Translated from our German original by AI. The German text was researched, written, and edited by the Psychedelia Foundation team and remains the authoritative version.
Analysis of 49 electrophysiological studies offers new insight into how serotonergic psychedelics work
Serotonergic psychedelics such as psilocybin and LSD appear to influence the activity of nerve cells in a far more differentiated way than many established models suggest. That is the conclusion of the study Electrophysiological mechanisms of psychedelic drugs: A systematic review, which systematically evaluated the existing electrophysiological research on the mechanisms of psychedelic substances.
Given the growing interest in psychedelics as potential treatments for psychiatric illness, a better understanding of their neurobiological mode of action is needed, the authors write. For the review, 23 in vitro and 26 in vivo studies were analyzed, all of them examining the effects of psychedelic compounds on the electrical activity of nerve cells.
One focus was on layer 5 pyramidal neurons in the prefrontal cortex. These nerve cells carry a high density of 5-HT2A receptors, which are considered the central point of attack for serotonergic psychedelics.
The review shows that the effects of psychedelic substances on neuronal excitability, synaptic transmission, and local brain rhythms are heterogeneous. In the authors’ assessment, the findings contradict the widespread notion that psychedelics raise the excitability of the cerebral cortex across the board.
Instead, the data suggest that these substances modulate excitatory and inhibitory processes differently depending on cell type, cell compartment, dose, and biological context. The authors also found indications of biphasic and dose-dependent response patterns.
Activation of 5-HT2A receptors is accordingly linked to complex calcium signaling pathways. In many of the neurons studied, excitatory currents and the firing rate of the cells declined. At the same time, increased release of the neurotransmitter glutamate and the activation of certain projection fibers were observed.
Presynaptic and extrasynaptic NMDA receptors containing the GluN2B subunit are named as a possible key factor in these effects. The authors also found indirect indications that 5-HT2A receptors located inside the cell could be involved as well.
The researchers conclude that the available data argue for a reassessment of current models of how psychedelic substances work. At the same time, the findings underline the importance of electrophysiological studies for the further development of psychedelic neuropharmacology.
