Divergent effects of ketamine and psilocybin on EEG power spectral density in a mismatch negativity paradigm

Ketamine and psilocybin, two drugs with therapeutic potential for depression, produce distinct effects on brain electrical activity. Ketamine disrupts the balance between excitation and inhibition in neural circuits, as shown by changes in the aperiodic components of EEG spectra, and reduces beta band activity. Psilocybin also reduces alpha power in similar brain regions but does not affect beta activity or aperiodic components in the same way. These differences reflect their different mechanisms: ketamine blocks NMDA receptors while psilocybin targets serotonin receptors. Ketamine's unique EEG signature supports its role as a model for prodromal psychosis.

Study at a glance

Abstract

RationaleKetamine and psilocybin have demonstrated therapeutic potential for mental disorders, including major depressive disorder, yet they engage distinct mechanisms of action. Ketamine, a dissociative hallucinogen, acts by blocking N-methyl-D-aspartate receptors (NMDAR), whereas psilocybin primarily targets serotonin receptors. These divergent mechanisms are reflected in their electrophysiological biomarkers.ObjectivesThis study aimed to investigate the divergent effects of ketamine and psilocybin on different elements of the EEG frequency spectrum, focusing on aperiodic components as an indicator of excitation-inhibition balance in the neural circuitry.MethodsWe re-analyzed a previously acquired EEG dataset from healthy volunteers using a placebo-controlled within-subject crossover design (Schmidt et al., Neuropsychopharmacology 37(4):865-875 2012). Participants received either placebo or S-ketamine (N=19) and placebo or psilocybin (N=16) during an auditory roving paradigm. Spectral parameters including periodic and aperiodic were extracted and partial least squares analysis was employed.ResultsKetamine significantly altered the offset and slope of the EEG spectrum, suggesting a disruption in excitatory-inhibitory balance. While both drugs commonly reduced alpha power in similar regions, beta band activity was decreased exclusively under ketamine.ConclusionsThese findings highlight ketamine's unique effects on aperiodic EEG components, reinforcing its role as a neurochemical model of prodromal psychosis. Psilocybin's effects appear distinct, emphasizing its targeted influence on oscillatory activity.