Licorice Root

Overview

Glycyrrhiza (family Fabaceae) is a genus of perennial herbs native to Mediterranean Europe, central Asia, and East Asia. The name derives from Greek glykys (sweet) + rhiza (root) — the dried rhizome and root are approximately 50 times sweeter than sucrose due to glycyrrhizin. Two principal species dominate pharmaceutical use: Glycyrrhiza glabra (Spanish/Italian licorice) for European and Western pharmacopoeial preparations; and Glycyrrhiza uralensis (Chinese licorice; gancao, 甘草) as the dominant species in Traditional Chinese Medicine, one of the most frequently prescribed TCM herbs, used as a "harmonising" agent to moderate other ingredients and for cough, gastric ulcers, and detoxification.

Licorice root is among the oldest documented medicinal plants — found in Egyptian tombs (including Tutankhamun's), described by Dioscorides and Hippocrates, and used in TCM and Ayurveda for peptic ulcers, cough/bronchitis, and adrenal support. These traditional uses align closely with the modern mechanistic understanding. The primary active constituent is glycyrrhizin (glycyrrhizic acid) — a triterpene saponin constituting 4–20% of dry root weight — which is hydrolysed by intestinal bacterial β-glucuronidase to glycyrrhetic acid (GA), the bioactive aglycone that drives both therapeutic and toxic effects through 11β-HSD2 inhibition.

DGL (Deglycyrrhizinated Licorice) is a processed form with >97% glycyrrhizin removal, retaining the flavonoid and mucilagenic components responsible for mucosal healing while eliminating the mineralocorticoid-excess risk entirely. DGL and whole licorice root are pharmacologically distinct preparations — they must never be substituted for each other in clinical practice. Additional active constituents include flavonoids (liquiritin, liquiritigenin, isoliquiritin), chalcones (isoliquiritigenin — antispasmodic, MAO-A inhibition, AMPK activation), and formononetin (phytoestrogen).

Mechanism of Action

11β-HSD2 Inhibition — Pseudo-Hyperaldosteronism (Apparent Mineralocorticoid Excess)

  Normal renal physiology (collecting duct):
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  Cortisol [high] → 11β-HSD2 → Cortisone (inactive)
  Aldosterone [low] → MR activation → normal Na+/K+ balance

  With Glycyrrhetic Acid:
  ─────────────────────────────────────────────────
  Glycyrrhizin → gut β-glucuronidase → Glycyrrhetic Acid (GA)
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          ▼
  GA inhibits 11β-HSD2 (Ki ~0.1–1 μM)
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  Cortisol NOT converted → accumulates in renal cells
          │
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  Cortisol activates Mineralocorticoid Receptor (MR)
          │
          ├── ↑ ENaC expression   →  Na+ reabsorption ↑
          ├── ↑ Na+/K+-ATPase     →  K+ secretion ↑
          ├── Volume expansion    →  BP ↑
          ├── Hypokalemia         →  QT prolongation risk
          └── Renin ↓, Aldosterone ↓ (volume-suppressed)
              = PSEUDO-HYPERALDOSTERONISM / AME

1. Intestinal hydrolysis: Ingested glycyrrhizin is cleaved by gut bacterial β-glucuronidase, releasing glycyrrhetic acid (GA) — the bioactive aglycone that reaches systemic circulation with sufficient plasma levels for renal 11β-HSD2 inhibition
2. Renal 11β-HSD2 inhibition: GA (Ki ~0.1–1 μM) competitively inhibits 11β-HSD2 in the collecting duct — the enzyme that normally converts cortisol to inactive cortisone, protecting mineralocorticoid receptors from cortisol which circulates at 100–1000× higher concentrations than aldosterone
3. Cortisol-driven MR activation: Uninhibited cortisol freely activates MR → ↑ENaC expression in principal cells → Na+ reabsorption; ↑Na+/K+-ATPase → K+ secretion and enhanced Na+ efflux; volume expansion follows osmotically
4. Clinical syndrome emerges: Na+ retention → osmotic water reabsorption → plasma volume expansion → hypertension; K+ wasting → hypokalemia; renin and aldosterone are suppressed by volume expansion (diagnostic hallmark distinguishing pseudo-hyperaldosteronism from primary hyperaldosteronism)
5. QT prolongation and arrhythmia risk: Hypokalemia reduces the transmembrane K+ gradient → prolongs cardiac action potential repolarisation (QT interval) → predisposes to ventricular arrhythmias including torsades de pointes — a potentially fatal consequence

