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.
Highlights
In 1953, relatively high concentrations of serotonin (5-hydroxytryptamine or 5-HT) were found in the brain [1]
We focused our analyses on the cingulate cortex based on high 5-HT2A receptors (5-HT2Ar) expression levels compared to other limbic regions
We found rostral anterior cingulate thickness predicted all four sub-scales of Unity, Spiritual Experience, Blissful State, and Insightfulness, whereas the caudal anterior and posterior cingulate did not
Summary
In 1953, relatively high concentrations of serotonin (5-hydroxytryptamine or 5-HT) were found in the brain [1]. Despite the generality of the psilocybin experience, there is a high amount of inter and intra-individual variability in psilocybin subjective responses. We previously used a pooled analyses of 261 individuals to test 24 non-pharmacological variables as predictors of the subjective effects of psilocybin and found, a variety of set and setting variables are associated with many aspects of the psilocybin response in healthy volunteers [22]. It is reasonable to presume individual differences in brain morphologic measures may predict the individual subjective experience of psilocybin. Because the subjective effects of psilocybin are primarily mediated by the 5-HT2Ar [18], we chose regions of the limbic system with the highest 5-HT2Ar protein expression, and identified the cingulate cortex based on prior research (Figure 1A) [38].
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