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

Abstract

<h4>Rationale</h4>Ketamine 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.<h4>Objectives</h4>This 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.<h4>Methods</h4>We 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.<h4>Results</h4>Ketamine 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.<h4>Conclusions</h4>These 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.

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