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

Psychedelic compounds such as psilocybin, mescaline and DMT produce acute perceptual changes and feelings of insight, connectedness and awe, and recent research has renewed interest in their therapeutic potential for conditions including addiction, anxiety and depression. MDMA, often classed as an 'empathogen' rather than a classic psychedelic, is also under investigation, notably for post-traumatic stress disorder. Both classes of drugs act primarily on the brain's serotonin (5-HT) system but by different mechanisms: MDMA increases synaptic serotonin via effects on the serotonin transporter (SERT), whereas classic psychedelics are 5-HT 2A receptor (5-HT2A-R) agonists. Clinical and experimental studies have reported that single or a few psychedelic/MDMA dosing sessions can produce effects that outlast the pharmacokinetic presence of the drug, including durable changes in personality, particularly increases in the Big Five trait openness to experience. Erritzoe and colleagues set out to investigate cross-sectional associations between recreational use of psychedelics or MDMA and (a) personality, measured with the Revised NEO Personality Inventory (NEO-PI-R), and (b) molecular markers of cortical serotonergic signalling measured by PET imaging of SERT and 5-HT2A-R binding. They hypothesised that openness would be higher among psychedelic and/or MDMA users than non-using controls, and that openness among users would correlate negatively with cortical 5-HT2A-R binding. The study therefore aims to link naturalistic exposure to serotonergic recreational drugs with both personality measures and neurochemical imaging markers to better characterise putative mechanisms underlying enduring effects of these compounds.

The investigators used a cross-sectional case-control design with single time-point assessments of personality and PET measures in young adults. The sample comprised 24 recreational serotonergic drug users divided into two subgroups—10 psychedelic-preferring users (PPUs) and 14 MDMA-preferring users (MPUs)—and 21 age- and gender-matched non-using controls. Eligibility for users required age 18–35, at least 12 lifetime exposures to psychedelics or MDMA and use within the previous year. Exclusion criteria included prior or current neurological or axis I psychiatric disorders. Controls were limited to no more than 15 lifetime cannabis exposures and no other illegal drug history; abstinence for seven days prior to scanning was required and confirmed by urine screening, and recent MDMA use was corroborated by hair analysis covering ~3 months. Personality was assessed with the 240-item Revised NEO Personality Inventory (NEO-PI-R), yielding scores for Neuroticism, Extraversion, Openness, Agreeableness and Conscientiousness and six facets for each domain. PET imaging quantified frontal cortical SERT and 5-HT2A-R binding using [11C]DASB and [18F]altanserin, respectively. Scans were acquired on a three-dimensional 18-ring GE-Advance scanner. Outcome measures were non-displaceable binding potential (BPND) for [11C]DASB and BPp for [18F]altanserin, with the cerebellum used as the reference region. Frontal regions of interest were automatically delineated via MR co-registration using a template-based approach. Not all users had complete 5-HT2A-R scans: analyses involving altanserin excluded two subjects, so 19 users were included in 5-HT2A-R analyses. Statistical analyses were performed in SPSS and R. Group differences in NEO-PI-R domains were tested with one-way ANOVA and Tukey post-hoc correction. Lifetime psychedelic use was modelled after a log2 transformation (doublings of lifetime exposures) and related to openness using linear regression; frontal SERT and frontal 5-HT2A-R binding were tested as predictors of openness in separate regressions. Interaction analyses probed group-specific associations and age was included as an adjustment in robustness checks. The investigators tested whether frontal SERT binding mediated the relationship between lifetime psychedelic exposures and openness using structural equation modelling with the lava package in R; approximate standard errors were obtained via the delta method and confidence intervals were compared with non-parametric bootstrap estimates (1,000 resamples). The study was conducted in Copenhagen with ethics approval and written informed consent.

