as the more conventional targets of internalizing (linked to neuroticism). 2 Furthermore, disorders characterized by a premeditation-based impulsivity may also be good candidates for PT, including substance use disorder, behavioral addiction (e.g. gambling), and self-harm. PT has already shown promising signs of efficacy in treating treatment-resistant cigarette use disorderand alcohol use disorder. Other therapeutic targets such as borderline personality disorder and mania may also be relevant to explore, though more research is needed to determine the safety of psychedelic therapy for these populations in view of higher degrees of mood lability and self-harm. Given neuroticism's overlap with the shared variance of internalizing disorders, PT's efficacy may extend to multiple internalizing disorders via a common mechanism, as well as phenotypes of disinhibiting and antagonistic externalizing disorders wherein externalizing behaviors proximally originate in states of emotional distress (e.g. as in negative urgency within some presentations of substance use disorder,. We suggest that the present results guide enhanced investment in research exploring PT's utility across these relevant mental health disorders. Unique benefits of PT Our results may also hold important implications for how PT remediates depression. Given introversion/extraversion's overlap with positive emotion, sociability, energy, and agency, therapies that differentially decrease introversion (or increase extraversion) may be particularly relevant in remediating symptoms of anhedonia and amotivation, and may also furnish the energy and inclination for exploring new environmental rewards. Given evidence that patients with persistent depression are disproportionately higher in disagreeable traits, therapies that resolve disagreeableness may be clinically useful for longerterm and treatment-resistant profiles of depression. In addition, when considering these effects in therapeutic context, it may be useful to understand that whereas adaptive changes in neuroticism and disagreeableness have shown longer-term maintenance, adaptive changes in introversion may be more time-limited (c.f.. Possible benefits and risks related to absorption PT's influence on absorption may also bear important health-related implications. On one hand, enhanced absorption may be beneficial as absorption is associated with novel engagement with imagined and exterior sensory and affective experiences, vivid spiritual experience, and creative style and capacity. On the other hand, there is a small body of literature that links absorption, albeit weakly, to thought disorder and psychoticism, schizotypal personality (r = 0.23), and anxiety sensitivity. Convergent with these findings is recent evidence that the shared variance between esthetic openness and psychoticism (which is likely to overlap with absorption)are empirically linked to apophenia, indexed by false-positive errors on multiple behavioral tasks). Absorption's association with apophenia, a tendency toward implausible pattern detection, may also be consistent with a recent study that observed higher absorption participants to report a higher frequency of extraordinary experiences while wearing a sham helmet. A disposition toward false-positive pattern detection could be advantageous in certain domains (e.g. art, spirituality, invention), but some scholars have raised concerns about maladaptive effects, especially when expressed in the absence of intelligence, subserving reality-testing. For example, such a disposition has been proposed as a potential risk factor for the development of psychosis. We support future research examining psychedelics' contribution to psychosis risk, especially in view of empirical suggestions of links thereof. However, we do not wish to conflate absorption with psychopathology. Asalso caution, cognition is only psychopathological to the degree that it accompanies distress or impairment. Importantly, we refer the reader to studies that have not shown evidence of emergent psychosis following psychedelic experience.

