Glycyrrhetinic Acid

Glycyrrhetinic Acid at a Glance

Glycyrrhetinic acid (also enoxolone or 18β-glycyrrhetinic acid) is the oleanane pentacyclic triterpenoid aglycone of glycyrrhizin, the sweet saponin of licorice (Glycyrrhiza). When licorice or glycyrrhizin is swallowed, gut bacteria strip the two glucuronic-acid sugars from glycyrrhizin to release glycyrrhetinic acid, and this aglycone — not the parent glycoside — is the species actually absorbed and responsible for licorice’s systemic effects ^{7,8Reference 7Takeda S et al. · 1996AnimalBioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysisView study →Reference 8Ploeger B et al. · 2001The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modelingView study →}.

Two of those effects define the molecule. The first is therapeutic: a genuine anti-ulcer and mucosal-protective action, historically exploited through glycyrrhetinic acid’s hemisuccinate derivative carbenoxolone, once a licensed peptic-ulcer drug ^{1,9Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 9Rees WD et al. · 1979Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirinView study →}. The second is the reason chronic licorice is genuinely hazardous: glycyrrhetinic acid inhibits the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), letting cortisol illicitly activate the mineralocorticoid receptor to produce apparent mineralocorticoid excess (pseudoaldosteronism) — hypertension, hypokalaemia and sodium/water retention ^{2,5,6Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 5Benediktsson R · 1994Apparent mineralocorticoid excessView study →Reference 6Shimojo M · 1995Apparent mineralocorticoid excess syndromesView study →}.

The molecule carries a further, more specialised identity as one of pharmacology’s canonical gap-junction (connexin) blockers, used as a laboratory tool to switch off cell-to-cell coupling ^{11,12Reference 11Davidson JS · 1988Glycyrrhetinic acid derivatives: a novel class of inhibitors of gap-junctional intercellular communicationView study →Reference 12Davidson JS et al. · 1986Reversible inhibition of intercellular junctional communication by glycyrrhetinic acidView study →}. Its efficacy and its toxicity run through overlapping biochemistry, which is why it earns a moderate safety flag rather than a benign one.

Apparent Mineralocorticoid Excess: The 11β-HSD2 Mechanism

This is the mechanistic hinge of the whole molecule — the single reason licorice can raise blood pressure and drop potassium, and the defining safety story of the plant.

The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) sits in mineralocorticoid target tissues (kidney, colon, salivary glands) and continuously converts active cortisol into inactive cortisone. Its job is to protect the mineralocorticoid receptor — which binds cortisol and aldosterone with equal affinity — from cortisol, which circulates at concentrations far higher than aldosterone. Glycyrrhetinic acid is a direct inhibitor of 11β-HSD2, so cortisol is no longer inactivated locally: it accumulates and activates the mineralocorticoid receptor exactly as aldosterone would, and the molecule may also bind the receptor weakly itself ^{2,5,6Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 5Benediktsson R · 1994Apparent mineralocorticoid excessView study →Reference 6Shimojo M · 1995Apparent mineralocorticoid excess syndromesView study →}.

The result is apparent mineralocorticoid excess with a suppressed renin–aldosterone axis (aldosterone is low precisely because the receptor is already being driven): renal sodium and water retention, potassium and hydrogen wasting, and plasma-volume expansion. Clinically that reads as hypertension, hypokalaemia, metabolic alkalosis and oedema ^{2,4,5Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 4Penninkilampi R et al. · 2017Meta-analysisThe association between consistent licorice ingestion, hypertension and hypokalaemia: a systematic review and meta-analysisView study →Reference 5Benediktsson R · 1994Apparent mineralocorticoid excessView study →}. This is not an idiosyncratic reaction but a predictable, dose- and duration-dependent pharmacological effect — the same enzyme block that underlies most of glycyrrhetinic acid’s toxicity, and the reason it and licorice have long served as the textbook pharmacological cause of acquired mineralocorticoid excess ^{5,6Reference 5Benediktsson R · 1994Apparent mineralocorticoid excessView study →Reference 6Shimojo M · 1995Apparent mineralocorticoid excess syndromesView study →}.

Glycyrrhetinic acid also inhibits the related isoenzyme 11β-HSD1, which regenerates cortisol in tissues such as fat and skin; topical glycyrrhetinic acid measurably reduced subcutaneous thigh-fat thickness in a human study attributed to this local action ^{10Reference 10Armanini D et al. · 2005Glycyrrhetinic acid, the active principle of licorice, can reduce the thickness of subcutaneous thigh fat through topical applicationView study →}.

