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Serotonin syndrome (SS) is an adverse outcome of selective serotonin reuptake inhibitors, though its mechanism is not understood and there is no specific clinical biomarker. In this article, metabolic profiles of the SS model rats and causes of metabolome disruption were investigated.Gas chromatography-tandem mass spectrometry (GC/MS/MS)-based metabolomics, clinical biomarker measurements and qRT-PCR analysis for UCP-3 in skeletal muscles were performed.Metabolome analysis demonstrated that 55, 22, 49 and 41 of those were significantly altered in plasma, liver, gastrocnemius muscle, and trapezius, respectively. In particular, lactic acid significantly accumulated in the gastrocnemius muscle of the model, while the branched chain amino acids were not consumed in the trapezius, suggesting site differences in abnormal muscular contractions in the model. This result was supported by UCP-3 expression analysis.Alteration of the urea cycle was observed in the liver of the model, attributed mainly to catabolism of proteins and/or amino acids from excess skeletal muscle activity, which was supported by plasma BUN: BUN levels in the model were significantly higher than those in the control. In contrast, almost all metabolites including amino acids and TCA-cycle intermediates significantly increased in plasma of the model, suggesting these were not consumed in some parts of the muscle due to acceleration of anaerobic respiration.Metabolic profiling revealed that abnormal muscular contractions occurred in specific skeletal muscles and enhanced energy production by up-regulation of anaerobic respiration, followed by excess expression of UCP-3, which contributes to the hyper-thermogenesis observed in the SS model.