Recreational use of psychedelics is associated with elevated personality trait openness: Exploration of associations with brain serotonin markers

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David Erritzoe, James Smith, Patrick M Fisher,

First Published February 28, 2019 Research Article Find in PubMed https://doi.org/10.1177/0269881119827891

Article information  : British Association for Psychopharmacology

Abstract

Background:

Recent studies have suggested therapeutic benefits of psychedelics for a variety of mental health conditions. The understanding of how single psychedelic administrations can induce long-lasting effects are, in large, still lacking. However, recent studies in both healthy and clinical populations suggest a role for personality changes.

Aim:

To test support for some of these plausible mechanisms we evaluated (cross-sectional) associations between recreational use of psychedelics and 3,4-methylene-dioxymethamphetamine (MDMA) and (a) personality measures and (b) key markers of cerebral serotonergic signalling (serotonin transporter and serotonin-2A-receptor binding).

Methods:

In 10 psychedelic-preferring recreational users, 14 MDMA-preferring users and 21 non-using controls, personality was assessed using the ‘big five‘ instrument Revised NEO Personality Inventory (NEO-PI-R). Frontal serotonin transporter and serotonin-2A-receptor binding potentials were quantified using [11C]DASB and [18F]altanserin positron emission tomography, respectively.

Results:

Of the five NEO-PI-R traits, only openness to experience scores differed between the three groups; psychedelic-preferring recreational users showing higher openness to experience scores when compared with both MDMA-preferring users and controls. Openness to experience scores were positively associated with lifetime number of psychedelic exposures, and among all MDMA-preferring user/psychedelic-preferring recreational user individuals, frontal serotonin transporter binding – but not frontal serotonin-2A-receptor binding – was positively associated with openness to experience.

Conclusion:

Our findings from this cross-sectional study support increasing evidence of a positive association between psychedelic experiences and openness to experience, and (a) expands this to the context of ‘recreational’ psychedelics use, and (b) links serotonergic neurotransmission to openness to experience. A modulation of personality induced by psychedelic experiences may have important therapeutic implications via its impact on peoples’ value systems, cognitive flexibility, and individual and social behaviour.

Keywords Openness, psychedelics, 3,4-methylene-dioxymethamphetamine, serotonin, serotonin transporter

Introduction

Psychedelic substances, such as psilocybin, mescaline, and dimethyltryptamine (DMT) have been used in various cultures for more than 5000 years (El-Seedi et al., 2005), and may belong to the first class of psychopharmacological agents known to man (Nichols, 2016). In the acute state, these agents typically produce characteristic perceptual changes together with a sense of insightfulness, connectedness and awe (Carhart-Harris et al., 2018). After having been practically inaccessible for scientists for decades, research investigating the potential therapeutic value of psychedelics has recently re-surfaced. Thus, clinical pilot studies designed to test the use of psychedelics in conjunction with psychotherapies to treat a variety of mental health conditions, from addiction to anxiety and depression have been carried out (Carhart-Harris and Goodwin, 2017). Alongside the revival of psychedelic science, 3,4-methylene-dioxymethamphetamine (MDMA) or ‘ecstasy’, often referred to as an ‘empathogen’ rather than a psychedelic, is also currently being studied for its treatment potential, in particular for post-traumatic stress disorder (Mithoefer et al., 2013). Both psychedelics and MDMA exert their main mode of action on the brain’s serotonin (5-HT) system. However, whereas MDMA mainly boosts the release of 5-HT into the synapse by reversing the serotonin transporter (SERT) (Battaglia et al., 1988), the psychedelics directly stimulate (or agonise) 5-HT receptors, in particular the 5-HT2A receptors (5-HT2A-Rs) (Vollenweider et al., 1998).