Carbenoxolone & The Anti-Ulcer Story

The molecule’s most concrete therapeutic legacy is a semisynthetic drug made from it. Carbenoxolone is the hemisuccinate ester of glycyrrhetinic acid, developed in the 1960s as one of the first drugs shown to accelerate the healing of gastric and duodenal ulcers ^{1Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →}. Its mucosal-protective action is generally attributed to prostaglandin sparing — enhancing the quantity and quality of gastric mucus, prolonging mucosal-cell life, and inhibiting the breakdown of protective prostaglandins — rather than to acid suppression ^{1,16Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 16Pastorino G et al. · 2018ReviewLiquorice (Glycyrrhiza glabra): A phytochemical and pharmacological reviewView study →}.

Carbenoxolone’s story is also a cautionary one that closes the loop with the mechanism above: because it shares glycyrrhetinic acid’s 11β-HSD inhibition, it reliably produced sodium retention, oedema, hypertension and hypokalaemia, and it was largely superseded and withdrawn once H2-blockers and proton-pump inhibitors arrived without that mineralocorticoid liability ^{2,5Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 5Benediktsson R · 1994Apparent mineralocorticoid excessView study →}. The same tension explains why, for the mucosal benefit of whole licorice, the preparation of choice is deglycyrrhizinated licorice (DGL) — which removes glycyrrhizin (and hence the aglycone) specifically to keep the soothing effect while avoiding the pressor one. In rats, DGL reduced aspirin-induced gastric mucosal damage, and it lowered aspirin-associated faecal blood loss in people ^{9Reference 9Rees WD et al. · 1979Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirinView study →}.

Gap-Junction (Connexin) Inhibition

A distinct identity that has little to do with licorice as a medicine and everything to do with the laboratory: glycyrrhetinic acid is one of the most widely used pharmacological blockers of gap junctions. Gap junctions are channels built from connexin proteins that directly couple the cytoplasm of neighbouring cells, allowing ions and small molecules to pass. Glycyrrhetinic acid reversibly closes these channels ^{12Reference 12Davidson JS et al. · 1986Reversible inhibition of intercellular junctional communication by glycyrrhetinic acidView study →}, and structure–activity work on a series of its derivatives established this triterpenoid scaffold as “a novel class of inhibitors of gap-junctional intercellular communication” ^{11Reference 11Davidson JS · 1988Glycyrrhetinic acid derivatives: a novel class of inhibitors of gap-junctional intercellular communicationView study →}. Mechanistically, 18β-glycyrrhetinic acid drives disassembly of gap-junction plaques and dephosphorylation of connexin 43 ^{13Reference 13Guan X et al. · 1996Gap-junction disassembly and connexin 43 dephosphorylation induced by 18 beta-glycyrrhetinic acidView study →}.

This makes it (and carbenoxolone) a standard reagent for testing whether a biological signal depends on direct cell-to-cell coupling — in cardiac, neural and epithelial tissue — and it is the property behind much of the molecule’s preclinical anticancer interest, since disrupted connexin communication is implicated in tumour-cell behaviour ^{11,13Reference 11Davidson JS · 1988Glycyrrhetinic acid derivatives: a novel class of inhibitors of gap-junctional intercellular communicationView study →Reference 13Guan X et al. · 1996Gap-junction disassembly and connexin 43 dephosphorylation induced by 18 beta-glycyrrhetinic acidView study →}. It is a research-tool property, not an established human therapy.

What It's Used For

Glycyrrhetinic acid’s literature is broad, but its shape is unusual: a real historical anti-ulcer drug (via carbenoxolone), a wide preclinical spread (anti-inflammatory, hepatoprotective, antiviral, anticancer), and a laboratory-tool pharmacology (gap junctions) — all shadowed by the fact that its most reliable in vivo effect in people is the mineralocorticoid one. Most efficacy data are on the isolate in cell and animal systems; the human record is largely licorice-level rather than isolate trials ^{1,14Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 14Fiore C et al. · 2008Antiviral effects of Glycyrrhiza speciesView study →}.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. Only the anti-ulcer use (via carbenoxolone) has a historical controlled-drug record; the rest is preclinical or mechanism, so scores stay measured.

