Network control energy reductions under DMT relate to serotonin receptors, signal diversity, and subjective experience

This re-analysis (n=14) applies a receptor-informed network control theory framework to investigate the effects of DMT on the brain’s control energy landscape. It reveals that DMT, like LSD and psilocybin, reduces global control energy, with these trajectories correlating with EEG signal diversity and subjective intensity ratings. Furthermore, the regional effects of DMT correlate with serotonin 2a receptor density, demonstrating a potential proof-of-concept for predicting pharmacological intervention effects on brain dynamics using control models.

Abstract of Network control energy reductions under DMT relate to serotonin receptors, signal diversity, and subjective experience

“Psychedelics offer a profound window into the human brain through their robust effects on perception, subjective experience, and brain activity patterns. The serotonergic psychedelic N,N-dimethyltryptamine (DMT) induces a profoundly immersive altered state of consciousness lasting under 20 min, allowing the entire experience to be captured during a single functional magnetic resonance imaging (fMRI) scan. Using network control theory, we map energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. We find that global control energy is reduced after DMT injection compared to placebo. Longitudinal trajectories of global control energy correlate with longitudinal trajectories of electroencephalography (EEG) signal diversity (a measure of entropy) and subjective drug intensity ratings. At the regional level, spatial patterns of DMT’s effects on these metrics correlate with serotonin 2a receptor density from positron emission tomography (PET) data. Using receptor distribution and pharmacokinetic information, we recapitulate DMT’s effects on global control energy trajectories, demonstrating control models can predict pharmacological effects on brain dynamics.”

Authors: S. Parker Singleton, Christopher Timmermann, Andrea I. Luppi, Emma Eckernäs, Leor Roseman, Robin L. Carhart-Harris & Amy Kuceyeski

Summary of Network control energy reductions under DMT relate to serotonin receptors, signal diversity, and subjective experience

Serotonergic psychedelics such as LSD, psilocybin, and DMT are powerful neuromodulators that transiently alter the human experience. MAO enzymes metabolise DMT in the body and, therefore, must be combined with MAO inhibitors to be orally active.

Human neuroimaging studies with LSD and psilocybin have demonstrated that these compounds acutely decrease integrity within the brian’s functional sub-networks, while increasing integrity between functional sub-networks. This finding affords a unique opportunity to model and study the perturbation of brain dynamics using whole-brain computational models.

Network control theory is a linear dynamical systems approach that models state transitions occurring within a network. It has been applied to the brain in various cognitive states and neuropsychiatric/degenerative conditions, as well as throughout development and during neuromodulation and pharmacologically induced altered states.

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Find this paper

Network control energy reductions under DMT relate to serotonin receptors, signal diversity, and subjective experience

https://doi.org/10.1038/s42003-025-08078-9

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Cite this paper (APA)

Singleton, S. P., Timmermann, C., Luppi, A. I., Eckernäs, E., Roseman, L., Carhart-Harris, R. L., & Kuceyeski, A. (2025). Network control energy reductions under DMT relate to serotonin receptors, signal diversity, and subjective experience. Communications Biology8(1), 631.

Study details

Compounds studied
DMT

Topics studied
Neuroscience Healthy Subjects

Study characteristics
Original Re-analysis Placebo-Controlled Single-Blind Within-Subject Randomized

Participants
14 Humans

Authors

Authors associated with this publication with profiles on Blossom

Chris Timmermann
Chris Timmerman is a postdoc at Imperial College London. His research is mostly focussed on DMT.

Robin Carhart-Harris
Dr. Robin Carhart-Harris is the Founding Director of the Neuroscape Psychedelics Division at UCSF. Previously he led the Psychedelic group at Imperial College London.

Institutes

Institutes associated with this publication

Imperial College London
The Centre for Psychedelic Research studies the action (in the brain) and clinical use of psychedelics, with a focus on depression.

Compound Details

The psychedelics given at which dose and how many times

DMT 20 mg | 1x

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