Neural correlates of the psychedelic state as determined by fMRI studies with psilocybine

Robin L. Carhart-Harris, David Erritzoe, Tim Williams, James M. Stone, Laurence J. Reed, Alessandro Colasanti, Robin J. Tyacke, Robert Leech, Andrea L. Malizia, Kevin Murphy, Peter Hobden, John Evans, Amanda Feilding, Richard G. Wise, and David J. Nutt

PNAS, Proceedings of the National Academy of Sciences of the USA, 2012, 109, (6), 2138-2143.

doi:10.1073/pnas.1119598109

www.pnas.org/lookup/suppl/doi:10.1073/pnas.1119598109/-/DCSupplemental.

 

Abstract

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about howthey work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normalwaking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen leveldependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/ functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain’s key connector hubs, enabling a state of unconstrained cognition.

Keywords : default mode network | hallucinogens | serotonin | depression | 5-HT2A receptor

 

Psilocybin is the prodrug of psilocin (4-hydroxy-dimethyltryptamine), the primary hallucinogenic component of magic mushrooms, and a classic psychedelic (“mind-manifesting”) drug. Psilocybin has been used for centuries in healing ceremonies (1) and more recently in psychotherapy (2); it is capable of stimulating profound existential experiences (3), which can leave a lasting psychological impression (4). However, despite a wealth of literature on its phenomenology, we currently know very little about how its effects are produced in the brain. The present study sought to address this question using complementary functional MRI (fMRI) techniques and a protocol designed to image the transition from normal waking consciousness to the psychedelic state. Two groups of healthy subjects were scanned using arterial spin labeling (ASL) perfusion and blood-oxygen level-dependent (BOLD) fMRI during intravenous infusion of psilocybin. Infused over 60 s (2 mg in 10-mL saline), psilocybin’s subjective effects begin within seconds (5), allowing the capture of the corresponding change in brain state.

Results
ASL Perfusion fMRI. Fifteen healthy, hallucinogen-experienced subjects (five females), mean age 34.1 (SD 8.2) were scanned with ASL. Subjects underwent an anatomical scan followed by two taskfree functional scans, each lasting 18 min. Subjects were instructed to relax and a fixation cross was displayed. Solutions were infused manually over 60 s, beginning 6 min after the start of each functional scan. Subjects received placebo (10-mL saline) in the first scan and psilocybin (2 mg in 10-mL saline) in the second. The intensity of the subjective effects was rated via button press on a 0– 10 visual analog scale (10 = extremely intense effects) at the start of each functional scan, just before infusion, 5-min postinfusion, and 12-min postinfusion. The average rating 5-min postinfusion was 6.7 (±1.9), and 5.2 (±2.3) 12-min postinfusion. Earlier work showed that the effects of 2 mg i.v. psilocybin are comparable with ∼15 mg of orally administered psilocybin, which is considered a moderate dose (6). Nineteen additional items were rated immediately after each ASL scan. Fig. 1 displays the top 10 rated items from the two studies. Ratings for all of the items used in the ASL and BOLD studies can be found in Table S1.

The interaction between cerebral blood flow (CBF) and the infusion event was modeled, contrasting CBF before and after infusion. The subjective effects began toward the end of the infusion period and reached a sustained peak after ∼4 min (5). The first level results were entered into a higher level analysis, contrasting CBF after psilocybin with CBF after placebo for all 15 subjects. Fig. 2 displays these results.

The group level results (Fig. 2) revealed significant CBF decreases in subcortical (bilateral thalamus, putamen, and hypothalamus) and cortical regions [the posterior cingulate cortex (PCC), retrosplenial cortex, precuneus, bilateral angular gyrus, supramarginal gyrus, rostral and dorsal anterior cingulate cortex (ACC), paracingulate gyrus, medial prefrontal cortex (mPFC), frontoinsular cortex, lateral orbitofrontal cortex, frontal operculum, precentral gyrus, and superior, middle and inferior frontal gyrus] (Fig. S1). The decreases were localized to high-level association regions (e.g., the PCC and mPFC) and important connector hubs, such as the thalamus, PCC and ACC/mPFC. To assess the temporal dynamics of the CBF changes postinfusion, thalamic, ACC, and PCC masks were made; voxels within these were restricted to those that were significantly decreased after psilocybin. For each region of interest (ROI), the percent CBF change postinfusion was plotted against time (Fig. 3). All ROIs showed steep decreases in CBF after psilocybin that were sustained for the duration of the scan.

To test for a relationship between regional CBF changes and subjective effects, we plotted each subjects’ ROI CBF change postpsilocybin against their ratings of drug effects intensity (Fig. 3D). For each ROI, it was evident that the greater the decreases in CBF, the more intense the subjective effects.

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