01Anti-Ulcer / Mucosal (Carbenoxolone)Promising52%Carbenoxolone (GA hemisuccinate) as a licensed ulcer drug; prostaglandin/mucus mechanism ^{1,9,16Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 9Rees WD et al. · 1979Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirinView study →Reference 16Pastorino G et al. · 2018ReviewLiquorice (Glycyrrhiza glabra): A phytochemical and pharmacological reviewView study →}

02Anti-Inflammatory / Glucocorticoid-PotentiatingShaky42%11β-HSD inhibition sparing cortisol; topical dermatological use; mechanism strong, human efficacy indirect ^{1,10Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 10Armanini D et al. · 2005Glycyrrhetinic acid, the active principle of licorice, can reduce the thickness of subcutaneous thigh fat through topical applicationView study →}

03HepatoprotectiveShaky36%Aglycone of the IV-hepatitis agent glycyrrhizin; preclinical liver-injury protection ^{1,14Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 14Fiore C et al. · 2008Antiviral effects of Glycyrrhiza speciesView study →}

04Antiviral / AntimicrobialShaky32%In-vitro/animal activity across several viruses and bacteria ^{1,14Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 14Fiore C et al. · 2008Antiviral effects of Glycyrrhiza speciesView study →}

05Anticancer (Preclinical)Shaky26%Cell/animal models; linked in part to gap-junction/connexin effects ^{1,13Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 13Guan X et al. · 1996Gap-junction disassembly and connexin 43 dephosphorylation induced by 18 beta-glycyrrhetinic acidView study →}

Mechanisms

The load-bearing point is that 11β-HSD2 inhibition is the same event whether it is framed as a benefit (cortisol-sparing, anti-inflammatory) or a harm (pseudoaldosteronism) — one enzyme block, two faces.

Pharmacokinetics

Glycyrrhetinic acid is the lipophilic, absorbable half of the licorice story. Swallowed glycyrrhizin is large and highly polar and is barely absorbed intact; gut bacterial β-glucuronidase hydrolyses off its two sugars to release glycyrrhetinic acid, which is the species that actually crosses the gut wall — bacterial hydrolysis is indispensable to that absorption in rats ^{7Reference 7Takeda S et al. · 1996AnimalBioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysisView study →}. The freed aglycone then undergoes extensive presystemic metabolism and enterohepatic recycling, well captured by physiologically-based pharmacokinetic modelling of the glycyrrhizic-acid system ^{8Reference 8Ploeger B et al. · 2001The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modelingView study →}. Two consequences dominate the compound page: (1) because generation depends on gut flora, systemic exposure varies widely between individuals and is blunted by antibiotics or germ-free conditions ^{7Reference 7Takeda S et al. · 1996AnimalBioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysisView study →}; and (2) the aglycone’s slow clearance and enterohepatic cycling give a long effective half-life, so it accumulates over days of repeated intake — the pharmacological reason licorice toxicity is characteristically dose- and duration-dependent rather than a single-dose event ^{8Reference 8Ploeger B et al. · 2001The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modelingView study →}. Robust oral-bioavailability figures for the pure isolate in humans are not well established; the historical way around the absorption problem was the water-soluble hemisuccinate carbenoxolone ^{1Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →}.

Clinical Trials

Direct human trials of the isolated aglycone are sparse; its clinical footprint is largely historical (carbenoxolone) and indirect (as glycyrrhizin’s metabolite).

Last checked: July 2026.

Isolate vs. Plant Studies

The evidence splits along an unusual seam. The anti-ulcer use is isolate/derivative — carbenoxolone is a defined semisynthetic drug made from glycyrrhetinic acid ^{1Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →} — and the mechanistic pharmacology (11β-HSD inhibition, gap-junction blockade, preclinical anti-inflammatory/antiviral/anticancer work) is overwhelmingly the isolated molecule in cell and animal systems ^{1,11,13Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 11Davidson JS · 1988Glycyrrhetinic acid derivatives: a novel class of inhibitors of gap-junctional intercellular communicationView study →Reference 13Guan X et al. · 1996Gap-junction disassembly and connexin 43 dephosphorylation induced by 18 beta-glycyrrhetinic acidView study →}. That is a genuine strength for a phytochemical. Where the isolate framing breaks down is ordinary oral exposure: people almost never ingest glycyrrhetinic acid directly — they ingest licorice or glycyrrhizin, and the aglycone is generated in the gut, so real-world effect is inseparable from the whole-root matrix, the microbiome and dose accumulation ^{7,8Reference 7Takeda S et al. · 1996AnimalBioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysisView study →Reference 8Ploeger B et al. · 2001The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modelingView study →}. The safety literature is likewise whole-licorice — confectionery, teas, extracts and supplements — where glycyrrhizin (and thus aglycone) content is variable and often unlabelled ^{4,17,19Reference 4Penninkilampi R et al. · 2017Meta-analysisThe association between consistent licorice ingestion, hypertension and hypokalaemia: a systematic review and meta-analysisView study →Reference 17Sabbadin C et al. · 2019Licorice: From Pseudohyperaldosteronism to Therapeutic UsesView study →Reference 19Yang LY et al. · 2019Case reportLiquorice-induced severe hypokalemic rhabdomyolysis with Gitelman syndrome and diabetes: a case reportView study →}. Net: strong isolate/derivative mechanism and drug history, but the everyday human reality is a flora-dependent whole-food exposure.

