Rationale <p>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.</p> Objectives <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>