Ekins, T. G.; Brooks, I.; Kailasa, S.; Rybicki-Kler, C.; Jedrasiak-Cape, I.; Donoho, E.; Mashour, G. A.; Rech, J.; Ahmed, O. J.

Classical psychedelic drugs are thought to increase excitability of pyramidal cells in prefrontal cortex via activation of serotonin 2A receptors (5-HT2ARs). Here, we instead find that multiple classes of psychedelics dose-dependently suppress intrinsic excitability of pyramidal neurons, and that extracellular delivery of psychedelics decreases excitability significantly more than intracellular delivery. A previously unknown mechanism underlies this psychedelic drug action: enhancement of ubiquitously expressed potassium M-current channels that is independent of 5-HT2R activation. Using machine-learning-based data assimilation models, we show that M-current activation interacts with previously described mechanisms to dramatically reduce intrinsic excitability and shorten working memory timespan. Thus, psychedelic drugs suppress intrinsic excitability by modulating ion channels that are expressed throughout the brain, potentially triggering homeostatic adjustments that can contribute to widespread therapeutic benefits.