N, N-Dimethyltryptamine and harmine formulation shifts metastable topography sequences in the cortex
Maria Niedernhuber, Dila Suay, Michael J Mueller, Milan Scheidegger, Dario Dornbierer, Helena Aicher
bioRxiv (Cold Spring Harbor Laboratory) December 9, 2025 preprint DOI: 10.64898/2025.12.04.692302 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind, placebo-controlled study |
|---|---|
| Sample size | 25 |
| Population | Human participants |
| Interventions | ayahuasca-inspired formulation (intranasal N N-DMT and buccal harmine) |
| Topics | 5-MeO-DMT DMT |
| Keywords | Ministate Metastability Hallucinating Neocortex State computer science Visual cortex Local field potential Bedaquiline Frontal cortex Statistical physics Artificial intelligence Markov chain Sequence biology Neural activity Pattern recognition psychology Indeterminacy philosophy Cortex anatomy Communication |
| Citations | 1 |
| Key points | Psychedelic states induced by DMT and harmine accelerate neural dynamics and increase syntactic structure in microstate sequences, rather than simply randomizing brain activity. |
Abstract
Abstract Classic serotonergic psychedelics are potent modulators of conscious awareness, yet the principles governing their effects on the temporal dynamics of brain activity remain unclear. Dominant theories propose that psychedelics increase the signal diversity and metastability of neural states, but whether this reflects a simple randomization of activity or a more structured reorganization is unknown. Here, we used high-density EEG (n=25) in a double-blind, placebo-controlled study to delineate the effects of an ayahuasca-inspired formulation (intranasal N,N-DMT and buccal harmine) on the syntax of whole-brain functional states. Using microstate analysis, we show that psychedelic states induced by DMT and harmine are characterized by a profound acceleration of neural dynamics, evidenced by a reduced microstate duration and an increased frequency of state transitions. Despite that, the sequence of microstates became less random, as indicated by a higher first-order Markov statistic. This syntactic restructuring involved a systematic de-prioritization of transitions into one state (M2) and a corresponding increase in the prevalence and accessibility of two other states (M3 and M5). These findings reveal that the psychedelic state leads to a syntactically reconfigured state of heightened metastability. By showing that psychedelics both lead to an accelerated exploration of an expanded repertoire of neural states governed by increased syntactic structure, our findings improve our understanding of neural metastability in psychedelic states.
Comparable studies
Other randomized controlled trials on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Dose-Response Study of N,N-Dimethyltryptamine in Humans Experienced hallucinogen users | 1994 | Double-blind, saline placebo-controlled, randomized study | n = 12 |
| Psychological Effects of (S)-Ketamine and N,N-Dimethyltryptamine (DMT): A Double-Blind, Cross-Over Study in Healthy Volunteers Healthy volunteers | 2005 | Double-blind crossover study | n = 9 |
| Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans Experienced hallucinogen users | 1996 | Randomized controlled trial | n = 13 |
| Pharmacokinetics of N,N-dimethyltryptamine in Humans. Healthy adults | 2023 | Phase I component of a phase I/IIa randomised, double-blind, placebo-controlled, parallel-group, dose-escalation trial | n = 24 |
| Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis Healthy volunteers | 2007 | Double-blind crossover study | n = 15 |
Citations in the library
Cites 34
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacology & Therapeutics May 1, 2019
- Enhanced repertoire of brain dynamical states during the psychedelic experience Human Brain Mapping July 3, 2014
and 29 more in the library