Despite sharing a primary serotonergic action with the pharmaceuticals used to treat affective disorders, such as selective serotonin-reuptake inhibitors, therapies using MDMA and psychedelic compounds differ significantly from traditional pharmacotherapies in psychiatry. Thus, in contrast to the continued daily dosing of conventional pharmaceuticals, the psychedelic/MDMA treatment models employ only 1–3 dosing session(s) with a moderate to high dose of the compound. Intriguingly, the treatment effect after such sessions appears to last for several months (Carhart-Harris and Goodwin, 2017), and thus much longer than the actual presence of the compounds in blood (i.e. with half-lives ranging from minutes to a few hours). In follow-up studies, exposure to both a psychedelic or MDMA, in well-supported experimental/therapeutic settings, has been shown to lead to long-lasting changes in personality. Intriguingly, an increase in openness to experience (Openness), one of the ‘big five’ personality traits, has been observed after a single administration of psilocybin to psychedelic-naïve healthy individuals (MacLean et al., 2011) and a single dose of lysergic acid diethylamide (LSD) to healthy subjects with previous experience with psychedelics (Lebedev et al., 2016). In clinical pilot studies, 2–3 therapeutic sessions with either psilocybin for depression (Erritzoe et al., 2018) or MDMA for post-traumatic stress disorder (Wagner et al., 2017) has also led to increases in Openness scores. The possible implication of the change in personality in relation to the therapeutic effects of psychedelics/MDMA is currently being investigated. In good agreement with the results arising from such intervention-based experimental/therapeutic studies, cross-sectional studies have recently shown that recreational or ceremonial use of psychedelics is also associated with increased Openness scores (Barbosa et al., 2016; Nour et al., 2017). Interestingly, cognitive flexibility has been shown to be positively modulated by 5-HT2A-R functioning (Boulougouris and Tsaltas, 2008; Furr et al., 2012) and 5-HT2A-R agonists (such as LSD, DMT and psilocybin) to facilitate enhanced cognitive flexibility and creative thinking (Frecska et al., 2012; Harman et al., 1966; Janiger and Dobkin de Rios, 1989; King et al., 1974; Kuypers et al., 2016; McGlothlin et al., 1967; St John Sessa, 2008). Based on these observations in combination with evidence that repeated administrations of 5-HT2A agonist psychedelics pre-clinically cause 5-HT2A-R down-regulation (Buckholtz et al., 1988), it is possible that 5-HT2A-R binding is negatively associated with Openness scores among recreational users of substances that directly (psychedelics) or indirectly (MDMA) stimulate the 5-HT2A-R – a relationship not yet explored.

The mechanisms underlying the long-lasting therapeutic effects of MDMA and psychedelic therapies, as well as the personality changes observed in relation to exposure to psychedelics/MDMA, are poorly understood. Investigation of the neurobiology behind personality changes associated with naturalistic/recreational exposure to psychedelics/MDMA offers an important approach to better characterise these compounds and key aspects of their roles in new promising treatment paradigms. Therefore, the aim of this study was to evaluate potential links between molecular brain imaging markers of key features of 5-HT signalling, namely frontal SERT and 5-HT2A-R binding (as imaged with positron emission tomography (PET)), and personality domain scores among individuals who recreationally use psychedelics/MDMA and non-using matched controls. We hypothesised that Openness scores would be higher among MDMA and psychedelic users as compared with non-using controls, and that Openness scores among psychedelic and/or MDMA users would correlate negatively with cortical 5-HT2A-R binding.

Methods

Study design

This is a case-control study with single time point assessment of personality structure and serotonergic brain imaging markers in 24 young adult users of recreational serotonergic (10 psychedelic preferring users and 14 MDMA preferring users) and 21 age-gender-matched non-using controls. The main PET imaging outcomes, SERT and 5-HT2A receptor binding, for the same study sample have been published previously without the personality data (Erritzoe et al., 2011).

