LSD Relaxes Structural Constraints on Brain Dynamics and Default Mode Decoupling Predicts Ego Dissolution

Abstract Psychedelics profoundly alter conscious experience, yet how they reshape the relationship between brain anatomy and electrophysiological dynamics remains unclear. Here we use source-localized magnetoencephalography mapped onto connectome harmonics to quantify structure–function coupling in humans under lysergic acid diethylamide (LSD) and placebo. LSD induces a robust decoupling of low-frequency (theta, alpha and beta) activity from anatomical constraints, indicating a global loosening of structure-aligned large-scale dynamics. High-frequency gamma activity shows selective reorganization rather than uniform disruption. Decoupling within core default-mode network regions predicts ego dissolution intensity across individuals, linking frequency-selective DMN reorganization to subjective loss of self. Functional decoding further reveals system-specific rebalancing: visual and attentional systems preferentially decouple while auditory networks exhibit strengthened coupling. Together, these findings provide electrophysiological evidence that psychedelic states emerge from a frequency-dependent relaxation of structural constraints on brain activity and identify default-mode reorganization as a neural correlate of ego dissolution. These results offer a mechanistic framework for understanding how LSD may exert therapeutic effects by transiently relaxing rigid structural constraints and enhancing dynamical flexibility within networks involved in self-related processing. Competing Interest Statement RC-H reports providing scientific advice for TRYP therapeutics, Osmind, Otsuka, and Red Light Holland. Others declare no competing interests. Footnotes - Title updated to better convey the core findings - Bootstrapping added to investigate the stability of the phenomenology regression analysis - Github code made available, the language pointing towards the git repo updated - Several updates on language, e.g. softened the claims regarding phenomenology regression analysis