Brain substates induced by DMT relate to sympathetic output and meaningfulness of the experience.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic, known to rapidly induce short-lasting alterations in conscious experience, characterized by a profound and immersive sense of physical transcendence alongside rich and vivid auditory distortions and visual imagery. Multimodal neuroimaging data paired with dynamic analysis techniques offer a valuable approach for identifying unique signatures of brain activity - and linked autonomic physiology - naturally unfolding during the altered state of consciousness induced by DMT. We leveraged simultaneous fMRI and EKG data acquired in 14 healthy volunteers prior to, during, and after intravenous administration of DMT, and, separately, placebo. EKG data was used to derive continuous heart rate; fMRI data was preprocessed to derive individual dynamic activity matrices, reflecting the similarity of brain activity in time, and community detection algorithms were applied on these matrices to identify brain activity substates. We identified a brain substate occurring immediately after DMT injection, characterized by increased superior temporal lobe activity, and hippocampal and medial parietal deactivations under DMT. Superior temporal lobe hyperactivity correlated with the intensity of the auditory distortions, while hippocampus and medial parietal cortex hypoactivity correlated with scores of meaningfulness of the experience. During this first post-injection substate, increased heart rate under DMT correlated negatively with the meaningfulness of the experience and positively with hippocampus/medial parietal deactivation. These results suggest a chain of influence linking sympathetic regulation to hippocampal and medial parietal deactivations under DMT, which combined may contribute to positive mental health outcomes related to self-referential processing following psychedelic administration.