N,N-Dimethyltryptamine and harmine formulation alters transient EEG topography sequences near the peak of the psychedelic state

Background: Psychoactive serotonin 5-HT2A receptor agonists are potent modulators of awareness. Influential theories propose that psychedelics alter whole-brain dynamics by increasing neural signal diversity and dynamic flexibility. Beyond temporal variability, it is an open question whether psychedelics impact the characteristics of transient neural state sequences themselves. Aims: Our goal was to assess how an ayahuasca-inspired formulation (intranasal N,N-Dimethyltryptamine (DMT) and buccal harmine) modulates parameters of neural state sequences close to the peak of the psychedelic state. Methods: In a double-blind, randomised, placebo-controlled Electroencephalography (EEG) study, participants ( n = 25) were administered the following interventions on separate testing days: (1) a DMT/harmine formulation; (2) harmine alone and (3) a placebo. We used EEG microstate analysis to compare the neural dynamics between the three conditions. Results/Outcomes: Compared to harmine and placebo, DMT/harmine was linked to reduced microstate duration but increased microstate occurrence and complexity. Higher first-order Markov statistics revealed that transition sequences became less random when DMT/harmine was administered. Conclusions/Interpretation: Our finding that DMT/harmine is associated with more complex and predictable neural state sequences as well as accelerated state transitions is consistent with models of increased metastability and signal diversity. By revealing a more diverse repertoire of neural state sequences under DMT/harmine, our findings improve our understanding of neural dynamics in psychedelic states. Clinical trial registration: Neurodynamics of prosocial emotional processing following serotonergic stimulation with N,N-DMT and harmine in healthy subjects. https://clinicaltrials.gov/ct2/show/NCT04716335 .