The unique neural signature of your trip: Functional connectome fingerprints of subjective psilocybin experience
Using brain‑fingerprinting on fMRI from volunteers given psilocybin or placebo, the study shows psilocybin increases functional‑connectome idiosyncrasy via greater intersubject dissimilarity and shifts idiosyncratic features from frontoparietal regions to the default mode network (DMN). They identify a DMN‑centred connectivity signature—reduced within‑DMN and DMN‑limbic coupling and increased DMN‑attentional connectivity—that predicts subjective psilocybin experience, demonstrating the value of brain‑fingerprinting for pharmacological neuroimaging.
Authors
- Johannes Ramaekers
- Nathalie Mason
- Paolo Mallaroni
Published
Abstract
The emerging neuroscientific frontier of brain fingerprinting has recently established that human functional connectomes (FCs) exhibit fingerprint-like idiosyncratic features, which map onto heterogeneously distributed behavioral traits. Here, we harness brain-fingerprinting tools to extract FC features that predict subjective drug experience induced by the psychedelic psilocybin. Specifically, in neuroimaging data of healthy volunteers under the acute influence of psilocybin or a placebo, we show that, post psilocybin administration, FCs become more idiosyncratic owing to greater intersubject dissimilarity. Moreover, whereas in placebo subjects idiosyncratic features are primarily found in the frontoparietal network, in psilocybin subjects they concentrate in the default mode network (DMN). Crucially, isolating the latter revealed an FC pattern that predicts subjective psilocybin experience and is characterized by reduced within-DMN and DMN-limbic connectivity, as well as increased connectivity between the DMN and attentional systems. Overall, these results contribute to bridging the gap between psilocybin-mediated effects on brain and behavior, while demonstrating the value of a brain-fingerprinting approach to pharmacological neuroimaging.
Research Summary of 'The unique neural signature of your trip: Functional connectome fingerprints of subjective psilocybin experience'
Introduction
Psychedelic compounds such as LSD, DMT and psilocybin produce transient but profound altered states of consciousness (ASCs) that are increasingly investigated for therapeutic potential in conditions including depression, obsessive–compulsive disorder and addiction. Prior neuroimaging work indicates that these subjective effects are largely mediated by 5-HT2A receptor agonism and are accompanied by systematic reconfigurations of the brain's functional connectome (FC), notably reduced activity and connectivity within higher-level association systems such as the default-mode network (DMN) and increased connectivity among lower-level sensory systems. However, individuals differ markedly in both neural response and subjective experience under psychedelics, and it remains unclear which subject-specific FC features map onto the multifaceted acute drug experience. Tolle and colleagues set out to address this gap by applying brain-fingerprinting methods to 7-Tesla resting-state fMRI collected from healthy volunteers who received either 0.17 mg/kg psilocybin (n=21) or placebo (n=25). The study aimed to (i) compare FC fingerprint properties between psilocybin and placebo conditions and (ii) determine whether idiosyncratic FC edges—that is, connections that are temporally stable within an individual yet variable across individuals—improve prediction of each subject's retrospective report of their psilocybin experience using the 5D-ASC questionnaire decomposed into 11 subdimensions.
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Study Details
- Study Typeindividual
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- APA Citation
Tolle, H. M., Farah, J. C., Mallaroni, P., Mason, N. L., Ramaekers, J. G., & Amico, E. (2024). The unique neural signature of your trip: Functional connectome fingerprints of subjective psilocybin experience. Network Neuroscience, 8(1), 203-225. https://doi.org/10.1162/netn_a_00349
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Mallaroni, P., Singleton, P., Mason, N. L. et al. · Molecular Psychiatry (2026)
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