Losing Your Mind, Precisely: Psilocybin and the Biological Reorganization of Hierarchical Inference

Abstract

Psychedelics reveal that perceptual stability is not given but constructed, exposing how a defined biological perturbation can propagate across neural systems to reorganize hierarchical inference. Despite extensive work at the molecular, systems, and computational levels, there remains no fully integrated account of how these levels relate in a principled way. This thesis addresses that gap by arguing that psilocybin induces a biologically driven destabilization of hierarchical inference that begins with 5-HT₂A receptor activation on layer V pyramidal neurons, propagates through cortical microcircuitry and large-scale network organization, and ultimately reduces the precision of high-level priors. Drawing together evidence on receptor localization, intracellular signaling, default mode network disintegration, increased global connectivity, reduced alpha-band oscillations, and elevated neural entropy, the thesis evaluates predictive processing and REBUS as frameworks for explaining these effects. Predictive processing provides the necessary computational architecture for describing changes in perception, but remains insufficiently constrained at the level of biological implementation. REBUS, by contrast, links these computational changes to a specific pharmacological mechanism and generates more precise predictions about the direction and structure of hierarchical disruption, though it remains incomplete without the broader inferential framework provided by predictive processing. The central claim is therefore not that one framework supersedes the other, but that psychedelic effects are best understood through their integration, as a coordinated process in which biological perturbations reorganize hierarchical inference across levels of analysis. Finally, by comparing psychedelic states with dreaming, the thesis proposes that both reflect distinct perturbations of a common predictive system under reduced constraint, offering a broader account of hallucination-like experience as a consequence of increased influence of internally generated activity. Taken together, this work argues that psychedelics do not simply distort perception, but make visible the mechanisms by which the brain constructs, stabilizes, and, under specific conditions, reorganizes its model of the world.