Electrophysiological mechanisms of psychedelic drugs: A systematic review

Serotonergic psychedelics are known for their profound effects on consciousness and are gaining renewed interest as potential psychiatric treatments. These advances underscore the need to clarify the mechanisms of action of these compounds. This systematic review compiles and critically evaluates 23 in vitro and 26 in vivo electrophysiological studies on psychedelic compounds, with an emphasis on layer 5 pyramidal neurons in the prefrontal cortex, where 5-HT_2A receptors are densely expressed. Our findings reveal that psychedelics exert complex, heterogeneous effects on neuronal excitability, synaptic transmission, and local oscillations. These results challenge the simplified view that psychedelics uniformly increase cortical excitability. Instead, they modulate both excitatory and inhibitory processes in a cell-type- and compartment-specific manner, with evidence for biphasic, dose-dependent, and context-sensitive responses. Activation of 5-HT_2A receptors leads to 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, and some indirect evidence supports the involvement of intracellular 5-HT_2A receptors. These insights prompt a reassessment of prevailing models of psychedelic action and underscore the value of incorporating electrophysiological data into psychedelic neuropharmacology.