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

TLDR

Psychedelic drugs such as psilocybin are increasingly studied for treating disorders involving self‑distortion, yet the role of the glutamate system in human responses remains untested. In a double‑blind, placebo‑controlled study, ultra‑high‑field multimodal imaging revealed that psilocybin (0.17 mg/kg) produced region‑specific glutamate changes that predicted ego‑dissolution experiences. Higher medial prefrontal glutamate correlated with negatively experienced ego dissolution, whereas lower hippocampal glutamate correlated with positively experienced ego dissolution, offering neurochemical insights that may underlie therapeutic effects.

Abstract

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.