Glycyrrhetinic acid

Glycyrrhetinic acid is the primary bioactive aglycone of glycyrrhizin, a triterpenoid saponin derived from licorice root (Glycyrrhiza glabra). It exerts its principal effects by inhibiting 11β-hydroxysteroid dehydrogenase (11β-HSD), the enzyme responsible for interconverting active cortisol and inactive cortisone in peripheral tissues.

Origin & History

Glycyrrhetinic acid is a pentacyclic triterpenoid aglycone derived from glycyrrhizin, found in the roots of Glycyrrhiza glabra, commonly known as licorice. It is produced through the extraction and acid hydrolysis of glycyrrhizin, yielding a crystalline powder.

Historical & Cultural Context

Glycyrrhetinic acid is derived from licorice root, which has been used traditionally in various cultures, though specific historical uses or practices are not detailed in the research.

Health Benefits

• Acts as a nonselective inhibitor of 11β-hydroxysteroid dehydrogenase, potentially increasing cortisol activity (preclinical evidence).
• Exhibits antioxidative properties (preclinical evidence).
• Demonstrates anti-inflammatory effects (preclinical evidence).
• Shows antimicrobial activity (preclinical evidence).
• Possesses anti-ulcerative properties (preclinical evidence).

How It Works

Glycyrrhetinic acid nonselectively inhibits both isoforms of 11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2), reducing the conversion of cortisol to cortisone in peripheral tissues and thereby amplifying local glucocorticoid activity. It also suppresses NF-κB signaling and inhibits prostaglandin-synthesizing enzymes such as cyclooxygenase-2 (COX-2) and phospholipase A2, contributing to its anti-inflammatory profile. Additionally, glycyrrhetinic acid scavenges reactive oxygen species (ROS) and upregulates endogenous antioxidant enzymes including superoxide dismutase (SOD) and catalase.

Scientific Research

No specific human clinical trials or meta-analyses directly on glycyrrhetinic acid were found in the research. The evidence is primarily preclinical or inferred from studies on glycyrrhizin.

Clinical Summary

Most evidence for glycyrrhetinic acid derives from in vitro cell studies and rodent models rather than large randomized controlled trials in humans. Small human studies on topical glycyrrhetinic acid formulations (0.5–2%) have demonstrated measurable reductions in skin inflammation and eczema severity, though sample sizes typically range from 20–60 participants. Oral licorice root extracts standardized to glycyrrhizin/glycyrrhetinic acid content have shown modest blood pressure-elevating and potassium-lowering effects in controlled human trials, consistent with its 11β-HSD2 inhibition mechanism. Overall, clinical evidence remains preliminary, and well-powered, placebo-controlled trials specifically isolating glycyrrhetinic acid are lacking.

Nutritional Profile

Glycyrrhetinic acid is a pure bioactive triterpenoid compound (pentacyclic oleanane-type), not a whole food ingredient, and therefore contains no macronutrients (protein, fat, or carbohydrates), micronutrients, vitamins, minerals, or dietary fiber. As an isolated compound, it is typically studied and used in doses ranging from 50–500 mg/day in clinical and preclinical contexts. Molecular weight: 470.68 g/mol. It exists in two stereoisomeric forms: 18α-glycyrrhetinic acid and 18β-glycyrrhetinic acid, with the 18β form being the predominant biologically active isomer derived from hydrolysis of glycyrrhizin (the primary saponin of licorice root, Glycyrrhiza glabra). Bioavailability: Oral bioavailability is moderate; when derived from dietary glycyrrhizin, gut microbiota convert glycyrrhizin to glycyrrhetinic acid via hydrolysis of the glucuronide moieties, with peak plasma concentrations typically reached 8–24 hours post-ingestion. It undergoes significant hepatic first-pass metabolism and enterohepatic recirculation, contributing to a prolonged plasma half-life of approximately 10–32 hours. Plasma protein binding is high (>99%, primarily to albumin). Lipophilicity (log P ≈ 5.7) facilitates membrane permeability but limits aqueous solubility (~0.04 mg/mL in water). No significant vitamin, mineral, or fiber content is applicable to this isolated compound.

Preparation & Dosage

No clinically studied dosage ranges or standardization details are specified for glycyrrhetinic acid. Consult a healthcare provider before starting any new supplement.

Synergy & Pairings

Licorice root extract, Ashwagandha, Turmeric, Ginseng, Green tea extract

Safety & Interactions

Chronic or high-dose consumption of glycyrrhetinic acid can cause pseudoaldosteronism—characterized by sodium retention, hypokalemia, and hypertension—due to excessive inhibition of 11β-HSD2 in the kidneys; the European Food Safety Authority (EFSA) has flagged daily intakes above 100 mg glycyrrhizin as a concern. It may potentiate the effects of corticosteroids and antihypertensive drugs, and can reduce serum potassium when combined with diuretics or cardiac glycosides such as digoxin. Glycyrrhetinic acid is contraindicated in individuals with hypertension, hypokalemia, renal insufficiency, liver cirrhosis, or hyperaldosteronism. Pregnant women should avoid supplemental doses, as glycyrrhizin and its metabolites have been associated with adverse fetal neurodevelopmental outcomes in epidemiological studies.