N, N-Dimethyltryptamine and harmine formulation shifts metastable topography sequences in the cortex

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.