Psychedelics such as LSD and NBOH produce complex, heterogeneous effects on brain cells, challenging the idea that they simply increase cortical excitability. A systematic review of 23 in vitro and 26 in vivo electrophysiological studies found that these compounds modulate both excitatory and inhibitory processes in a cell-type- and compartment-specific manner, with biphasic, dose-dependent, and context-sensitive responses. Activation of 5-HT2A receptors triggers intricate calcium signaling, downregulating excitatory currents and firing rates in many neurons while enhancing glutamate release and activating a subset of projection fibers. Modulation of presynaptic and extrasynaptic GluN2B-containing NMDA receptors appears central to these effects.
Serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signaling network that drives neuroplastic changes. Using a neural stem cell-derived in vitro model, a panel of tryptamines, phenethylamines, and ergolines was tested alongside ketamine and TrkB agonists. TrkB silencing abolished dendritogenic responses to all tested compounds, while 5-HT2A receptor silencing selectively impaired psychedelic-induced plasticity. Most compounds increased synaptogenesis and induced c-Fos and Egr-2 expression, with ligand-specific differences for psilocin, DOI, and Ariadne. Gq/11 or Gi/o protein coupling differentially modified neuroplastic and transcriptional responses. Psychedelics also induced a 5-HT2A receptor-dependent lactate response sensitive to disruption of either Gq/11 or Gi/o coupling.