Prevalence in Nature

Glycyrrhetinic acid is effectively licorice-specific — it is not a widespread plant metabolite like the simple terpenes or phenolic acids, but the aglycone of the defining saponin of the genus Glycyrrhiza (Fabaceae) ^{15,16Reference 15Wahab S et al. · 2021ReviewGlycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and ToxicologyView study →Reference 16Pastorino G et al. · 2018ReviewLiquorice (Glycyrrhiza glabra): A phytochemical and pharmacological reviewView study →}. In the intact root it is present partly as the free aglycone and mostly bound as its glycoside glycyrrhizin, which itself accounts for roughly 2–6% of the dried root (occasionally reported up to ~15%) — so the root’s effective glycyrrhetinic-acid pool tracks its glycyrrhizin content ^{15Reference 15Wahab S et al. · 2021ReviewGlycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and ToxicologyView study →}. That content varies substantially with species — Glycyrrhiza glabra (European/Middle-Eastern licorice), G. uralensis (Chinese licorice / Gan Cao) and G. inflata — and with provenance, age and extraction ^{15,16Reference 15Wahab S et al. · 2021ReviewGlycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and ToxicologyView study →Reference 16Pastorino G et al. · 2018ReviewLiquorice (Glycyrrhiza glabra): A phytochemical and pharmacological reviewView study →}. In the root the aglycone co-occurs with its parent glycoside and with licorice’s characteristic flavonoids such as glabridin and liquiritin; the whole complex is the reason “licorice” is chemically a genus, not a single molecule.

Beyond the plant, a further pool of free glycyrrhetinic acid is generated in the human gut from ingested glycyrrhizin — pharmacologically the most important “source” of the absorbed molecule ^{7Reference 7Takeda S et al. · 1996AnimalBioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysisView study →}. (In traditional practice licorice is also classically combined with white peony in the Shaoyao-Gancao pairing, marked by paeoniflorin — a co-formulation, not a botanical co-occurrence of the two molecules.)

Discovery & Synthesis

Glycyrrhetinic acid entered chemistry as the aglycone of licorice’s sweet principle: once glycyrrhizin was recognised as the crystalline saponin behind licorice’s sweetness in the nineteenth century, its hydrolysis product — the pentacyclic triterpene glycyrrhetinic acid — and the two glucuronic-acid sugars were worked out over the twentieth ^{15,16Reference 15Wahab S et al. · 2021ReviewGlycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and ToxicologyView study →Reference 16Pastorino G et al. · 2018ReviewLiquorice (Glycyrrhiza glabra): A phytochemical and pharmacological reviewView study →}. The name traces through the botanical Glycyrrhiza (Greek glykys, “sweet”; rhiza, “root”), the same root that gives “licorice.” Its International Nonproprietary Name, enoxolone, marks its use as a pharmaceutical ingredient.

The molecule’s defining chemical event was derivatisation, not total synthesis: in the 1960s glycyrrhetinic acid was converted to its water-soluble hemisuccinate ester, carbenoxolone, which became a licensed anti-ulcer drug ^{1Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →}. Because glycyrrhetinic acid is a large, complex pentacyclic triterpene, total synthesis has never been the commercial route — it is obtained by acid hydrolysis of glycyrrhizin extracted from licorice root, and supplied as the pure aglycone (enoxolone) for topical use or as the carbenoxolone derivative ^{1,15Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 15Wahab S et al. · 2021ReviewGlycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and ToxicologyView study →}.

Patents: not yet researched.

