Acute effects of psilocybin on glutamate concentration levels, functional connectivity and subjective state

Background

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for increasingly common and difficult to treat disorders like depression. Thus an important question is how these substances act in the brain. Accumulating evidence suggests that psychedelics stimulate 5-HT2A receptors located on neocortical pyramidal cells, which is the suggested primary mechanism of action. However, it has also been recognized that, in rodents, psychedelics elevate levels of glutamate, which has been implicated in the acute and persisting effects on brain function and behavior. To our knowledge, no study has yet investigated the acute effect of a psychedelic on brain glutamate levels in humans. Therefore, the aim of the present study was to assess the acute influence of psilocybin on brain glutamate levels in the medial prefrontal cortex (glu-mPFC) and hippocampus (glu-hip). Additionally, we aimed to assess the relationship between glutamate levels and brain and behavioral outcomes previously found to be affected by psychedelics, including disrupted within-network functional connectivity and well-known subjective effects.

Methods

60 healthy participants were allocated to a treatment condition (.17 mg/kg psilocybin or placebo), and underwent ultra-high field (7T) proton magnetic resonance spectroscopy and resting-state fMRI 60 minutes after treatment administration. Participants also completed validated questionnaires designed to assess altered states of consciousness. In order to assess FC, independent component analysis (ICA) was performed using previously described group-ICA procedures. Metabolite concentration values and unthresholded ICA components were compared between treatment groups via independent samples t-tests (for FC: Bonferonni corrected cluster threshold p< 0.004, cluster-size FDR corrected, two-sided), whereas questionnaire ratings were compared via nonparametric mann-whitney tests. Finally, kendall’s tau b correlations were conducted to evaluate the association between psilocybin induced changes in glutamate concentrations, subjective effects, and FC.

Results

Administration of psilocybin was associated with increased ratings on all dimensions of the 5D-ASC (U=13.5- 225; p ≤ 0.00; d =.43 -.84) and in ego dissolution (U=91.5, p < 0.001, d=0.67). Administration also increased glu-mPFC (t=2.93, p= 0.005, d =0.77), and decreased glu-hip (t=- 2.19, p= 0.034, d =0.55). Significantly decreased coactivation under the drug condition relative to placebo was found in visual network 1 and 2, both subcomponents of the default mode network (anterior and posterior DMN), and the auditory network. Correlation analysis revealed a positive correlation between glu-mPFC and ratings of anxiety (TB=.288, p=.044), whereas a negative association was Abstracts S65 found between glu-hip and ego dissolution (TB=-.328,.034). Finally, analysis revealed a positive correlation between gluhip and mean anterior DMN activity (TB=.399, p=.017).

Conclusion

Our data demonstrate that psilocybin acutely induces region dependent alterations in glutamate that correlate with established biological and behavioral changes during the psychedelic state, providing further insights into potential underlying neurobiological mechanisms. Importantly, as enhanced glu-mPFC has been associated with increased neurogenesis in rodent models, and acute feelings of ego dissolution and DMN activity have been correlated with long-term increases in subjective well-being, our data provide a neurochemical basis for how these substances may be giving rise to therapeutic effects as witnessed in ongoing clinical trials.