Electrophysiological mechanisms of psychedelic drugs: A systematic review.
Javier Hidalgo Jiménez, Karl Kristjan Kaup, Jaan Aru
Neuroscience and biobehavioral reviews June 1, 2026 Peer reviewed DOI: 10.1016/j.neubiorev.2026.106649 via PubMed
Summary
Psychedelics have complex effects on brain function, particularly in layer 5 pyramidal neurons of the prefrontal cortex. This systematic review of 49 electrophysiological studies indicates that psychedelics do not simply increase neuronal excitability; instead, they can both enhance and inhibit neural activity depending on the context. Activation of 5-HT2A receptors is crucial for these varied effects, affecting calcium signaling and modulating glutamate release.
Study at a glance
| Design | systematic review |
|---|---|
| Sample size | 49 |
| Population | electrophysiological studies on psychedelic compounds |
| Key finding | Psychedelics modulate both excitatory and inhibitory processes in a cell-type- and compartment-specific manner, challenging the notion that they uniformly increase cortical excitability. |
Abstract
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-HT2A 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-HT2A 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-HT2A receptors. These insights prompt a reassessment of prevailing models of psychedelic action and underscore the value of incorporating electrophysiological data into psychedelic neuropharmacology.