Toxicity & Safety

Glycyrrhetinic acid earns a moderate flag — well above a typical dietary triterpenoid — because it is a bona-fide 11β-HSD2 inhibitor, and in enough quantity, for long enough, it reliably produces pseudoaldosteronism. It is the molecule that makes licorice genuinely, and occasionally dangerously, active.

Pseudoaldosteronism (Apparent Mineralocorticoid Excess)

Through the 11β-HSD2 mechanism above, glycyrrhetinic acid causes a syndrome that mimics aldosterone excess while aldosterone and renin are actually suppressed: hypertension, hypokalaemia, sodium and water retention with oedema, and metabolic alkalosis ^{2,5,6Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 5Benediktsson R · 1994Apparent mineralocorticoid excessView study →Reference 6Shimojo M · 1995Apparent mineralocorticoid excess syndromesView study →}. A systematic review and meta-analysis found that consistent licorice ingestion raises blood pressure and lowers serum potassium across studies ^{4Reference 4Penninkilampi R et al. · 2017Meta-analysisThe association between consistent licorice ingestion, hypertension and hypokalaemia: a systematic review and meta-analysisView study →}. It is dose- and duration-dependent and cumulative, reflecting the aglycone’s long effective half-life ^{8Reference 8Ploeger B et al. · 2001The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modelingView study →}.

Severe & Fatal Cases

At the heavy end this is not a nuisance effect. Case reports document severe hypokalaemia with rhabdomyolysis (muscle breakdown, dark urine, acute kidney injury) from chronic licorice intake ^{19Reference 19Yang LY et al. · 2019Case reportLiquorice-induced severe hypokalemic rhabdomyolysis with Gitelman syndrome and diabetes: a case reportView study →}, and the hypokalaemia can precipitate dangerous ventricular arrhythmias. A New England Journal of Medicine case record described a man who suffered sudden cardiac arrest linked to excessive black-licorice consumption, with the hypokalaemia and apparent mineralocorticoid excess of glycyrrhetinic-acid toxicity ^{18Reference 18Edelman ER et al. · 2020Case 30-2020: a 54-year-old man with sudden cardiac arrestView study →}. These are the reason “it’s only candy” is the wrong intuition.

Populations At Risk & Drug Interactions

Regulatory guidance is conservative: the EU Scientific Committee on Food suggested a habitual upper intake of about 100 mg glycyrrhizic acid per day, above which mineralocorticoid effects become likely — a threshold readily reached with strong licorice confectionery, licorice tea or extracts ^{3,17Reference 3Ceccuzzi G et al. · 2023ReviewLiquorice Toxicity: A Comprehensive Narrative ReviewView study →Reference 17Sabbadin C et al. · 2019Licorice: From Pseudohyperaldosteronism to Therapeutic UsesView study →}. Risk is higher, and reached at lower doses, in people with hypertension, cardiac disease, kidney disease or pre-existing hypokalaemia, in older adults, and (as reported) in women ^{2,3Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 3Ceccuzzi G et al. · 2023ReviewLiquorice Toxicity: A Comprehensive Narrative ReviewView study →}. The interactions follow from the mechanism and are potassium-centred ^{2,3Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 3Ceccuzzi G et al. · 2023ReviewLiquorice Toxicity: A Comprehensive Narrative ReviewView study →}:

• Potassium-wasting diuretics (thiazides, loop diuretics) — additive hypokalaemia.
• Cardiac glycosides (digoxin) — hypokalaemia potentiates digoxin toxicity/arrhythmia.
• Corticosteroids — glycyrrhetinic acid potentiates corticosteroid action (cortisol-sparing via 11β-HSD) and can compound their sodium-retaining, potassium-losing effects.
• Antihypertensives — the pressor effect can oppose blood-pressure control.
• QT-prolonging / antiarrhythmic drugs — added arrhythmia risk via hypokalaemia.

Regarding reproduction, the risk is documented at the licorice/glycyrrhizin level: in a Finnish cohort, heavy maternal glycyrrhizin intake (≈500 mg/week) was associated with roughly double the risk of preterm (<37 weeks) delivery ^{20Reference 20Strandberg TE et al. · 2002ObservationalPreterm birth and licorice consumption during pregnancyView study →}, and follow-up of exposed offspring reported poorer cognitive performance and more psychiatric (including ADHD-type) problems, consistent with glycyrrhizin/glycyrrhetinic acid lowering placental 11β-HSD2 and increasing fetal glucocorticoid exposure ^{21Reference 21Räikkönen K et al. · 2009ObservationalMaternal licorice consumption and detrimental cognitive and psychiatric outcomes in childrenView study →}. Per site policy, the pregnancy/lactation decision belongs on the licorice herb and product pages where intake is chosen; the finding is stated here as a cited risk, not a molecule-level verdict.

