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.

Endogenous theta stimulation during meditation predicts reduced opioid dosing following treatment with Mindfulness-Oriented Recovery Enhancement

“…In turn, enhancing natural reward via mindfulness practice is theorized to restructure reward processing by shifting valuation of drug-related rewards back to valuation of natural rewards, and thereby reducing addictive behavior [53]-a contention supported by recent neurophysiological data in chronic opioid users [31]. This possibility is especially intriguing, given the role of glutamatergic mPFC activity in both ego dissolution occasioned by psychedelics [54], reward, and the regulation of chronic opioid use [4]. Thus, Veterans who learned to self-generate internal reward via meditation may have been less compelled to consume opioids to obtain hedonic equilibrium, which may have accounted for the observed opioid sparing effects of MORE.…”

The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain

“…One of the most robust effects of salvinorin A was a decrease in sFC within the DMN, and using connectomebased classification, we found within-DMN sFC and eFC to be especially predictive of the effects of SA on brain function compared to other network interactions. Decreases in DMN sFC during the acute effects of hallucinogens have been a replicable finding, occurring with psilocybin 30,34 , LSD 25,35 , DMT 33 , and ketamine 31,32 . Although it might be tempting to speculate that these effects reflect "ego dissolution" 30,40 , decreases in sFC within the DMN have also been observed with acute administration of drugs not typically associated with ego dissolution such as THC 62 , alcohol 63 , and amphetamine 64 .…”

“…Like classic psychedelics 25 – 27 and dissociative anesthetics 28 , 29 , SA decreased oscillatory power in low frequency bands at rest, suggesting that pharmacologically distinct hallucinogens have partially overlapping neural mechanisms. In functional magnetic resonance imaging (fMRI) studies, both classic psychedelics and dissociative anesthetics have been shown to decrease static functional connectivity (sFC; the strength of association between brain regions over time) within canonical resting state networks, especially within the default mode network (DMN) 25 , 30 – 35 , increase between-network sFC 25 , 31 , 35 – 37 , and increase or decrease sFC among visual regions 25 , 34 , 35 , 38 , 39 . A recent hypothesis suggests that classic psychedelics make the brain more “entropic,” particularly among interactions involving the DMN 40 , 41 .…”

Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals

“…This is noteworthy because DMN disintegration has been reported when scanning participants during the psychedelic experience (Carhart-Harris et al, 2012;Preller et al, 2020) and may be implicated in the therapeutic effects of psilocybin as DMN connectivity is elevated in a range of conditions and is reduced following administration of psilocybin to experienced meditators (Smigielski et al, 2019;Whitfield-Gabrieli and Ford, 2012). Although we do not see a persistent effect on DMN connectivity, acute disruption of the DMN may still be therapeutically relevant (Carhart-Harris and Friston, 2019;Mason et al, 2020). Intake of both Salvinorin-A, a 5-HT2AR-independent hallucinogen, and MDMA, which has a subjective effect profile distinct from serotonergic psychedelics (Doss et al, 2020;Müller et al, 2020;Roseman et al, 2014), leads to a reduction in DMN connectivity.…”