Clinical risk factors of licorice-induced pseudohyperaldosteronism: a 2026-updated narrative review

Pseudohyperaldosteronism induced by the root of Glycyrrhiza uralensis Fisch. and Glycyrrhiza glabra L (licorice) is a frequent adverse effect of Japanese traditional Kampo medicines, characterized by hypokalemia and hypertension due to the inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). While daily licorice dosage is a primary risk factor, it often fails to explain inter-individual variability, where some patients develop pseudohyperaldosteronism at low doses while others tolerate high doses. This updated narrative review redefines clinical risk factors based on recent pharmacokinetic discoveries, specifically the identification of 3-epi-18β-glycyrrhetinic acid (3-epi-GA) and the role of intestinal microbiota. We reviewed recent pharmacological and pharmacokinetic evidence regarding the absorption, distribution, metabolism, and excretion of glycyrrhizin and its metabolites. We discuss the pharmaceutical factors altering the absorption of glycyrrhizin, one of the constituents of licorice, such as pH-dependent solubility in Schisandra-containing formulations and enzymatic competition by baicalin in Scutellaria-containing formulations. Importantly, we highlight the "epimerization phenotype," where specific intestinal microbiota convert glycyrrhizin into 3-epi-GA. Unlike typical GA, 3-epi-GA is resistant to hepatic sulfation by sulfotransferase (SULT) 2A1, leading to prolonged accumulation. Furthermore, hypoalbuminemia increases free metabolite levels, potentially facilitating direct luminal access to renal tubules via glomerular filtration. Combined with the age-related decline in 11β-HSD2 activity and renal excretion via organic anion transporters, these factors create a high-risk metabolic profile. We propose a precision medicine approach for risk assessment that integrates formulation characteristics, host intestinal microbiota function, and physiological reserve, moving beyond simple dosage counting to prevent this iatrogenic condition.