RESPONSE EXPECTANCY OBSERVED FOR ET CONDITION

Analyses adjusting for pre-trial expectancy found evidence of substantial moderation of changes in neuroticism via positive expectancy for escitalopramand this moderation was exclusive to the ET condition i.e., not observed in the PT condition. Specifically, higher initial expectancy about the efficacy of escitalopram for remediating depression was associated with greater reported decreases in neuroticism, and estimates from a counterfactual model were suggestive that significant change in neuroticism would not be present among patients had there been no positive expectancy for escitalopram. This asynchrony in response expectancy was surprising given that expectancy effects have been observed across a number of pharmacological and psychotherapeutic treatmentsincluding psychedelic modalities, and both SSRIs and psilocybin are associated with substantial levels of unblinding even within double-blind randomized controlled trials. Why expectancy response was not observed in the PT arm is not clear. Variance in pre-trial expectancy was not lower in the PT v. ET arm, and there was no evidence of a ceiling effect in PT arm scores, e.g., mean expectancy was 54% out of 100%. As a speculative explanation that requires further research, the acute experience related to PT may have been sufficiently psychologically dramatic as to disrupt the implicit effects of expectancy that would have obtained had the treatment been more subtle. Another relates to the fact that all patients endorsed non-zero positive pre-trial expectancy; it is conceivable that a hidden non-linear effect of expectancy obtained such that PT patients in the trial tended not to meaningfully differ in expectancy response regardless of their positive expectancy rating, but had PT patients been included endorsing zero expectancy, these patients could have exhibited lower expectancy response. Nevertheless, a potential implication of these findings is that ET's causal influence on neuroticism is to some degree called into question, especially in a study wherein patients were likely to know they were in the SSRI condition. A critical look at between-condition differences According to interaction tests, between-condition differences in personality change were not statistically significant, though suboptimal statistical power in a small sample undoubtedly contributed to lower sensitivity (see online Supplementary Materials IV for sensitivity power analyses). One interpretation of the present findings therefore is that PT and ET have comparable effects on personality. We are cautious to draw such conclusions prematurely, however, in view of three considerations. First, limits on statistical power make replications in larger samples necessary. Second, as just mentioned, positive expectancy (otherwise known as the 'placebo effect') may have disproportionately affected the SSRI condition, raising the possibility of PT's superiority in reducing neuroticism. Third, we failed to hypothesize a between-condition difference in change in absorption within our preregistration [erroneously given its empirical overlap with openness]. We accordingly refrain from concluding a between-condition difference here, but encourage future researchers to examine absorption in future clinical trials involving PT, and submit the hypothesis that increases in trait absorption will be greater for PT than for SSRI + psychotherapy treatment. If PT were found to differentially increase trait absorption, this would have important implications because increased absorption may either present a benefit to receptive patients, e.g., being predictive of greater therapeutic improvement, or confer iatrogenic risk, e.g., by promoting traits related to psychoticism.

FUTURE DIRECTIONS

Our findings logically lead to a number of future lines of research. Methodologically, we believe there is value in (1) replicating this study with a larger sample to enable detection of smaller (but still clinically meaningful) between-condition differences; (2) implementing periodic tests of expectancy and blind-breaking throughout the study period; (3) employing expectancy measures tailored to the personality domains under study; and (4) adapting global personality measures (i.e. referring to questions about general psychological and behavioral patterns) to be retrospective over short time-periods (e.g. 3 h and/or 1 day) to afford greater sensitivity to change, in line with calls for more ecologically valid intensive longitudinal measurementand the density distribution conceptualization of personality. Clinically, there is value in using these findings as a basis for (1) designing clinical trials examining psychedelic therapeutic applications for putatively responsive clinical phenotypes identified in the present work, e.g., behavioral addiction, self-harm, antisocial personality disorder, involving impulsivity and disagreeableness; and (2) probing the effect of PT on trait absorption as well as evaluating the risks and benefits associated with such increases. Finally, this study was focused exclusively on psychological outcomes and did not examine potential neurobiological mechanisms relating to the observed personality changes. Recent neuroimaging findings from the present trial's cohort and a previous TRD trial of ours revealed decreased brain network modularity post-PT in both trials that correlated with decreases in symptom severity in both independent samples. Merging the Research Domain Criteriaand HiTOP approaches to psychopathologymay invite hypothesis testing regarding relationships between post-PT changes in network modularity or alternative imaging Psychological Medicine metrics and related changes in high-level domains of psychopathology.

Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression

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Psilocybin vs Escitalopram for Major Depressive Disorder: Comparative Mechanisms

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Abstract

Research Summary of 'Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression'

Introduction

Methods

INTRODUCTION

PERSONALITY AS A SIGNAL OF RELEVANT TREATMENT TARGETS

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Study Details

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Results

Discussion

Conclusion

USING PERSONALITY TO PROBE THERAPEUTIC RESPONSE IN DEPRESSION

EVIDENCE FOR PERSONALITY CHANGE ACCOMPANYING PT AND SSRI THERAPIES

SECTION

PRESENT STUDY

STUDY DESIGN AND PARTICIPANTS

PERSONALITY OUTCOMES

ACUTE FACTORS

EXPECTANCY

ANALYTIC PLAN

DESCRIPTIVES OF CHANGE IN PERSONALITY OVER TIME

EXAMINING PERSONALITY CHANGE AT WEEK SIX ASSESSMENT

EXAMINING PERSONALITY CHANGE AT MONTH SIX ASSESSMENT

EXAMINING DIFFERENCES IN PERSONALITY CHANGE BETWEEN TREATMENT CONDITIONS

EXAMINING MODERATION OF PERSONALITY CHANGE

DISCUSSION

A POTENTIAL TREATMENT ALTERNATIVE TO SSRI PHARMACOTHERAPY

ADDITIONAL TREATMENT APPLICATIONS OF PT

RESPONSE EXPECTANCY OBSERVED FOR ET CONDITION

LIMITATIONS

FUTURE DIRECTIONS

CONCLUSION

NOTES