Rostral Anterior Cingulate Thickness Predicts the Emotional Psilocybin Experience

This fMRI study (n=55) found that a thicker rostral anterior cingulate (where there are many serotonin 2A receptors) predicted higher subjective ratings on the altered states of consciousness (5D-ASC) questionnaire after administration of psilocybin (11-15mg/70kg).

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.”

Authors: Candace R. Lewis, Katrin H. Preller, B. Blair Braden, Cory Riecken & Franz X. Vollenweider

Summary

Article

Psilocybin, the psychoactive compound of mushrooms in the psilocybe species, affects a number of serotonin receptors, and results in a range of subjective experiences. We investigated if cingulate cortex thickness predicted subjective psilocybin experiences in healthy adults, and found that the rostral anterior cingulate predicted all four emotional sub-scales.

1. Introduction

Psilocybin, an indole alkaloid of the tryptamine family, was isolated from mushrooms in 1953 and is rapidly dephosphorylated into the psychoactive metabolite psilocin. Psilocin primarily binds to 5-HT2A receptors and has a range of psychoactive effects on human behavior.

The subjective response to psilocybin is highly determined by the extra-pharmacological parameters of set and setting, and there is a lack of research specifically assessing biological drivers of the psilocybin experience.

Individual brain morphology measures can be used to predict various pharmacological challenges and behavior, including depression, risk factors, neurobiological correlates, and pharmacological treatment response.

The effects of psilocybin on emotionality have been studied, and it was hypothesized that greater cingulate cortex thickness would predict higher subjective ratings in healthy participants who received psilocybin (either low dose: 0.160 mg/kg or high dose: 0.215 mg/kg).

Figure 1 shows the FreeSurfer brain regions used in analyses.

2.1. Participants

The study included 55 participants, 33 males, 22 females, with a mean age of 25, SD 3.96 years, and range 20 – 37 years. All participants provided written informed-consent statements in accordance with the declaration of Helsinki before participation in the study.

2.2. Experimental Design and Psilocybin Administration

FreeSurfer analyses used the cingulate cortex and post central parcellations in the right hemisphere.

2.1. Participants

Participants were recruited through advertisements in local universities. They were given a low dose of psilocybin (0.16 mg/kg: Low) or a high dose of psilocybin (0.21 mg/kg: High) and provided written informed-consent statements before participation in the study.

2.2. Experimental Design and Psilocybin Administration

In a randomized, double blind, and placebo-controlled study, subjects received either oral psilocybin (0.16 mg/kg or 0.215mg/kg) or placebo in two separate sessions at least 10 days apart. A 5D-ASC was completed 360 min after drug administration to assess the subjective experience after drug intake.

2.3. Neuro-Imaging Acquisition

All MR data was acquired on a Philips Achieva 3.0T whole-body scanner using a standard T1-weighted three-dimensional (3D) magnetization prepared rapid gradient echo sequence.

2.4. Image Data Processing

T1-weighted images were processed to obtain cortical thickness using FreeSurfer version 6.0 image analysis suite. Regions of interest were based on high 5HT-2Ar expression in limbic regions, and a control region was chosen on lowest 5HT-2Ar expression in a cortical region.

2.5. Statistical Analyses

We ran an analysis of covariance (ANCOVA) and multivariate linear regressions to determine if there was a difference in the emotional sub-scales between dose groups. The Benjamini-Hochberg procedure was used to control for multiple comparisons and Type 1 error within each hemisphere.

3.2. Cingulate Thickness Predicting Sub-Scales

The right hemisphere rostral anterior cingulate cortex thickness was significantly correlated with Feeling of Unity, Bliss, Spiritual Experience, and Insightfulness.

We found a significant positive association between the right hemisphere rostral anterior cingulate thickness and all scales.

Partial correlation plots between responses to psilocybin and estimates of right hemisphere rostral anterior cingulate cortex thickness are shown in Figure 2.

Figure 2 shows the partial correlation between responses to psilocybin and estimates of right hemisphere rostral anterior cingulate cortex thickness.

Discussion

This study evaluated brain morphology as a predictor of the emotional subjective experience of psilocybin in healthy controls. The rostral anterior cingulate cortex specifically predicted all four sub-scales of Unity, Spiritual Experience, Blissful State, and Insightfulness.

The anterior cingulate is a region of the brain with connections to the limbic system and the prefrontal cortex. It is thought to play an important role in emotions, memory, and reward. While the posterior cingulate cortex was associated with the psilocybin emotional experience, the anterior cingulate was found to be involved in emotional processing and was also associated with Mindfulness-Based Stress Reduction interventions in back pain patients with depression.

Some evidence suggests the right hemisphere is involved in emotional processing, and the right hemisphere cingulate morphology is a better predictor of psilocybin-induced emotional experiences compared to the left hemisphere.

In a recent open-label trial using psilocybin for treatment resistant depression, the composite variable of Unity, Spiritual Experience, and Blissful State along with Insightfulness predicted therapeutic outcomes. This suggests that neuroimaging may benefit precision medicine approaches of future psychedelic assisted treatment options.

This study used modern neuroimaging methods to assess the relationship between brain morphology and psilocybin subjective states. The study was limited by the use of two separate doses of psilocybin and the use of self-report data from both psilocybin and placebo sessions.

Classic psychedelic compounds induce large inter- and intra-variability in subjective states. Investigating the relationship between psilocybin modulation and cingulate structure may provide insight into mechanisms underlying psilocybin’s profound emotional effects.

A study was conducted to investigate the effects of redox stress on the cytoskeletal system.

Notes

This paper is included in our ‘Top 12 Articles on Psychedelics and Serotonin (5HT) Receptors‘