Participants

Recreational users of psychedelics and/or MDMA in Denmark were recruited via flyers, advertisements, word of mouth and websites. Individuals between 18–35 years old with a minimum of 12 lifetime exposures to psychedelic drugs or MDMA, as well as use of such substances within the last year prior to inclusion were eligible for the study. Prior or current neurological or axis I psychiatric disorders were exclusion criteria. Control subjects were not allowed to have had more than 15 lifetime exposures to cannabis or any history of other illegal drug use, and use was not allowed for seven days prior to the brain imaging. In total, 24 adult users of psychedelics and/or MDMA (21 men and three women) with a mean (standard deviation (SD)) age of 24.6 (4.0) years and 21 controls (17 men and four women) with a mean age of 23.8 (3.4) users were included in the study. One user had never taken MDMA and three others had never used psychedelics, and users were divided into two groups according to their lifetime exposures to psychedelics and MDMA. The 10 drug users who had used psychedelics at more lifetime occasions than MDMA were named ‘psychedelic preferring users’ (PPUs) whereas the 14 users who had used MDMA at more occasions than psychedelics were named ‘MDMA preferring users’ (MPUs). PPUs had a lifetime history of 107±84 occasions with use of a psychedelic and 18±22 occasions with use of MDMA, whereas MPUs had used MDMA at 236±204 and psychedelics at 23±25 lifetime occasions. Abstinence from illegal drug intake in the week prior to scanning was confirmed by urine drug screenings. Self-reported recent use of MDMA was confirmed by gas chromatography mass spectroscopy analysis of hair segments which covered approximately three months prior to scan. More details about demographics, substance use history and results from group comparisons of PET-measured SERT and 5-HT2A-R data from the same study sample can be found elsewhere (Erritzoe et al., 2011; Frokjaer et al., 2014).

Personality assessment

The Revised NEO Personality Inventory (NEO-PI-R), which consists of 240 self-descriptive statements scored using a five-point Likert scale was used to assess the Big Five personality traits; Neuroticism, Extroversion, Openness, Agreeableness and Conscientiousness (Costa and McCrae, 1992). Each trait can further be divided into six correlated facets, and for for the trait Openness these are facets of fantasy, aesthetics, feelings, actions, ideas and values (McCrae and John, 1992).

Brain imaging

PET imaging of SERTs and 5-HT2A-Rs was conducted with [11C]–labelled 3-amino-4-[2-[(di(methyl)amino)methyl] phenyl] sulfanylbenzonitritile (DASB) and [18F]–labelled altanserin, respectively. Both scans were acquired on an 18-ring scanner (GE-Advance scanner; GE, Milwaukee, Wisconsin, USA) operating in three-dimensional acquisition mode. For [18F]altanserin scans, subjects underwent a 40-minute scan under tracer steady-state conditions (Pinborg et al., 2003), for [11C]DASB a dynamic 90-minute emission recording was initiated after intravenous injection of the radioligand (for scan protocol details, see Erritzoe et al., 2010). The cerebellum was used as a reference region for analysis of both radioligands because it represents non-specific binding. The PET imaging outcome measures were the non-displaceable binding potential (BPND) for [11C]DASB and BPp for [18F]altanserin). A frontal cortical region of interest (ROI) was automatically delineated on each participant’s transaxial magnetic resonance (MR) image sections in a user-independent fashion (Svarer et al., 2005). With this approach, a template set of 10 MR images was automatically co-registered to a new participant’s MR image. The identified transformation parameters were used to define the ROI in the new person’s MR image space and, through co-registration, these ROIs were transferred onto the PET images.

Statistical analysis

All analyses were conducted in SPSS version 21.0 and R version 3.3.1 (https://cran.r-project.org/). A p-value <0.05 was considered statistically significant, and all parametric tests were two-tailed. We used one-way analysis of variance (ANOVA) to analyse differences in Neuroticism, Extraversion, Openness, Agreeableness and Conscientiousness scores (as measured by NEO-PI-R) between MPUs, PPUs and controls. Correction for multiple comparisons was performed using the Tukey Test. Using linear regression analysis, we tested whether lifetime use of psychedelics (=logarithm 2 to lifetime number of exposures, as per Erritzoe et al., 2011) was associated with Openness scores. To probe neurobiological mediators of this association, we evaluated frontal SERTs and frontal 5-HT2A-Rs as predictors of Openness in two separate linear regression analyses. Group-specific associations (MPUs vs PPUs and MPUs/PPUs vs controls) were evaluated using an interaction analysis (group-by-frontal SERT/5-HT2A-R interaction term). The robustness of identified significant associations were investigated by adjusting for age. This was due to existing evidence of age-related changes in personality scores – although these are only modest (less than one T-score point per decade) (Terracciano et al., 2005). The sample used for these analyses included all users with a history of psychedelic use (21 of the 24 users) in order to maximise power, but for analysis including 5-HT2A-Rs, only 19 of the original 21 subjects with lifetime use of psychedelics were included since two subjects did not have [18F]altanserin scans.

