Context-dependent structurally informed effective connectivity under psilocybin
Matthew D. Greaves, Tamrin Barta, Leonardo Novelli, Devon Stoliker, Adeel Razi
bioRxiv (Cold Spring Harbor Laboratory) August 22, 2025 preprint DOI: 10.1101/2025.08.18.671000 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study with fMRI and dynamic causal modeling |
|---|---|
| Population | Humans (fMRI data from a hippocampo-thalamo-cortical network) |
| Intervention | Psilocybin |
| Topics | Psilocybin |
| Keywords | Context archaeology Hallucinogen Paleontology |
| Key findings | Psilocybin reorganizes directed inter-regional influences in a hippocampo–thalamo–cortical network while preserving structure-based scaling, and left-hippocampal efferents predict individual differences in mystical-experience intensity. |
Abstract
Abstract 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.
Comparable studies
Other experimental studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Participants in controlled laboratory experiments receiving a moderate to high oral... | 2015 | Validation study using pooled data from five laboratory experiments | n = 184 |
| Broadband Cortical Desynchronization Underlies the Human Psychedelic State Healthy human participants | 2013 | Experimental study | |
| Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer Participants with cancer-related psychiatric distress who completed a parent randomized... | 2020 | Long-term within-subjects follow-up analysis | n = 15 |
| Enzymatic Synthesis of Psilocybin | 2017 | Laboratory study |
Citations in the library
Cites 23
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences April 11, 2016
- Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Journal of Psychopharmacology October 6, 2015
- Mindfulness meditation training alters cortical representations of interoceptive attention Social Cognitive and Affective Neuroscience June 11, 2012
- Broadband Cortical Desynchronization Underlies the Human Psychedelic State Journal of Neuroscience September 18, 2013
and 18 more in the library