Major depression is a commonly occurring disorder associated with high morbidity, socio-economic burden, and rates of completed suicide (1, 2). It affects 10–15% of the general population and has been ranked by The World Health Organization (WHO) as the fourth leading contributor to the global burden of disease (5), with a forecast of becoming number one by 2030. Almost half of the cost and disease burden caused by depression has been attributed to treatment-resistant depression (TRD), typically defined as ‘a poor response to two adequate trials of different classes of anti-depressants’. TRD is associated with longer duration and higher severity of the disease, more protracted functional impairment, and poses a significant personal and public health problem. TRD affects about 30% of patients with major depression and up to 60% if TRD is defined as absence of remission. The poor prognosis and socio-economic burden associated with TRD give ground for research focusing on therapeutic interventions with alternative strategies to conventional pharmaceutical and therapeutic approaches.
The aim of the present study was to explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment-resistant depression, to investigate whether these changes relate to the quality of the psychedelic experience and to investigate whether such modulations could potentially help us understand the long-lasting nature of psychedelic-assisted therapy.
Beginning in the 1990s, neurobiological and psychiatric interest in classic serotonergic psychedelic compounds, such as psilocybin, N, Ndimethyltryptamine (DMT), and lysergic acid diethylamide (LSD), gradually re-emerged after decades of being suppressed. Recent pilot studies point to the potential of psychedelic-assisted therapy to treat conditions including tobacco and alcohol addiction, obsessive-compulsive disorder, end of life anxiety/depression, major depression, and Treatment-Resistant Depression.
Typically, psychedelic-assisted therapy involves only one or two sessions in which a moderate to high dose of a psychedelic compound is given in a supportive environment with the intention of evoking ‘peak’ or ‘mystical-type’ experiences, characterized by disintegration of ego boundaries and an accompanying sense of connectedness, oneness, or unity. This treatment paradigm differs from the approach of long-term daily pharmacological intervention associated with conventional antidepressant medication.
The mechanisms underlying the long-lasting therapeutic effects of psychedelic therapy remain unknown. There appears to be a relationship between the therapeutic outcome and the subjective experiences during the psychedelic sessions. Moreover, psilocybin and LSD may increase the NEO-PI-R personality trait Openness to Experience (or simply ‘Openness’) in healthy volunteers after a single dose. Interestingly, and constituting a possible link between the quality of the experience and the impact on personality, in the subgroup of participants who had mystical experiences during their psilocybin session,
Openness remained significantly higher than baseline more than 1 year after the session. Openness is considered to be one of the five major dimensions of personality and is linked to Openness to new ideas and values, imagination, aesthetic appreciation, novelty-seeking, non-conformity, and creativity. In major depression, effective treatment with antidepressants has been shown not only to increase Openness scores but also to significantly affect three of the remaining four NEO-PI-R personality domains: decreasing Neuroticism, increasing Extraversion and Conscientiousness, with Agreeableness remaining unchanged.
Summary of Findings
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 follow-up, 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 direction – that is toward the personality profile of healthy populations.
- 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.
- 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 – 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.
In summary, the study detected changes in personality measures from baseline to 3 months post psilocybin therapy in patients suffering major depression. Decreases in Neuroticism and (trend-level) 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. Additionally, the neurobiological correlates of personality change after psychedelics have yet to be investigated.