High Doses of Melatonin Induce Seizure-like Cortical Activity: Electrophysiological and Behavioral Evidence

Melatonin is widely used as a neurohormone and dietary supplement for sleep regulation and is generally regarded as safe in therapeutic doses. However, its neuropharmacological effects at supraphysiological concentrations have remained insufficiently characterized. In the present study, we investigated the behavioral and electrophysiological consequences of high-dose melatonin administration and examined the ability of classical anticonvulsant drugs to modulate its excitatory effects. Adult male Wistar rats received melatonin (100 mg/kg, ip), and behavioral responses were systematically recorded. Cortical activity was assessed by electrocorticography (ECoG) with spectral analysis of delta to γ frequency bands. Additional experimental groups received PTE, PBT, or DZP during the excitatory phase to evaluate pharmacological control of seizure-like activity. Melatonin induced a reproducible biphasic profile, characterized by an initial sedative and myorelaxant phase, followed by marked cortical hyperexcitability accompanied by tremors and clonic seizures. ECoG recordings revealed an increase in signal amplitude and power spectral density during the excitatory phase, particularly within β and γ oscillations, consistent with ictal-like activity. The administration of anticonvulsant agents significantly attenuated these electrophysiological alterations and reduced the behavioral manifestations of hyperexcitability. These results demonstrate that melatonin, at high doses, can shift from an inhibitory to a proexcitatory neuropharmacological profile, likely involving underlying mechanisms of disruption of central nervous system homeostasis. The study highlights a paradoxical action of melatonin on cortical excitability, raising concerns about the potential for intoxication in susceptible patients, such as children who are at risk.