Group comparisons across the three groups revealed a single significant difference among the five NEO-PI-R domains: openness to experience. Psychedelic-preferring users (PPUs) scored higher than both MDMA-preferring users (MPUs) and controls. Reported means ± SD were 147±16 for PPUs, 126±15 for MPUs and 124±20 for controls; post-hoc tests showed PPUs > MPUs (p=0.017) and PPUs > controls (p=0.05), while MPUs did not differ from controls (p=0.972). No group differences were found for Neuroticism, Extraversion, Agreeableness or Conscientiousness. The control group's scores were broadly similar to a Danish norm sample for several traits but showed higher openness relative to that norm. Among all individuals with a history of psychedelic use (n=21), lifetime number of psychedelic exposures was positively associated with openness: the openness score increased by 4.6±1.7 points per doubling of lifetime psychedelic exposure (p=0.015). This association remained significant after adjusting for age (p=0.019). Facet-level analyses showed significant positive associations with openness-to-values (1.0±0.3 per doubling, p=0.009), openness-to-actions (1.0±0.3, p=0.010) and openness-to-ideas (1.2±0.5, p=0.013); openness-to-aesthetics showed a borderline association (1.1±0.6, p=0.087), while openness-to-feelings and fantasy were not associated. In PET analyses among combined MPUs/PPUs (n=24), frontal SERT binding was positively associated with openness: openness increased by 11.1±4.3 points per 0.1 unit increase in SERT BPND (p=0.016). Frontal 5-HT2A-R binding was not associated with openness (p=0.78). The SERT–openness relationship did not differ significantly between MPUs and PPUs (interaction p=0.70). No significant SERT–openness association was observed in controls (p=0.67), and the group-by-SERT interaction comparing users and controls was not statistically significant (p=0.11), providing only nominal evidence of a stronger SERT–openness relation in users. Mediation analysis did not support frontal SERT binding as a mediator of the relationship between lifetime psychedelic use and openness (mediated effect estimate 0.85±0.83, p=0.31). The authors note limited power for some analyses, particularly mediation testing.

Erritzoe and colleagues interpret their findings as supporting a positive association between recreational psychedelic exposure and higher openness to experience. In this sample, only psychedelic-preferring users showed elevated openness compared with both MDMA-preferring users and non-using controls, and within those with psychedelic histories openness correlated with lifetime exposure. The pattern of facet associations—especially increases in openness-to-actions and openness-to-values—parallels facet changes reported after therapeutic psilocybin sessions, suggesting overlap between effects seen in naturalistic and clinical contexts. The authors acknowledge that the cross-sectional design does not prove causality and concede that individuals with higher baseline openness might be more likely to use psychedelics. They argue, however, that this explanation is less parsimonious given that MPUs did not show elevated openness relative to controls and openness is not generally a predictor of substance misuse. They further note converging longitudinal data from prior studies in which single doses of psilocybin or LSD, and psilocybin therapy for depression, were followed by increased openness, which supports the possibility that psychedelic exposure can induce enduring personality change. Regarding neurobiology, frontal SERT binding correlated positively with openness among users while frontal 5-HT2A-R binding did not. The authors did not find evidence that SERT binding mediated the link between lifetime psychedelic use and openness, but they emphasise limited statistical power for mediation testing. They speculate about mechanisms: one possibility is that higher SERT (and thus greater synaptic clearance of 5-HT) could reflect lower basal 5-HT and lower basal 5-HT2A-R stimulation, which in turn might relate to greater propensity to experience increases in openness following 5-HT2A-R agonism; alternatively, psychedelics may produce more enduring modulation of SERT than of 5-HT2A-R binding. The hypothesised mechanisms remain speculative and the authors did not observe the expected negative association between 5-HT2A-R binding and openness. Limitations emphasised by the investigators include the cross-sectional design, small sample size, poly-substance use within the preferring groups and incomplete PET data for some participants. The potential influence of context is discussed: recreational psychedelic use often occurs in more introspective settings compared with MDMA's common association with club/party contexts, which may help explain why PPUs but not MPUs showed elevated openness. The authors conclude that their data add to evidence that psychedelic experiences are associated with enduring changes in openness, and that clarifying the serotonergic mechanisms behind these effects could inform understanding of both the serotonin system and the therapeutic actions of these compounds. They call for further research to resolve causal directions and neurobiological mechanisms.