Psychedelics and neuroanesthesia: A narrative review of converging mechanisms

Anesthesia and psychedelics both disrupt the default-mode network, reduce frontoparietal connectivity, increase between-network interactions, and produce similar EEG signatures, particularly during emergence from anesthesia. Classical serotonergic psychedelics target 5-HT2A receptors, ketamine blocks NMDA receptors, and nitrous oxide modulates GABA-A receptors, yet all produce comparable network-level cortical effects. The controlled setting of anesthesia provides a platform to separate drug pharmacology from expectancy and subjective experience, as demonstrated by ketamine trials masked by surgical anesthesia. This narrative review synthesizes evidence on shared molecular targets, neural-network signatures, and EEG correlates, with implications for perioperative monitoring, sedation in vulnerable patients, and designing placebo-controlled psychedelic studies.

Study at a glance

Abstract

Current neuroscience research calls into question the binary model of anesthesia as a state of consciousness shifted by unconsciousness, replacing it with an idea of consciousness as a continuum created by interactions between large-scale cortex and subcortical regions.Meanwhile, psychedelic drugs are making a comeback as potential treatments for treatment-resistant depression, post-traumatic stress disorder, anxiety during life-threatening illness and substance use disorders.Classical serotonergic psychedelics (like psilocybin and lysergic acid diethylamide) have a primary target on 5-hydroxytryptamine 2A receptors, while the dissociative anesthetic ketamine inhibits Nmethyl-D-aspartate receptors, and the weak gamma-aminobutyric acid-A receptor modulation is a component of the action of nitrous oxide.These agents interact differently with receptors, but have similar network-level effects on the human cortex, such as disruption of integrity of the default-mode network, loss of frontoparietal directed connectivity, increased between-network interactions, and characteristic EEG signatures that are strikingly similar to those seen during emergence from general anesthesia.The anesthesiology paradigm offers a very unique and well controlled platform for dissecting the relative contribution of drug pharmacology, expectancy, and the conscious subjective experience -something that has been recently shown by ketamine masked by surgical anesthesia trials.Here, the current narrative review aims to bring together the latest available evidence on the intersection of psychedelic pharmacology and clinical anesthesia, focusing on common molecular targets, neural-network signatures, EEG correlates, and the therapeutic relevance of anesthetic emergence in specific psychiatric patient populations.The implications for perioperative monitoring, perioperative sedation in vulnerable patients, and designing future placebo-controlled studies of psychedelics are discussed.These two literatures bring the neuroanesthesiologist into a crucial role in the future of clinical psychedelic science.