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

This brain imaging study (n=48) with psilocybin (12mg/70kg) investigated the changes in glutamate levels in various brain areas and found that lower levels of hippocampal glutamate were correlated with positively experienced ego dissolution. Higher levels of medial prefrontal cortical (mPFC) glutamate correlated with negatively experienced ego dissolution.

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 the brain and behaviour; 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.”

Authors: Natasha M. Mason, Kim P. C. Kuypers, Felix Müller, Johannes Reckweg, D. H. Y. Tse, Stefan W. Toennes, Nadia R. P. W. Hutten, J. F. A. Jansen, Peter Stiers, Amanda Feilding & Johannes G. Ramaekers

Summary

Introduction

Psychedelics are psychoactive substances that induce altered states of consciousness, including transient and dose-dependent distortions in the subjective experience of one’s self. These substances have been used in the treatment of anxiety, depression, and addiction.

Converging evidence suggests that serotonin (5-HT2A) receptors located on cortical pyramidal neurons are the primary mechanism of action for classical psychedelics’ hallucinogenic effect. However, accumulating evidence also emphasizes the role of the glutamate system in 5-HT2A receptor-mediated effects on brain function and behavior.

The present study was designed to assess the contribution of glutamate to the psychedelic state by using ultra-high field (7T) proton magnetic resonance spectroscopy. It found that glutamate levels were increased in the psilocybin-treated brain, and that this was associated with the experience of ego dissolution.

The mPFC and the hippocampus were chosen as key regions in modulating the psychedelic experience based on previous anatomical, functional, and behavioral evidence implicating them. Specifically, both areas contain a high density of 5-HT2A receptors and overlap with the DMN.

Resting state functional magnetic resonance imaging was used to assess RSN FC, and subjective state was characterized via a well-established altered states of consciousness questionnaire and a validated questionnaire to assess ego dissolution.

Materials and methods

This study was conducted according to the code of ethics on human experimentation established by the declaration of Helsinki and was approved by the Medical Research Involving Human Subjects Act.

Participants underwent structural MRI, single-voxel proton MRS in the mPFC and hippocampus, and fMRI during peak subjective drug effects. Outcome measures for MRS were concentration ratios of glutamate, GABA, NAA, and mI, to total Creatine.

258 whole-brain EPI volumes were acquired at rest, and participants were instructed to focus on a black cross on a white background while laying as still as possible.

Imaging data was processed with LCModel, segmented into gray and white matter and cerebrospinal fluid, and smoothed with a 6 mm Gaussian kernel.

For the assessment of between-network FC, time courses between all RSNs were extracted and compared for both conditions using bivariate correlations.

Canonical correlations were conducted to evaluate the association between psilocybin-induced changes in relative glutamate concentration levels in the mPFC and hippocampus, ratings of ego dissolution, and scores on the EDI.

Results

The psilocybin group did not differ in respect to demographic variables, and the psilocin concentration levels in serum reached a peak 80 min postdrug administration, and then began to fall.

Psilocybin administration was associated with increased ratings on all (sub)dimensions of the 5D-ASC and on the EDI.

Medial prefrontal cortex showed higher glutamate and tNAA levels after psilocybin, compared with placebo. GABA levels were also higher after psilocybin, compared with placebo.

Glutamate concentrations were lower after psilocybin than after placebo in the hippocampus. No other significant differences were seen between groups.

Independent component analysis identified several networks, including the visual networks 1 – 3, the cerebellar network, the auditory network, the executive control network and the frontoparietal networks 1 and 2. The DMN and the sensorimotor network were split up into several components, which were included in the analysis.

Canonical correlation analysis was conducted using the four biological variables as predictors of the three ego dissolution variables. The results indicated that the first two functions explained 36.3% and 28.2% of the variance, respectively.

Function 1 indicated that anxious ego dissolution was the dominant contributor, with oceanic boundlessness making a secondary contribution. Function 2 indicated that mPFC glutamate was the strongest predictor of negatively experienced ego dissolution.

The dominant contributor to positively experienced ego dissolution was ratings on the EDI, with OB as a secondary contribution.

Discussion

Using an ultra-high field multimodal MRI approach, we demonstrated that psilocybin increased glutamate levels in the mPFC and decreased glutamate levels in the hippocampus. These changes were correlated with different dimensions of ego dissolution.

Previous studies have demonstrated that the mPFC is highly enriched with 5-HT2A receptors, which modulate excitatory transmission in cortical circuits. This study demonstrated that activation of 5-HT2A receptors in the mPFC results in both excitation and inhibition of cortical pyramidal cells, potentially resulting in an increased metabolic rate.

Participants who received psilocybin demonstrated lower relative glutamate concentrations in the hippocampus compared with the mPFC, suggesting that psilocybin decreases glutamate in this area. This decrease could be due to agonism of 5-HT2A receptors located on GABAergic interneurons, or to activation of postsynaptic inhibitory 5-HT1A receptors. We were unable to quantify GABA in the hippocampus due to low signal-to-noise and low concentration levels. Future studies should make further attempts to quantify GABA in the hippocampus.

Psilocybin increased scores on all dimensions of the 5D-ASC and the EDI, and altered within-network FC similarly to LSD. It also increased between-network FC across all networks.

We assessed the relationship between psilocybin-induced changes in the brain and the subjective experience of sense of self. Increasing levels of mPFC glutamate were the strongest predictor in regards to feelings of AED. Serotonergic psychedelics have been found to increase feelings of anxiety, whereas long-term clinical trials suggest relief. This may be because of localized glutamate-induced hyperfrontality, whereas long-term reductions may be due to agonist-induced 5-HT2A receptor downregulation in the mPFC.

Psilocybin-induced brain changes were associated with positively experienced ego dissolution, including ratings on the EDI and scores of OB on the 5D-ASC. Previous work has implicated both the MTL (containing the hippocampus) and DMN circuitry in the neural correlates of the self, and our data suggest that modulations of hippocampal glutamate may be a key mediator in the decoupling underlying feelings of (positive) ego dissolution.

The findings of this study extend beyond understanding the neurobiology of the acute psychedelic experience and drug-induced ego dissolution, and may identify novel therapeutic targets. In addition, the degree of ego dissolution has been found to correlate with long-term clinical outcomes and increases in well-being.

A low to moderate dose of psilocybin was administered to participants in a fMRI study to induce a relevant psychedelic state. The dose was effective in inducing significantly higher levels of both positively and negatively experienced ego dissolution compared with placebo, as well as the other subjective effects representative of a psychedelic state.

In conclusion, our data demonstrate that psilocybin induces region dependent alterations in glutamate that correlate with established behavioral changes during the psychedelic state.

Notes

This paper is included in our ‘Top 10 Articles on Psychedelics in the Year 2020‘

This study was funded, in part, by the Beckley Foundation.

Several participants were excluded from the final analysis (because of incomplete data, head movement, etc.), so the analysis was done on 48 of the 60 initial participants.

“Within the respective network, significantly less coactivation under the drug condition relative to placebo was found in visual network 1 and 2, both subcomponents of the DMN (anterior and posterior), and the auditory network.”

This is in contrast to the increase in between-network functional connectivity (FC) for the drug group (those who got psilocybin).