Psychedelics Align Brain Activity with Context
Using the largest psychedelic neuroimaging dataset to date (62 adults, fMRI and EEG, before and after 19 mg psilocybin), the authors show that psilocybin reorganises brain dynamics—increasing global connectivity in associative regions and decreasing it in sensory areas—so that neural activity aligns with contextual stimuli and eyes-open versus eyes-closed states. This reorganisation, revealed by low-dimensional trajectories, produces an “embeddedness” state linking distinct neural patterns to boundary-dissolving subjective experiences and next-day mindset changes, offering a framework for how psychedelics exert context-sensitive behavioural and therapeutic effects.
Authors
- Otto Simonsson
- Robin Carhart-Harris
- Katrin Preller
Published
Abstract
Psychedelics can profoundly alter consciousness by reorganising brain connectivity; however, their effects are contextsensitive. 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 structured patterns of brain activity that reflected the context and quality of subjective experience, revealing an organisation that was missed by conventional analyses. Stronger self- and boundary-dissolving effects were linked to next-day mindset changes and associated with more distinct and cohesive neural representations. This reorganisation induces a state we represent as ‘embeddedness’ that arises when brain networks that usually segregate internal and external processing coherently integrate, aligning neural dynamics with context. This state corresponded to the felt experience of being part of the environment. Embeddedness serves as a bridging framework for understanding both the subjective and therapeutic effects of psychedelics, demonstrating that psychedelics introduce context- and quality-dependent reorganisation in neural dynamics. These findings reveal that the organisation of brain activity covaries with the experiential coherence of the psychedelic state, providing a new framework for understanding how psychedelics shape neurobiology and behaviour through context-sensitive brain dynamics.
Research Summary of 'Psychedelics Align Brain Activity with Context'
Introduction
Stoliker and colleagues frame the study around how psychedelics reorganise brain connectivity in ways that depend on psychological and sensory context. Earlier research has shown that agents such as psilocybin act at 5-HT2A receptors to induce structural and functional plasticity, relax constraints on associative networks such as the default mode network (DMN), and can produce profound subjective effects including intensified immersion and self-boundary dissolution. However, prior human studies have often used small samples, single imaging modalities, or limited contexts, leaving open how context shapes large-scale functional integration and the neural mechanisms that relate reorganisation to subjective and therapeutic outcomes. This study set out to address those gaps by acquiring a large, multimodal dataset (fMRI and high-density EEG) in a predominantly psychedelic-naïve cohort and systematically varying contextual conditions (eyes-closed rest, guided meditation, music listening, and eyes-open movie watching). Using a fixed 19 mg oral psilocybin dose and repeated baseline (no-psilocybin) and post-dose imaging, the investigators aimed to map how psilocybin changes global and local connectivity, signal variability, directed interactions (via dynamic causal modelling), and low-dimensional neural embeddings, and how those neural changes covary with subjective experience and short-term psychological changes. The work emphasises context-sensitive mechanisms and introduces machine-learning embedding approaches to link neural dynamics with phenomenology and potential adaptive outcomes.
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Study Details
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- APA Citation
Stoliker, D., Novelli, L., Khajehnejad, M., Biabani, M., Barta, T., Greaves, M. D., Williams, M., Chopra, S., Bazin, O., Simonsson, O., Chambers, R., Barrett, F., Deco, G., Preller, K. H., Carhart-Harris, R., Seth, A., Sundram, S., Egan, G. F., & Razi, A. (2025). Psychedelics Align Brain Activity with Context. https://doi.org/10.1101/2025.03.09.642197
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