We evaluated evidence for frontal SERT binding mediating the association between lifetime number of exposures and Openness using a structural equation model and approximate standard errors using the delta method including only the n=21 individuals with lifetime psychedelic use. Confidence intervals were compared with non-parametric bootstrap estimates (1000 resamples with replacement), which produced similar results. Structural equation models were estimated using the lava-package version 1.5 in R (Holst and Budtz-Jørgensen, 2013).

The study took place in Copenhagen, Denmark, and was approved by the local ethics committee of Copenhagen and Frederiksberg, and was conducted in accordance with the Declaration of Helsinki (Ethics reference number VEK KF-01-124-04). Written informed consent was obtained from all participants.

Results

NEO-PI-R scores and psychedelic use

Group comparison of PPUs, MPUs and controls showed a statistically significant difference in Openness scores (F(2,42)=6.02, p=0.005). Post-hoc testing revealed that PPUs had statistically significantly higher levels of Openness than MPUs (147±16 vs 126±15, p=0.017) and non-using controls (147±16 vs 124±20, p=0.05), whereas there was no statistically significant difference in Openness score between MPUs and controls (126±15 vs 124±20, p=0.972) (Figure 1). Also, there were no group differences in any of the other four personality domains (Neuroticism, Extraversion, Agreeableness or Conscientiousness scores), data presented in Table 1. Of note, the reported NEO-PI-R personality scores of the 21 controls did not differ significantly from an age-matched sample of healthy adults from a Danish norm group (Hansen and Mortensen, 2004) on the traits of Agreeableness, Conscientiousness, or Extraversion, but our sample showed a significantly higher score on trait Openness (p<0.01) and borderline lower scores on trait Neuroticism (p=0.06).

figure

Figure 1. Psychedelic preferring users had significantly higher levels of openness to experience (Openness) than 3,4-methylene-dioxymethamphetamine (MDMA) preferring users (147±16 vs 126±15, p=0.017) and non-using controls (147±16 vs 124±20, p=0.05), whereas there was no statistically significant difference in Openness score between MDMA preferring users and controls.

Table 1. Groups and personality differences.

Table 1. Groups and personality differences.

View larger version

Among all individuals who had used psychedelics (n=21), lifetime number of psychedelic exposures was positively associated with Openness (Openness score increased with 4.6±1.7 per doubling in lifetime psychedelic exposure, p=0.015) (Figure 2) on regression analysis. This relationship remained significant when adjusting for age (p=0.019). Explorative analysis of the Openness’ facets revealed that openness to values (1.0±0.3 increase in score per doubling in lifetime psychedelic exposure, p=0.009), openness to actions (1.0±0.3, p=0.010), and openness to ideas (1.2±0.5, p=0.013) showed significant positive associations with lifetime psychedelic use, openness to aesthetics showed a borderline association (1.1±0.6, p=0.087), whereas openness to feelings and fantasy were not associated (p=0.770 and p=0.782, respectively).

figure

Figure 2. Lifetime number of psychedelic exposures was positively associated with openness to experience (Openness; this score increased with 4.6±1.7 per doubling in lifetime psychedelic exposure, p=0.015) within the group with a history of psychedelic use (n=21).

SERT and 5-HT2A-R binding: Possible mediators of the effect on Openness?

