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

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.

Fig. 1. Retrospective ratings of drug effects.

Violin plots displaying reported scores on the 5 main dimensions of the 5D-ASC (a), ratings on the ego dissolution inventory (b) for each treatment group. Each stick in the violin indicates a data point, whereas the density is scaled to the relative count across all bins.

Fig. 2. Raincloud plots displaying metabolite concentrations in the mPFC and the hippocampus, which demonstrated significant differences between treatment groups.

a glutamate in the mPFC, b NAA in the mPFC, c glutamate in the hippocampus, d GABA in the mPFC. The plot consists of a probability density plot, a boxplot, and raw data points. In the boxplot, the line dividing the box represents the median of the data, the ends represent the upper/lower quartiles, and the extreme lines represent the highest and lowest values excluding outliers. The code for raincloud plot visualization has been adapted from Allen et al. [99].

Fig. 3. Within-network resting state functional connectivity.

Resting state networks that demonstrated significant differences in within-network functional connectivity, for each group (placebo and psilocybin).