Psychedelics Align Brain Activity with Context

Psychedelics can profoundly alter consciousness by reorganising brain connectivity; however, their effects are context-sensitive. To understand how this reorganisation depends on the context, we collected and comprehensively analysed the largest psychedelic neuroimaging dataset to date. Sixty-two adults were scanned with functional MRI and EEG during rest and naturalistic stimuli (meditation, music, and visual), before and after ingesting 19 mg of psilocybin. Half of the participants ranked the experience among the five most meaningful of their lives. Under psilocybin, functional MRI and EEG signals recorded during eyes-closed conditions became similar to those recorded during an eyes-open condition. This change manifested as an increase in global functional connectivity in associative regions and a decrease in sensory areas. We used machine learning to directly link the subjective effects of psychedelics to neural activity patterns characterised by low-dimensional embeddings. We show that psilocybin reorganised these low-dimensional trajectories into cohesive patterns of brain activity that were structured by context and quality of subjective experience, with stronger self- and boundary-related effects–which were linked to day-after mindset changes—leading to more structured and distinct neural representations. This reorganisation induces a state of ‘embeddedness’ that arises when brain networks that usually segregate internal and external processing coherently integrate, aligning neural dynamics with context. This state corresponded to profound transformations of perception and self-boundaries, reducing the distinction between self and environment. Embeddedness serves as a bridging framework for understanding both the subjective and therapeutic effects of psychedelics. These findings provide a new account of the large-scale neurocognitive effects of psychedelics and demonstrate the utility of using machine learning methods in assessing state- and context-dependent neural dynamics and their association with psychological outcomes.