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

This seminal fMRI study (n=30) found decreases in blood flow of hub regions in the brain (thalamus, ACC, PCC). The study is the first to report on these findings with psilocybin (2mg iv ~15mg oral).

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 how they 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 normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (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.”

Authors: 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 & David J. Nutt

Notes

  • Decreases in blood flow and oxygen levels were mostly seen in hub regions (e.g. thalamus and anterior & posterior cingulate cortex)
  • There was a decoupling between the medial prefrontal cortex and the posterior cingulate cortex
  • This decoupling is hypothesized to be responsible for the psychedelic state

This study was supported, in part, by the Beckley Foundation, MAPS, and the Heffter Research Institute.

“The group-level results revealed significant CBFdecreases 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]. 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.”

Half of the participants (15) were scanned with one fMRI measure (ALS perfusion), the other with another measure (BOLD fMRI). The arterial spin labeling (ALS) results above were similar to those of the blood-oxygen level-dependent (BOLD) measures. “There were, however, additional BOLD signal decreases (e.g., in higher order visual areas) that were not observed with ASL.”

“It has been commonly assumed that psychedelics work by increasing neural activity; however, our results put this into question. Psilocin is a mixed serotonin receptor agonist, but there is a general consensus that the characteristic subjective and behavioral effects of psychedelics are initiated via stimulation of serotonin (5-Hydroxytryptamine, 5-HT) 2A receptors.”

“Stimulation of the 5-HT2A receptor increases excitation in the host cell by reducing outward potassium currents. Thus, if the 5-HT2A receptor did mediate the observed deactivations, then it may have been via 5-HT2A-induced excitation of fast-spiking interneurons terminating on pyramidal cells or 5-HT2A-induced excitation of pyramidal cells projecting onto interneurons.”

The findings by Carhart-Harris and colleagues is counter-intuitive and in the discussion, they posit various explanations for their findings. The findings also differ from earlier work with EEG and different ways of measuring brain activity may be the cause of that incongruity.

“It seems relevant therefore that activity in and connectivity with the mPFC is known to be elevated in depression and normalized after effective treatment. The mPFC was consistently deactivated by psilocybin (Fig. 4) and the magnitude of the deactivations correlated with the drug’s subjective effects. Depression has been characterized as an “overstable” state, in which cognition is rigidly pessimistic. Trait pessimism has been linked to deficient 5-HT2A receptor stimulation, particularly in the mPFC, and mPFC hyperactivity has been linked to pathological brooding… Our results suggest a biological mechanism for this: decreased mPFC activity via 5-HT2A receptor stimulation. Further work is required to test this hypothesis and the putative utility of psilocybin in depression.”

More research is needed to confirm this hypothesis, but this paper was the first to offer a hypothesis in this direction.

The same applies to the finding of the possible mechanisms (and relief of) cluster headaches “We also observed decreased CBF in the hypothalamus after psilocybin, which may explain anecdotal reports that psychedelics reduce symptoms of cluster headaches.”

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