Among all MPU/PPU individuals (n=24), frontal SERT binding was positively associated with Openness (Openness score increased with 11.1±4.3 per 0.1 unit increase in SERT BPND, p=0.016) (Figure 3), but not frontal 5-HT2A-R binding (p=0.78) in a regression analyses. This association was not significantly moderated by MPU/PPU group (interaction: p=0.70), suggesting a similar association across these two groups. This positive SERT vs Openness association was not present in controls (n=21, p=0.67) but there was no significant group (MPUs/PPUs vs controls) by frontal SERT binding effect on Openness (interaction: p=0.11), providing only nominal evidence that MPU/PPU individuals have a more positive SERT vs Openness association compared with controls (see figure in the Supplementary Material). Lastly, we did not observe that SERT binding mediated the observed association between lifetime psychedelic use and Openness (mediation parameter estimate: 0.85±0.83, p=0.31).

figure

Figure 3. Frontal serotonin transporter (SERT) binding was positively associated with openness to experience (Openness; this score increased with 11.1±4.3 per 0.1 unit increase in SERT non-displaceable binding potential BPND, p=0.016).

Discussion

In this study, recreational drug users who had been predominantly using psychedelic substances (n=10) were found to score higher on the NEO-PI-R trait, Openness, than both MPUs (n=14) and non-using matched controls (n=21). None of the other four NEO-PI-R traits differed between the three groups. Furthermore, among individuals who had used psychedelics, Openness was positively associated on regression analysis with lifetime psychedelic use, and Openness was also positively associated with frontal SERT binding among psychedelic/MDMA users, while not associated with postsynaptic 5-HT2A-R binding. These result were tested for robustness by adjusting for age due to existing evidence of age-related changes in personality scores.

In good agreement with this finding, people with regular ceremonial use of the psychedelic brew, ayahuasca, also had higher Openness scores than matched ayahuasca-naive controls (Barbosa et al., 2016). In addition, users of psychedelics compared with users of other substances such as cannabis, amphetamine and heroin (Lerner and Lyvers, 2006) have been shown to be more creative – a trait tightly linked with Openness (Kaufman et al., 2016; McCrae, 1987). Of close resemblance to our main finding in the present study, Openness – although assessed with a much shorter instrument (Ten-Item Personality Inventory) – was recently found to be positively associated with self-reported lifetime psychedelic use (and also with preferential psychedelic versus cocaine use) in an on-line survey with 893 participants (Nour et al., 2017). However, the cross-sectional nature of these studies, as well as our dataset, does not allow for conclusions about the direction of causality between psychedelic use and Openness, and it is important to point out that, in theory, individuals with high Openness could be more prone to use psychedelics. However, under the assumption that someone with greater Openness would be more likely to search for drug experiences in general, one might also expect that MPUs in our study would score above control levels. This was not the case and, furthermore, Openness is not known from the literature to be a predictor of substance misuse in general (Kotov et al., 2010). Thus, although no firm conclusion can be made on this from a cross-sectional study, our observation of higher Openness scores among PPUs might reflect an increase in the trait due to exposure to psychedelics. Further support for this interpretation comes from longitudinal studies where personality has been assessed before and after exposure to a psychedelic (Erritzoe et al., 2018; Lebedev et al., 2016; MacLean et al., 2011). Thus, both single administration of psilocybin (MacLean et al., 2011) and LSD (Lebedev et al., 2016) has been shown to lead to increases in Openness at 14 months and two weeks follow-up, respectively. More recently, psilocybin therapy given to patients suffering treatment resistant major depression also led to increases in Openness scores at three months post-session follow-up (Erritzoe et al., 2018). Overall, personality changes in this pilot trial in depression overlapped with what has been observed previously when assessing personality pre- and post treatment of depression (Costa et al., 2005), although the increase in Openness appears even more pronounced with the psychedelic therapy (Erritzoe et al., 2018). Further 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 on-line, of a psychedelic experience conducted by our team. Here, Openness changed equally for depressed and non-depressed whereas, for example, changes in Neuroticism were only observed among depressed individuals (Erritzoe et al., 2018). Together these studies suggest psychedelic experiences can cause increases in Openness.

