Regional Specificity of the Cingulate Cortex Thickness Association with the Intensity of Psilocybin Experience: A Replication Study

Abstract

Rationale: Individual variability in psilocybin response is a major challenge for psychedelic-assisted therapy, with structural brain features potentially serving as predictive biomarkers. Lewis et al. (2020) reported that rostral anterior cingulate cortex thickness predicted emotional experiences under psilocybin, suggesting cortical morphometry as a marker of psychedelic responsivity.

Objectives: This study sought to replicate and extend these findings by examining associations between cingulate thickness and psilocybin-induced altered states of consciousness using comprehensive assessment and rigorous statistical control.

Methods: Twenty-five healthy participants underwent a double-blind, placebo-controlled crossover design with psilocybin (0.26 mg/kg) and placebo. High-resolution T1-weighted magnetic resonance imaging (MRI) measured cortical thickness across cingulate subregions. Subjective effects were assessed with the Altered States of Consciousness (ASC) questionnaire. Analyses applied false discovery rate (FDR) correction for multiple comparisons.

Results: The primary Lewis et al. finding—that rostral anterior cingulate cortex thickness predicts emotional psilocybin responses—was not replicated. Instead, we identified a robust anterior–posterior gradient in cingulate thickness that significantly predicted global psychedelic intensity (r = 0.549, FDR p = 0.013). Moreover, general cingulate thickness was associated with the balance between anxiety-dominated and visionary states (r = 0.495, FDR p = 0.016).

Conclusions: Findings indicate that structural organization of the cingulate cortex provides a neuroanatomical marker of variability in psychedelic response, with implications for personalized dosing and anticipatory management in psychedelic-assisted therapy. Results highlight the importance of broad cortical organizational patterns, rather than focal regional measures, when predicting psychedelic effects.