Rostral Anterior Cingulate Thickness Predicts the Emotional Psilocybin Experience

Lewis and colleagues situate their study in a long history of serotonin and psychedelic research, noting that psilocybin is converted in vivo to psilocin and primarily acts at the 5-HT2A receptor. Previous work has established broad cognitive, perceptual, and emotional effects of psilocybin, but substantial inter- and intra-individual variability in subjective responses remains poorly explained. The authors note that historical explanations emphasise "set and setting" (personality, expectation, and environment), yet biological predictors — including brain morphological measures that have predicted other drug responses and psychiatric treatment outcomes — have been less explored in the psychedelic literature. The study therefore aimed to test whether cortical thickness of limbic regions with high 5-HT2A receptor expression predicts the emotional component of the psilocybin experience in healthy adults. Using the Five-Dimensional Altered States of Consciousness scale (5D-ASC), the investigators focused on four emotionally valenced subscales (Feeling of Unity, Blissful State, Spiritual Experience, and Insightfulness) and hypothesised that greater cingulate cortical thickness would be associated with larger psilocybin-induced changes on these subscales.

The study pooled data from two groups of healthy volunteers recruited at universities who received either a low (0.16 mg/kg) or high (0.215 mg/kg) oral psilocybin dose. After screening by medical history, examination, blood work and ECG, 55 participants (33 males, 22 females; mean age 25, SD 3.96, range 20–37) entered the analysis. All participants provided written informed consent and study approvals were obtained from relevant Swiss authorities. A randomised, double-blind, placebo-controlled design was used: each subject completed two sessions at least 10 days apart and received placebo (maltose) in one session and psilocybin in the other. Participants were required to abstain from smoking for at least 60 minutes before MRI and from caffeine on the test day. Anatomical MRI scans (T1-weighted MP-RAGE, 1 × 1 × 1 mm voxels) were acquired on a Philips Achieva 3.0T scanner 60 minutes after drug administration. Subjective effects were assessed retrospectively with the 5D-ASC completed 360 minutes after intake; the authors used the difference between psilocybin and placebo session scores (Δ = psilocybin − placebo) for analysis. Image processing used FreeSurfer v6.0 to derive cortical thickness (distance from white/grey boundary to pial surface) from the placebo-session T1 images; segmentations were visually inspected. Regions of interest were chosen for high 5-HT2A expression in limbic areas: rostral anterior cingulate, caudal anterior cingulate, and posterior cingulate. The postcentral gyrus, selected for low 5-HT2A expression, served as a control region. Thickness values were extracted using the Desikan atlas. Statistical analyses first tested dose differences on 5D-ASC subscales with ANCOVA controlling for sex and age; no dose differences were found, so dose was treated as a covariate in further models. Multivariate linear regressions assessed whether cingulate thickness predicted each of the four emotional Δ-subscales, controlling for sex, age, the control-region thickness, and dose. The Benjamini–Hochberg false discovery rate (FDR) procedure controlled for multiple comparisons within each hemisphere. As follow-up, the authors compared correlated correlation coefficients among the three right-hemisphere cingulate regions to test whether predictive strengths differed between subregions. The extracted text indicates that standardized betas and other model statistics were reported in tables, but those numerical details are not fully provided in the extraction.

No significant differences emerged between the two psilocybin doses on the four emotional 5D-ASC subscales; consequently analyses collapsed across dose with dose retained as a covariate. The principal finding was a significant positive relationship between rostral anterior cingulate thickness in the right hemisphere and all four Δ-subscales (Feeling of Unity, Blissful State, Spiritual Experience, and Insightfulness): greater right rostral ACC thickness predicted larger psilocybin‑induced increases on these emotional measures. The extracted text states that standardized beta values, standard errors, p-values and FDR-corrected p-values for the rostral ACC models are provided in a table, but those precise numbers are not present in the provided extraction. No significant associations were observed between thickness of the caudal anterior cingulate or the posterior cingulate and any of the Δ-subscales. The postcentral control region was included as a covariate in the regressions. When comparing correlated correlation coefficients among right-hemisphere cingulate subregions, the differences in predictive strength were statistically significant for several subscales: Unity (p = 0.05), Spiritual Experience (p < 0.001), and Insightfulness (reported p < 0.001). The extraction duplicated some result paragraphs; no additional quantitative effect-size details or confidence intervals are available in the provided text.

Lewis and colleagues interpret their results as evidence that individual differences in cortical morphology — specifically thickness of the rostral anterior cingulate (rACC) — relate to the emotional quality of the psilocybin experience. They emphasise that the anterior cingulate is anatomically positioned between limbic and prefrontal regions and has extensive connections with structures implicated in emotion, memory, and reward, which aligns with the finding that the rostral but not caudal or posterior cingulate predicted emotional subscales. The absence of an association for the posterior cingulate, despite prior links to psilocybin, is noted and taken to underscore the particular relevance of anterior cingulate morphology for emotional processing. The authors highlight a right‑hemisphere lateralisation in their results, observing that right rACC thickness was a better predictor of emotional responses than left-hemisphere measures. They relate this to literature suggesting the right hemisphere plays a larger role in affective processing and suggest the lateralised effect may be relevant to the putative psychotherapeutic properties of psychedelics. The discussion links the measured subscales (Unity, Spiritual Experience, Blissful State, Insightfulness) with therapeutic outcomes reported in other clinical work and proposes that such emotional states may contribute to reductions in maladaptive behaviours and symptoms when combined with psychological support. Limitations acknowledged by the authors include the inability of the study design to infer causality between brain morphology and subjective states, the use of only medium-range doses (limiting dose–response inference), and the healthy volunteer sample which leaves clinical generalisability untested. They also note the potential value of expanding predictors to genomic and epigenetic measures in future research. The authors conclude that augmenting the classical set-and-setting framework with individual brain structure information may help explain variability in psychedelic experiences and could inform biomarker-driven, precision approaches to psychedelic-assisted therapies.