Of note, it was the same two Openness facets, openness to actions and to values, that significantly increased after psilocybin-therapy in the recent pilot trial in depression (Erritzoe et al., 2018), and that were particularly strongly (and significantly) correlated with lifetime psychedelic use in our present sample (note that the Openness facet scores were not tested in the study by MacLean and colleagues). The facet openness to actions includes items such as ‘I think it’s interesting to learn and develop new hobbies’ and pertains to not being set in one’s own way, and being ready to try and do new things, whereas openness to values contains items such as ‘I consider myself broad-minded and tolerant of other people’s lifestyles’ and is about permissiveness, open-mindedness, and tolerance to other peoples lifestyles. Thus, these two facets reflect an active approach of the individual to try new ways of doing things and re-define their own values and/or world-views. When considering the reason for openness to action and to values apparently being more strongly associated with the effects of psychedelics when compared with the other openness facets, one might think that these two facets are simply more tightly associated with the trait Openness itself. However, in contrast these two facets load less on the trait of Openness compared with the four other facets (Hansen and Mortensen, 2004), suggesting that these two facets specifically, rather than the more broad concept of trait of Openness, are the ones being modified by psychedelics. In line with the ability to nourish openness to action and values, use of LSD in ‘non-medical’ settings has in the past been associated with attitudes of ‘personal liberty’ and ‘foreign policy liberalism’ (McGlothlin and Arnold, 1971). Moreover, recent separate studies have now shown that psychedelic use is associated with greater liberalism and libertarianism (Nour et al., 2017), nature-relatedness and anti-authoritarianism (Lyons and Carhart-Harris, 2018), pro-environmental behaviour (Forstmann and Sagioglou, 2017), concerns for others and lower value on financial prosperity (Lerner and Lyvers, 2006). Importantly, the study by Lyons and colleagues suggests that psychedelics may be causal of these changes (Lyons and Carhart-Harris, 2018). It is well-established that Openness is closely associated with liberalism within individuals (Carney et al., 2008; Sibley et al., 2012; Xu et al., 2013) but in this study, we did not have additional ratings of political attitudes or similar concepts.

Interestingly, MDMA-assisted therapy for post-traumatic stress disorder has recently also been reported to lead to long-lasting increases in Openness (Wagner et al., 2017), which also led us to hypothesise that MPUs would score higher on Openness then non-using controls. It is therefore worth considering why it was the psychedelic preferring users exclusively – and not also MPUs – who had high Openness scores in our study. The context in which these drugs are taken, or administered, is understood to be of great importance (Erritzoe and Richards, 2017; Hartogsohn, 2016; Johnson et al., 2008), and a therapeutic setting with its focus on exploration of what is happening ‘inside’ in a safe and closely supported environment is likely to be a stronger facilitator of transformative experiences than, for example, when the same drugs are taken in a party context. Where recreational use of MDMA is known to be closely associated with a club/dance/party setting (Schifano et al., 2006; Smit et al., 2009), psychedelics are often taken recreationally under circumstances more closely associated with therapeutic applications, for example to promote introspection (Hallock et al., 2013). In further support of this distinction between the contexts of recreational use of MDMA versus psychedelics, MDMA is frequently used in combination with party drugs, such as amphetamine and cocaine, whereas we have previously found that this is 2–8 times less common for psilocybin or LSD (Licht et al., 2012). For these reasons, recreational psychedelic use might be more potent at boosting Openness than recreational MDMA use. An important limitation of our study – and of studies investigating substance use in general – is the use of more than more than one substance, also within the ‘preferring’ groups. Based on our group finding of higher openness among psychedelic preferring users, we have focused our regression analyses on the use of psychedelics – but these results should be interpreted with some caution due to concurrent use of other substances including MDMA (details about substance use are listed in Erritzoe et al., 2011 reporting on the same sample).

