Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans

Psychedelic substances have been used across cultures to produce profound alterations in perception, emotion and cognition, and contemporary interest has focused both on their acute neural effects and their potential therapeutic uses. Molecular studies indicate that classic psychedelics acting as 5-HT2A agonists can trigger expression of immediate early genes and increase brain-derived neurotrophic factor, processes linked to synaptic plasticity; however, the long-term impact of repeated psychedelic exposure on human brain structure remains poorly characterised. Bouso and colleagues set out to test whether sustained use of a psychedelic preparation—ayahuasca—relates to differences in cortical structure and to psychometric and neuropsychological measures. They hypothesised that repeated psychedelic exposure would correlate with changes in cortical thickness and therefore compared chronic ayahuasca users with matched controls on MRI-derived cortical thickness (CT), personality, psychopathology and cognitive performance.

This cross-sectional study compared 22 Spanish ayahuasca users (Santo Daime church members) with 22 matched controls. Inclusion criteria for users required at least 50 ayahuasca sessions in the previous two years, no personal history of psychiatric or neurological disorders, lifetime cannabis use of 20 occasions or fewer, lifetime use of other drugs on ten occasions or fewer, and abstinence from ayahuasca and other drugs for two weeks prior to scanning, verified by urine toxicology. Participants were screened by a clinical psychologist and structural MRI scans were reviewed by a neuroradiologist to exclude gross CNS abnormalities. Groups were matched on sex (six male, 16 female per group), age, years of education, and verbal and fluid IQ; routine demographic comparisons reported no significant between-group differences on these matching variables. High-resolution structural T1-weighted MRI was acquired at 3 T (MPRAGE; 1 mm3 voxels; TR 2300 ms; TE 1 ms). Cortical thickness was estimated with FreeSurfer v5.0.0. Images were mapped into a common spherical coordinate system and spatially smoothed (Gaussian, FWHM = 10 mm). A general linear model (GLM) assessed voxelwise CT differences with group (ayahuasca users versus controls) as the factor and average hemispheric CT entered as a covariate to account for global differences. Statistical maps were thresholded at p < 0.002 uncorrected with a spatial extent threshold of 20 voxels, and significant clusters were identified using a parcellation atlas. Personality was measured with the Spanish Temperament and Character Inventory-Revised (TCI-R), focusing on temperament dimensions (harm avoidance, novelty seeking, reward dependence, persistence) and character dimensions including self-transcendence (ST). Psychopathology used the SCL-90-R. Three neuropsychological tasks were administered digitally: a two-back working-memory task, the Wisconsin Card Sorting Test (WCST) for executive function, and a task-switching paradigm assessing set-shifting. Data distribution was tested with Kolmogorov-Smirnov; normally distributed TCI scores were compared with independent-samples t-tests, while non-normally distributed SCL-90-R and neuropsychological measures were analysed with Mann-Whitney tests. Correlations used Pearson's or Spearman's coefficients as appropriate, with significance set at p < 0.05.

Structural MRI revealed regional differences in cortical thickness between ayahuasca users and controls. Thinning in the ayahuasca group was observed in six cortical areas: middle frontal gyrus, inferior frontal gyrus, precuneus, superior frontal gyrus, posterior cingulate cortex (PCC), and superior occipital gyrus. Conversely, cortical thickening in users was found in the precentral gyrus and the anterior cingulate cortex (ACC). Cluster-level details (Talairach coordinates, Brodmann areas, voxel counts and peak t values) were reported in the paper's table. Personality assessment showed that ayahuasca users scored lower on harm avoidance (HA) [t(42) = -2.08, p = 0.044], an effect driven by the anticipatory worry subscale [t(42) = -2.98, p = 0.005]. Users scored substantially higher on self-transcendence (ST) [t(42) = 5.16, p < 0.001], with all three subscales of ST elevated in the ayahuasca group. Psychopathology scores on the SCL-90-R did not differ significantly between groups using Mann-Whitney tests. On neuropsychological measures, ayahuasca users performed better on several variables from the two-back task (all comparisons significant except for percentage false alarms and correct rejections). In the WCST there was a trend toward more correct responses and fewer errors in users, though most WCST variables did not differ. In the task-switching test, users had a higher percentage of correct responses and fewer errors for non-switch trials; other task-switching metrics showed no group differences. Correlation analyses linked lifetime ayahuasca exposure to structural change: lifetime number of ayahuasca sessions correlated inversely with CT in the PCC (r = -0.444; p = 0.038), and years of use also correlated negatively with PCC CT (r = -0.492; p = 0.020). Age at first use showed a trend (r = 0.390; p = 0.073), with earlier initiation associated with lower PCC thickness. ST scores correlated with PCC CT within each group (ayahuasca users: r = -0.479, p = 0.024; controls: r = -0.571, p = 0.005), and similar independent correlations were reported for the transpersonal identification subscale (ayahuasca: r = -0.545, p = 0.009; controls: r = -0.606, p = 0.003). No other significant correlations were reported.

Bouso and colleagues interpret their findings as evidence that regular ayahuasca use is associated with regional differences in cortical thickness, most notably increased CT in the ACC and decreased CT in the PCC. These medial cortical changes corresponded with behavioural measures: users exhibited higher self-transcendence and lower harm avoidance, while showing no increase in psychopathology and preserved or improved performance on several neuropsychological tests. The authors relate their structural results to prior functional and electrophysiological studies of psychedelics that implicate the ACC and PCC in acute drug effects, noting reports of increased medial frontal blood flow and changes in ACC and PCC activity after psilocybin and ayahuasca. Two explanatory mechanisms are proposed: a direct pharmacological effect of repeated 5-HT2A receptor activation leading to altered gene expression (for example c-fos, egr-1, egr-2) and increased brain-derived neurotrophic factor with downstream synaptic plasticity, or an adaptive/experience-driven neural response. Supporting evidence cited in the paper includes animal and molecular studies showing long-lasting gene-expression changes after chronic psychedelic exposure. They further situate the ACC and PCC findings within the default mode network (DMN) framework: the PCC is a DMN hub linked to internally directed mentation and the sense of self, whereas the ACC is associated with attention and cognitive control. The opposing structural differences—thinning in PCC and thickening in ACC—are discussed in relation to acute psychedelic-induced loss of anti-correlated activity between DMN and attention networks and may help explain preserved or enhanced cognitive performance in experienced users. The observed association between higher ST and reduced PCC thickness is interpreted as a possible neural correlate of spirituality-related personality traits that have been reported to increase following psychedelic exposure. Finally, the authors acknowledge the cross-sectional design as a key limitation that prevents causal inference, and they note that their data only suggest that regular psychedelic use could lead to changes in brain tissue. They emphasise that, despite structural differences, long-term ayahuasca use in this sample was not associated with increased psychopathology and may relate to alterations in attention, internal thought processes and the sense of self, which could underlie personality changes reported after prolonged psychedelic use.