Ego‐disturbances have been a topic in schizophrenia research since the earliest clinical descriptions of the disorder. Manifesting as a feeling that one's “self,” “ego,” or “I” is disintegrating or that the border between one's self and the external world is dissolving, “ego‐disintegration” or “dissolution” is also an important feature of the psychedelic experience, such as is produced by psilocybin (a compound found in “magic mushrooms”). Fifteen healthy subjects took part in this placebo‐controlled study. Twelve‐minute functional MRI scans were acquired on two occasions: subjects received an intravenous infusion of saline on one occasion (placebo) and 2 mg psilocybin on the other. Twenty‐two visual analogue scale ratings were completed soon after scanning and the first principal component of these, dominated by items referring to “ego‐dissolution”, was used as a primary measure of interest in subsequent analyses. Employing methods of connectivity analysis and graph theory, an association was found between psilocybin‐induced ego‐dissolution and decreased functional connectivity between the medial temporal lobe and high‐level cortical regions. Ego‐dissolution was also associated with a “disintegration” of the salience network and reduced interhemispheric communication. Addressing baseline brain dynamics as a predictor of drug‐response, individuals with lower diversity of executive network nodes were more likely to experience ego‐dissolution under psilocybin. These results implicate MTL‐cortical decoupling, decreased salience network integrity, and reduced inter‐hemispheric communication in psilocybin‐induced ego disturbance and suggest that the maintenance of “self”or “ego,” as a perceptual phenomenon, may rest on the normal functioning of these systems. Hum Brain Mapp 36:3137–3153, 2015. © 2015 Wiley Periodicals, Inc.