Rostral Anterior Cingulate Thickness Predicts the Emotional Psilocybin Experience

Abstract

Psilocybin is the psychoactive compound of mushrooms in the psilocybe species. Psilocybin directly affects a number of serotonin receptors, with highest affinity for the serotonin 2A receptor (5HT-2Ar). Generally, the effects of psilocybin, and its active metabolite psilocin, are well established and include a range of cognitive, emotional, and perceptual perturbations. Despite the generality of these effects, there is a high degree of inter-individual variability in subjective psilocybin experiences that are not well understood. Others have shown brain morphology metrics derived from magnetic resonance imaging (MRI) can predict individual drug response. Due to high expression of serotonin 2A receptors (5HT-2Ar) in the cingulate cortex, and its prior associations with psilocybin, we investigate if cortical thickness of this structure predicts the psilocybin experience in healthy adults. We hypothesized that greater cingulate thickness would predict higher subjective ratings in sub-scales of the Five-Dimensional Altered State of Consciousness (5D-ASC) with high emotionality in healthy participants (n = 55) who received oral psilocybin (either low dose: 0.160 mg/kg or high dose: 0.215 mg/kg). After controlling for sex, age, and using false discovery rate (FDR) correction, we found the rostral anterior cingulate predicted all four emotional sub-scales, whereas the caudal and posterior cingulate did not. How classic psychedelic compounds induce such large inter-individual variability in subjective states has been a long-standing question in serotonergic research. These results extend the traditional set and setting hypothesis of the psychedelic experience to include brain structure metrics.

Keywords: 5HT2Ar; cingulate; emotion; psilocybin.

Figure 1

Schematic of FreeSurfer brain regions used in analyses. (A) Right hemisphere cingulate cortex parcellations used in primary analyses. Dark purple = rostral anterior cingulate; medium purple = caudal anterior cingulate; light purple = posterior cingulate. (B) Red = right hemisphere post central parcellation used as the control region analysis.

Figure 2

Partial correlation plots controlling for sex, age, and dose between responses to psilocybin (Unity, Bliss, Spiritual, and Insight) and estimates of right hemisphere rostral anterior cingulate cortex (R rACC) thickness with 95% confidence intervals. Scatter plots for non-significant results can be found in Supplementary Materials. Axes represent normalized values. Response to psilocybin is represented as the delta value; psilocybin – placebo.