Context-dependent structurally informed effective connectivity under psilocybin

The extent to which anatomical connectivity constrains pharmacologically altered brain dynamics remains poorly understood. Here, we combined psilocybin administration with a structurally informed effective-connectivity model to examine how structural connectivity shapes directed inter-regional influences across experiential contexts. Using dynamic causal modeling embedded in a hierarchical empirical Bayes framework, we analyzed fMRI data acquired from a hippocampo–thalamo–cortical network during rest, guided meditation, music listening and movie viewing. Across contexts, psilocybin reorganized directed interactions while preserving structure-based scaling. Effects converged on efferents (outgoing influences) from the left hippocampus—a hub interfacing mnemonic and associative systems with the default-mode network and thalamus. Notably, the left-hippocampus-to-thalamus pathway showed a sign-reversed association with mystical-experience scores (downregulation during guided meditation and upregulation during music listening). In model-based leave-one-out cross-validation, left-hippocampal efferents predicted individual differences in mystical-experience intensity. A minimal model-free benchmark (hippocampal signal variability) also showed modest associations with mystical experience. Together, these findings link context-specific, structurally informed effective connectivity to individual differences in the acute psychedelic experience, providing a mechanistic bridge between anatomy, neurodynamics, and phenomenology.