Electrophysiological mechanisms of psychedelic drugs: A systematic review.
Javier Hidalgo Jiménez, Karl Kristjan Kaup, Jaan Aru
Neuroscience & Biobehavioral Reviews June 1, 2026 DOI: 10.1016/j.neubiorev.2026.106649 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Topics | LSD |
| Keywords | 5-ht2a Doi Electrophysiology Nboh Psychedelics |
| Citations | 1 |
| Key findings | Psychedelics modulate both excitatory and inhibitory processes in a cell-type- and compartment-specific manner, challenging the simplified view 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.
Comparable studies
Other systematic reviews and meta-analyses on LSD, most cited first.
Citations in the library
Cited by 4
- Advancing Next-Generation Psychedelic Therapeutics through Selective 5-HT2A Activation, Precision Aerosol Delivery, and Optimized 5-MeO-DMT Treatment Paradigms ACS Medicinal Chemistry Letters July 10, 2026
- Nitrous Oxide as a Recreational Drug of Abuse: Multi-Omics Insights into MAPK/ERK/CREB-Mediated Neurotoxicity and Energy Metabolism Collapse Molecules August 1, 2026
- Cellular mechanisms of serotonergic psychedelics - apical hypercontextualisation. Neuroscience & Biobehavioral Reviews July 1, 2026
- Mapping excitatory synaptic plasticity evoked by single-dose psilocybin in mice
Cites 59
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 54 more in the library