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

Psychedelic substances like psilocybin are gaining interest for treating disorders involving self-experience distortions, such as depression. While preclinical evidence points to the glutamate system's role in psilocybin's effects, human studies are lacking. This study aimed to investigate the acute effects of psilocybin (0.17 mg/kg) on glutamate concentrations in specific brain regions and their relationship to subjective experiences, particularly ego dissolution—a reduction in self-referential thought disrupting self-boundaries and increasing feelings of unity. The study hypothesized that psilocybin would alter glutamate levels in the medial prefrontal cortex (mPFC) and hippocampus, regions rich in 5-HT2A receptors and involved in self-referential processing. These alterations were expected to correlate with changes in subjective experience, measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale and the Ego Dissolution Inventory (EDI). The study also assessed the impact of psilocybin on resting-state functional connectivity (RSN FC) within and between brain networks, particularly the default mode network (DMN), known for its role in self-referential thought. The choice of mPFC and hippocampus was based on their high 5-HT2A receptor density, involvement in self-referential processing, and preclinical evidence suggesting glutamate changes after 5-HT2A agonism. Resting-state fMRI and proton magnetic resonance spectroscopy (MRS) at 7T were used to measure brain activity and glutamate levels respectively. The study used a randomized, placebo-controlled, double-blind, parallel group design with 60 healthy participants with prior psychedelic experience.

Classical psychedelics like LSD, psilocybin, and DMT primarily affect serotonin (5-HT) receptors, particularly 5-HT2A receptors on pyramidal neurons. However, preclinical research highlights the glutamate system's involvement in 5-HT2A receptor-mediated effects on brain function and behavior. Activation of 5-HT2A receptors is suggested to lead to glutamate-dependent increases in pyramidal neuron activity in the prefrontal cortex, further activating AMPA receptors and increasing brain-derived neurotrophic factor (BDNF) expression. This suggests a common pathway for psychedelics' acute actions and potential therapeutic effects. Previous studies have shown that psychedelics decrease within-network connectivity in several resting-state networks (RSNs), including the default mode network (DMN), while increasing connectivity between networks. The DMN's association with self-referential mental activity makes it a key focus for understanding ego dissolution. The study leveraged existing literature indicating that alterations in DMN function are implicated in psychedelic-induced ego-dissolution experiences.

Sixty healthy participants with prior psychedelic experience (but not within the past 3 months) were randomly assigned to receive either 0.17 mg/kg psilocybin or a placebo. Groups were matched for age, sex, and education. Participants underwent structural MRI, proton MRS in the mPFC and hippocampus, and fMRI at peak subjective effects (approximately 60-102 minutes post-drug administration). MRS data were analyzed using LCModel to quantify glutamate, GABA, NAA, and mI relative to total creatine (tCr). fMRI data were processed using the CONN toolbox, employing independent component analysis (ICA) to identify RSNs. Within-network FC was compared between groups using two-sample t-tests, and between-network FC was assessed using bivariate correlations. Subjective state was assessed using the 5D-ASC and EDI questionnaires. Canonical correlation analysis examined the association between psilocybin-induced changes in glutamate levels, ego dissolution ratings, and within-network RSN FC.

Psilocybin significantly increased ratings on all 5D-ASC subdimensions and the EDI, indicating a robust psychedelic experience. MRS results showed that psilocybin increased glutamate/tCr in the mPFC but decreased it in the hippocampus compared to placebo. fMRI data revealed altered within-network FC in the DMN (anterior and posterior) and auditory network. Canonical correlation analysis revealed that increases in mPFC glutamate strongly predicted negatively experienced ego dissolution (anxious ego dissolution), while decreases in hippocampal glutamate were the strongest predictor of positively experienced ego dissolution. The study also found altered between-network functional connectivity under psilocybin, compared to placebo.

This study provides the first evidence in humans demonstrating region-specific effects of psilocybin on glutamate levels and their correlation with ego dissolution. The increase in mPFC glutamate aligns with previous research showing increased metabolic activity in this region after psilocybin administration, but doesn't necessarily indicate increased neuronal output given a concurrent increase in GABA. The decrease in hippocampal glutamate is consistent with reduced cerebral blood flow in the hippocampus observed in previous functional imaging studies. The correlational analysis suggests distinct neurobiological mechanisms underlying positive and negative aspects of ego dissolution. Increases in mPFC glutamate are linked to anxiety-related aspects, while decreases in hippocampal glutamate may be associated with the decoupling of MTL regions from the DMN, leading to a breakdown of personal identity and positive ego dissolution. These findings support the hypothesis that altered glutamatergic activity within specific brain regions contributes significantly to the subjective experience of ego dissolution induced by psilocybin and offers potential targets for therapeutic interventions.

This study provides crucial insights into the neurobiological mechanisms of psilocybin and its relationship to ego dissolution, identifying region-specific glutamate changes as key mediators of both positive and negative aspects of this experience. These findings have significant implications for understanding the therapeutic potential of psychedelics and suggest possible targets for novel treatments for psychiatric disorders. Future research should investigate long-term changes in receptor function and further explore the role of other brain regions in the experience of ego dissolution.

The study's relatively low dose of psilocybin may not have induced maximal effects. Geometric distortions associated with ultra-high field MRI could have affected BOLD signals in inferior brain regions. The inability to reliably quantify GABA in the hippocampus limited the scope of analysis. Participant awareness of the treatment condition could have affected results. Future studies could address these limitations by using higher doses, addressing MRI artifacts, employing advanced GABA quantification techniques, and incorporating active placebo controls.