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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.

Psilocybin, the active compound in psychedelic mushrooms, is an agonist of various serotonin receptors. Seminal psilocybin positron emission tomography (PET) research suggested regional increases in glucose metabolism in frontal cortex (hyperfrontality). However, a recent arterial spin labeling (ASL) study suggests psilocybin may lead to hypo-perfusion in various brain regions. In this placebo-controlled, double-blind study we used pseudo-continuous ASL (pCASL) to measure perfusion changes, with and without adjustment for global brain perfusion, after two doses of oral psilocybin (low dose: 0.160 mg/kg; high dose: 0.215 mg/kg) in two groups of healthy controls (n = 29 in both groups, total N = 58) during rest. We controlled for sex and age and used family-wise error corrected p values in all neuroimaging analyses. Both dose groups reported profound subjective drug effects as measured by the Altered States of Consciousness Rating Scale (5D-ASC) with the high dose inducing significantly larger effects in four out of the 11 scales. After adjusting for global brain perfusion, psilocybin increased relative perfusion in distinct right hemispheric frontal and temporal regions and bilaterally in the anterior insula and decreased perfusion in left hemispheric parietal and temporal cortices and left subcortical regions. Whereas, psilocybin significantly reduced absolute perfusion in frontal, temporal, parietal, and occipital lobes, and bilateral amygdalae, anterior cingulate, insula, striatal regions, and hippocampi. Our analyses demonstrate consistency with both the hyperfrontal hypothesis of psilocybin and the more recent study demonstrating decreased perfusion, depending on analysis method. Importantly, our data illustrate that relative changes in perfusion should be understood and interpreted in relation to absolute signal variations.

Epigenetic processes, including DNA methylation, are emerging as key areas of interest for their potential roles as biomarkers and contributors to the risk of neurodevelopmental, psychiatric, and other brain-based disorders. Despite this growing focus, there remains a notable gap in our understanding of how DNA methylation correlates with individual variations in brain function and structure. Additionally, the dynamics of these relationships during developmental periods, which are critical windows during which many disorders first appear, are still largely unexplored. The current study extends the field by examining if peripheral DNA methylation of myelination-related genes predicts white matter volume in a healthy pediatric population [N = 250; females = 113; age range 2 months-14 years; M age = 5.14, SD age = 3.60]. We assessed if DNA methylation of 17 myelin-related genes predict white matter volume and if age moderates these relationships. Results highlight low variability in myelin-related epigenetic variance at birth, which rapidly increases non-linearly with age, and that DNA methylation, measured at both the level of a CpG site or gene, is highly predictive of white matter volume, in early childhood but not late childhood. These novel findings propel the field forward by establishing that DNA methylation of myelin-related genes from a peripheral tissue is a predictive marker of white matter volume in children and is influenced by developmental stage. The research underscores the significance of peripheral epigenetic patterns as a proxy for investigating the effects of environmental factors, behaviors, and disorders associated with white matter., Competing Interests: Additional Declarations: No competing interests reported. Competing interests The authors have no conflict of interest to disclose. Supplementary Files This is a list of supplementary files associated with this preprint. Click to download. • SupplementalInformation.docx