Depressive DisordersNeuroimaging & Brain MeasuresPsilocybin

Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin

In a double-blind, placebo-controlled study using ultra-high-field multimodal imaging, psilocybin produced region-specific alterations in glutamate in humans that predicted the subjective experience of ego dissolution. Specifically, higher medial prefrontal glutamate was associated with negatively experienced ego dissolution, while lower hippocampal glutamate predicted positively experienced ego dissolution, suggesting a neurochemical mechanism that may underlie therapeutic effects.

Authors

  • Kim Kuypers
  • Johannes Ramaekers
  • Nathalie Mason

Published

Neuropsychopharmacology
individual Study

Abstract

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one’s self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.

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Research Summary of 'Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin'

Introduction

Psychedelics induce pronounced alterations of consciousness, including transient distortions in self-experience commonly described as ego dissolution, in which self-referential awareness is reduced and self–world boundaries are blurred. Earlier research links the hallucinogenic effects of classical psychedelics such as psilocybin to agonism of cortical 5-HT2A receptors, and preclinical work further implicates glutamatergic signalling downstream of 5-HT2A activation as a potential pathway mediating acute neural and behavioural effects. Functional imaging studies have also associated alterations in default mode network (DMN) function with ego-dissolution experiences, and both the medial prefrontal cortex (mPFC) and hippocampus are candidate regions due to their 5-HT2A receptor density and roles in self-referential processing. Mason and colleagues set out to test, in humans, whether acute psilocybin alters glutamate concentrations in key brain regions and whether such changes relate to subjective ego-dissolution and resting-state network functional connectivity (FC). Using ultra-high field proton magnetic resonance spectroscopy (7T MRS) targeted at the mPFC and right hippocampus, together with resting-state fMRI and validated questionnaires of altered states and ego dissolution, the study aimed to characterise region-specific neurometabolic changes during peak drug effects and assess their association with both network-level connectivity and subjective experience.

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References (36)

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