Ephedrae Herba-Associated Adverse Events: A Disproportionality Analysis Integrated with Network Pharmacology

Background/Objectives: Ephedrae Herba (EH) is widely used in traditional East Asian medicine, but safety concerns regarding its adverse events remain. This study aimed to investigate EH-associated adverse events using clinical pharmacovigilance data and to perform exploratory in silico analyses to propose potential molecular mechanisms underlying these adverse events. Methods: A disproportionality analysis was performed using individual case safety reports from the Korea Adverse Event Reporting System database. EH-containing products were compared with other herbal medicine products using reporting odds ratios (RORs), proportional reporting ratios, and information components. Network pharmacology identified adverse event-related genes and pathways, and protein-protein interaction networks were constructed. Molecular docking predicted direct adverse event-associated targets of ephedrine and compared mechanisms with control compounds (aconitine and spinosin). Results: Four adverse-event signals were detected in the primary analysis: sleep disorder, dry mouth, insomnia, and palpitations. Sensitivity analysis identified four signals, with three (dry mouth, insomnia, and palpitations) consistent across both analyses; constipation emerged only in the sensitivity analysis. Conclusions: Adverse event-associated network analysis predicted key pathways: Neuroactive ligand-receptor interaction, Pathways of neurodegeneration, and Dopaminergic synapse. Molecular docking predicted that ephedrine may act on downstream signaling mechanisms shared by neurotransmitter systems, including the dopaminergic system, distinct from control compounds.