The neurobiological correlates of personality changes related to experimental administration or recreational/ceremonial use of psychedelics are yet to be discovered. In this study we therefore explored indirect (cross-sectional) evidence whether cortical SERT or 5-HT2A-R binding mediated the observed drug-group-related differences in personality scores. SERT binding in the frontal cortex was found to be significantly positively associated with the trait of Openness among PPUs/MPUs. Further analysis did not support a model where SERT binding mediated the association between lifetime psychedelic use and Openness. Notably, we tested for this mediation effect in a small sample for such a model, owing in part to the uniqueness of this dataset; thus, we cannot rule out that our non-significant effects reflect a type-II error (MacKinnon et al., 2002). Also, we could not demonstrate a significant difference in association between frontal SERT and Openness between PPUs/MPUs and controls, i.e. only trend-wise did the slopes differ between groups (see figure in Supplementary Material), which we interpret with caution due to power limitations. We have previously published the comparison of both SERT and 5-HT2A-R binding between the PPUs, MPUs and matched non-using controls and reported no difference in either SERT or 5-HT2A-R binding between PPUs and controls, with only MPUs versus controls showing low SERT binding (Erritzoe et al., 2011). Thus, the detected association between frontal SERT and Openness scores reflects high Openness scores among individuals with high SERT binding among the psychedelic/MDMA users. It could be speculated that among people with a history of psychedelic or MDMA use, individuals with the highest SERT binding have greater synaptic clearance of 5-HT and subsequently lower basal synaptic 5-HT and lower basal 5-HT2A-R stimulation, and that this under-stimulation represents an adaptation to unusually high drug-induced 5-HT2A-R stimulation (driving an increase in Openness). This interpretation relies on the hypothesis that Openness would increase as a direct consequence of the 5-HT2A-R stimulation. In support of such a mechanism, cognitive flexibility has been found to be positively modulated by 5-HT2A-R functioning (Boulougouris and Tsaltas, 2008; Furr et al., 2012) and that 5-HT2A-R agonists (such as LSD, DMT and psilocybin) facilitate enhanced cognitive flexibility and creative thinking (Frecska et al., 2012; Harman et al., 1966; Janiger and Dobkin de Rios, 1989; King et al., 1974; Kuypers et al., 2016; McGlothlin et al., 1967; St John Sessa, 2008). Based on these observations and the evidence that repeated administrations of 5-HT2A agonist psychedelics pre-clinically cause 5-HT2A-R down-regulation (Buckholtz et al., 1988), we had hypothesized that 5-HT2A-R binding would be negatively correlated with Openness among the psychedelic users – however, this was not the case. It is possible that psychedelic use has a general effect on the 5-HT system in terms of modulating its mechanism for synaptic serotonin clearance (i.e. SERT) – rather than its main target receptor (i.e. the 5-HT2A-R). This possibility deserves further research. An alternative speculative explanation of the combined high SERT (≈low synaptic 5-HT) and high Openness is that 5-HT2A-R under-stimulation has driven high Openness individuals to use more psychedelics (5-HT2A-R agonists) to compensate for a deficiency – but this seems unlikely as psychedelics are not known to be ‘moreish’ drugs in this sense (Nichols, 2004).

In conclusion, this study supports other recent observations of a positive association between psychedelic experiences and Openness, and expands this to the context of ‘recreational’ psychedelic use. The increasing evidence that psychedelics modulate personality in an enduring way may have important implications if, for example, such changes impact on peoples’ value systems, cognitive flexibility, and individual and social behaviour (Forstmann and Sagioglou, 2017; Lyons and Carhart-Harris, 2018). Understanding why psychedelics do this may not only help us better understand the functioning of the serotonin system itself (Carhart-Harris and Nutt, 2017) but also the mechanisms behind the therapeutic effects of these compounds.

Acknowledgements

The authors would like to thank all volunteers for their participation, The Lundbeck Foundation, Familien Hede Nielsens Fond, Christopher Sabin for helping with the figures, and the staff in the PET and Cyclotron Unit at Rigshospitalet and in the MR department at Hvidovre Hospital for providing invaluable technical imaging assistance.

Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The study was sponsored by Rigshospitalet, The Lundbeck Foundation, Independent Research Fund Denmark, H:S (Copenhagen Hospital Cooperation) Research Council, Sawmill owner Jeppe Juhl and Wife Ovita Juhls Foundation, and the John and Birthe Meyer Foundation.

Supplemental material
Supplemental material for this article is available online.

ORCID iDs
David Erritzoe https://orcid.org/0000-0002-7022-6211

Robin Carhart-Harris https://orcid.org/0000-0002-6062-7150

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Journal of Psychopharmacology

ISSN: 0269-8811
Online ISSN: 1461-7285
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