Neural Mechanisms and Psychology of Psychedelic Ego Dissolution

Classic psychedelics work primarily by binding to serotonergic 5-HT2A receptors, and their agonist activity at these receptors changes synaptic efficacy, profoundly affecting hierarchical message-passing in the brain. This review synthesizes cognitive and neuroimaging evidence showing that psychedelics influence selfhood and subject-object boundaries—a phenomenon called ego dissolution—which may underlie their subjective and therapeutic effects. Because 5-HT2A receptors sit at the apex of the cortical hierarchy, their agonism may powerfully affect sentience and consciousness. Effects can last beyond the pharmacological half-life, suggesting psychedelics promote neural plasticity. Psychologically, they may disarm ego resistance, expanding the repertoire of perceptual hypotheses and enabling alternate pathways for thought and behavior. The authors interpret these effects through hierarchical predictive coding, offering testable predictions about effective connectivity in cortical hierarchies.

Study at a glance

Abstract

Neuroimaging studies of psychedelics have advanced our understanding of hierarchical brain organization and the mechanisms underlying their subjective and therapeutic effects. The primary mechanism of action of classic psychedelics is binding to serotonergic 5-HT2A receptors. Agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy that can have a profound effect on hierarchical message-passing in the brain. Here, we review the cognitive and neuroimaging evidence for the effects of psychedelics: in particular, their influence on selfhood and subject-object boundaries-known as ego dissolution-surmised to underwrite their subjective and therapeutic effects. Agonism of 5-HT2A receptors, located at the apex of the cortical hierarchy, may have a particularly powerful effect on sentience and consciousness. These effects can endure well after the pharmacological half-life, suggesting that psychedelics may have effects on neural plasticity that may play a role in their therapeutic efficacy. Psychologically, this may be accompanied by a disarming of ego resistance that increases the repertoire of perceptual hypotheses and affords alternate pathways for thought and behavior, including those that undergird selfhood. We consider the interaction between serotonergic neuromodulation and sentience through the lens of hierarchical predictive coding, which speaks to the value of psychedelics in understanding how we make sense of the world and specific predictions about effective connectivity in cortical hierarchies that can be tested using functional neuroimaging. SIGNIFICANCE STATEMENT: Classic psychedelics bind to serotonergic 5-HT2A receptors. Their agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy, resulting in a profound effect on information processing in the brain. Here, we synthesize an abundance of brain imaging research with pharmacological and psychological interpretations informed by the framework of predictive coding. Moreover, predictive coding is suggested to offer more sophisticated interpretations of neuroimaging findings by bridging the role between the 5-HT2A receptors and large-scale brain networks.