A Mesoscale Framework for Psychedelic Drug Action in the Human Brain

The mechanism of psychedelic drug action is a dynamic area of neuroscience, with two major lines of investigation: (1) laboratory studies at the molecular and cellular level, and (2) human neuroimaging studies of functional brain networks. Despite considerable progress, there remains insufficient understanding of the link between molecular/cellular substrates of psychedelics and the whole-brain network effects that result. Here we report a study of psychedelic action that focuses on the intermediate spatial scale of local brain regions (<1cm3). We analyzed the effects of classical psychedelics (dimethyltryptamine [DMT], lysergic acid diethylamide [LSD], psilocybin) and non-classical psychedelics (nitrous oxide, ketamine) in humans using functional magnetic resonance imaging. We found that all five drugs reduced regional homogeneity, that is, they disrupted local synchrony, in small-scale brain regions; this disruption occurred extensively in cortical regions and sparsely in subcortical regions. Dynamic analysis of both regional homogeneity and global functional connectivity showed an inverse pattern, with large-scale functional connectivity being enhanced as local synchrony declined. We then conducted dominance analysis to assess the contribution of various neurotransmitter receptors to changes in regional homogeneity. DMT, LSD, and psilocybin showed the 5-HT receptors as the most dominant association; by contrast, regional homogeneity changes attributable to both nitrous oxide and ketamine were most strongly associated with the NMDA receptor. Both neuronal (including interneurons) and non-neuronal cell types were linked to psychedelic-induced changes in synchrony at the level of local brain regions. These data, across five drugs from two drug classes, provide evidence that a diverse set of molecular and cellular events lead to a common outcome of disrupted synchrony in local brain regions, which in turn mediate drug-specific changes in global functional connectivity.