Pleiotropic Mechanisms

Clinical Use & Dosing

Key Studies

Safety & Drug Interactions

• Pseudo-hyperaldosteronism — dose-dependent and cumulative: Hypertension, hypokalemia, suppressed renin and aldosterone; can emerge at 100 mg/day glycyrrhizin in sensitive individuals; severe cases: K+ <2.0 mmol/L, rhabdomyolysis, hypertensive emergencies; monitoring required for all glycyrrhizin-containing preparations
• QT prolongation / ventricular arrhythmias: Hypokalemia from 11β-HSD2 inhibition prolongs the QT interval and predisposes to torsades de pointes; ECG monitoring required if K+ falls below 3.0 mmol/L; potentially fatal
• Antihypertensives — pharmacodynamic antagonism: Glycyrrhizin raises BP via Na+ retention, a mechanism independent of most antihypertensive drug targets; BP may remain elevated despite therapy; screen all hypertensive patients for licorice use
• Diuretics (thiazides, loop) — additive hypokalemia: Combined K+ loss can be severe and rapid; increases digoxin toxicity risk (digoxin sensitivity is K+-dependent); avoid combination without close monitoring
• Corticosteroids — synergism: Glycyrrhizin inhibits corticosteroid metabolism via 11β-HSD, prolonging steroid activity; both therapeutic and adverse steroid effects may be amplified; carefully monitor patients on concurrent steroid therapy
• Digoxin — hypokalemia-mediated toxicity: Glycyrrhizin-driven hypokalemia increases myocardial digoxin sensitivity; monitor serum K+ and digoxin levels; digoxin toxicity can be precipitated even at therapeutic digoxin doses
• Spironolactone — pharmacodynamic antagonism: Competitive MR antagonism may partially offset glycyrrhizin's mineralocorticoid effect; can mask toxicity signs and complicate clinical assessment
• Monitoring (glycyrrhizin preparations): BP at baseline and every 2–4 weeks; serum K+ every 4 weeks (target >3.5 mmol/L); renin and aldosterone levels (suppressed in pseudo-hyperaldosteronism); ECG if K+ <3.0 mmol/L
• Contraindications (whole licorice / glycyrrhizin): Hypertension, heart failure, renal disease, hypokalemia, hepatic cirrhosis, pregnancy (inhibits 11β-HSD1 in placenta, potentially reducing protective cortisone in fetal compartment); concurrent diuretic use without monitoring
• DGL safety profile: Generally very safe; rare Fabaceae (legume family) allergy; no cardiovascular monitoring required; suitable for long-term GI use; caution in known legume allergy

Connections

References

• Walker BR, Edwards CR. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am. 1994;23(2):359-77. PMID 8070431
• Cinatl J, Morgenstern B, Bauer G, et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361(9374):2045-6. doi:10.1016/S0140-6736(03)13615-X
• Glick L. Deglycyrrhizinated liquorice for peptic ulcer. Lancet. 1982;2(8302):817. doi:10.1016/S0140-6736(82)92724-4
• Arase Y, Ikeda K, Murashima N, et al. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer. 1997;79(8):1494-500. PMID 9118029
• Fiore C, Eisenhut M, Krausse R, et al. Antiviral effects of Glycyrrhiza species. Phytochemistry. 2008;69(3):631-45. doi:10.1016/j.phytochem.2007.07.010
• Evans WC. Trease and Evans' Pharmacognosy. 16th ed. Saunders; 2009.