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We have demonstrated that large-dose IV melatonin can exert hypnotic effects similar to those caused by thiopental and propofol. In this study, we compared the electroencephalographic (EEG) effects of melatonin with those of thiopental and propofol. Sprague-Dawley rats were assigned to receive equipotent bolus doses of thiopental (23.8 mg/kg), propofol (14.9 mg/kg), or melatonin (312 mg/kg). EEG effects were recorded at periodic intervals over 10 minutes. Of eight processed EEG variables analyzed, only relative total power (rTP), relative spectral edge 95% (rSE95), and relative approximate entropy (rAE) were altered by all drugs compared with their control vehicles. Drug administration decreased the values relative to baseline, with subsequent return toward baseline during the 10-min time course. Thiopental significantly increased rTP, whereas propofol and melatonin did not. All drugs significantly decreased rSE95. However, the time course of peak effect and duration differed for each, with melatonin exhibiting a slower onset and a more sustained EEG effect. All drugs significantly decreased rAE, with similar time courses for thiopental and propofol and a slower onset/longer duration for melatonin. Melatonin produced effects on processed EEG variables similar to those of thiopental and propofol, specifically a decrease in the rSE95 and a decrease in the rAE.