<p>Over the past decade, psychedelics research has returned to the forefront of global psychiatry and neuroscience. At Imperial College London (ICL), researchers find explanations for mental illness and healing in a brain system called the Default Mode Network (DMN) which they identify with the ego or self. Amidst the globalization of psychedelic science and medicine, this model has now become the dominant neurobiological explanation for the efficacy of these drugs. In this paper, I draw on archival and scientific literature, along with data from 24&#xa0;months of ethnographic research among neuropsychiatrists and substance-users in the psychedelic underground, to examine how neuroscientific claims operate in contemporary debates around a “triple crisis” in psychiatry. Through a sustained analysis of scientific publications by ICL researchers in the 2010s, I show how the conceptual, material, and technical infrastructure of the science depends on mystical notions of “ego-dissolution.” Adopting the heuristic lens of the “default”, I then undertake a semiotic analysis to track the epistemic, material and moral debts propelling the fortunes of the DMN as psychedelic commercialization gains force. The conclusion uses this lens to interpret the role of the DMN model in legitimizing, institutionalizing, and accelerating the Psychedelic Renaissance.</p>