Safety at a Glance

⚠️ Moderate toxicity

• Trace and topical exposure is not the hazard — habitual dose is. Small culinary amounts and short topical use differ entirely from regular heavy licorice; deglycyrrhizinated licorice (DGL) removes the precursor glycoside altogether.
• Pseudoaldosteronism is the defining risk. Inhibiting 11β-HSD2 causes hypertension, hypokalaemia, fluid retention and metabolic alkalosis — dose- and duration-dependently ^{2,4,5Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 4Penninkilampi R et al. · 2017Meta-analysisThe association between consistent licorice ingestion, hypertension and hypokalaemia: a systematic review and meta-analysisView study →Reference 5Benediktsson R · 1994Apparent mineralocorticoid excessView study →}.
• Heavy or prolonged use can be severe or fatal. Documented severe hypokalaemia with rhabdomyolysis, and rare sudden cardiac arrest from excessive licorice ^{18,19Reference 18Edelman ER et al. · 2020Case 30-2020: a 54-year-old man with sudden cardiac arrestView study →Reference 19Yang LY et al. · 2019Case reportLiquorice-induced severe hypokalemic rhabdomyolysis with Gitelman syndrome and diabetes: a case reportView study →}.
• Higher risk with hypertension, cardiac or renal disease, or existing low potassium — and with potassium-wasting diuretics, digoxin, corticosteroids and antihypertensives ^{2,3Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →Reference 3Ceccuzzi G et al. · 2023ReviewLiquorice Toxicity: A Comprehensive Narrative ReviewView study →}.
• The effect accumulates over days. The aglycone’s long effective half-life means regular intake builds up rather than clearing between doses ^{8Reference 8Ploeger B et al. · 2001The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modelingView study →}.
• Heavy licorice/glycyrrhizin intake in pregnancy is linked to preterm birth and adverse offspring neurodevelopment — a decision for the herb/product page, but a real signal ^{20,21Reference 20Strandberg TE et al. · 2002ObservationalPreterm birth and licorice consumption during pregnancyView study →Reference 21Räikkönen K et al. · 2009ObservationalMaternal licorice consumption and detrimental cognitive and psychiatric outcomes in childrenView study →}.

Dosage

There is no general therapeutic oral dose for isolated glycyrrhetinic acid, and the safety framing dominates. Its best-defined human dosing was as the derivative carbenoxolone — roughly 100–300 mg/day for peptic ulcer — a use now largely abandoned because of the mineralocorticoid side effects ^{1,2Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 2Omar HR et al. · 2012Licorice abuse: time to send a warning messageView study →}. Glycyrrhetinic acid itself is used topically at about 1–2% in soothing skin preparations ^{1,10Reference 1Shinu P et al. · 2023Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic PotentialView study →Reference 10Armanini D et al. · 2005Glycyrrhetinic acid, the active principle of licorice, can reduce the thickness of subcutaneous thigh fat through topical applicationView study →}. Oral exposure is otherwise indirect, as the absorbed metabolite of licorice’s glycyrrhizin: regulatory guidance places a habitual upper intake near 100 mg glycyrrhizic acid per day, above which pseudoaldosteronism becomes likely ^{3,17Reference 3Ceccuzzi G et al. · 2023ReviewLiquorice Toxicity: A Comprehensive Narrative ReviewView study →Reference 17Sabbadin C et al. · 2019Licorice: From Pseudohyperaldosteronism to Therapeutic UsesView study →}. Where the effect is unwanted (e.g. gastric use), deglycyrrhizinated licorice (DGL) is chosen specifically to remove it ^{9Reference 9Rees WD et al. · 1979Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirinView study →}. These are historical clinical and regulatory figures, not a personal recommendation.

References

1. Shinu P, Gupta GL, Sharma M, Khan S, Goyal M, Nair AB, Kumar M, Soliman WE, Rahman A, Attimarad M, Venugopala KN, Altaweel AAA (2023). Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic Potential. Plants (Basel). https://pubmed.ncbi.nlm.nih.gov/36903944/
2. Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, Yerramadha MR, Ali Y, Helal E, Camporesi EM (2012). Licorice abuse: time to send a warning message. Therapeutic Advances in Endocrinology and Metabolism. https://pubmed.ncbi.nlm.nih.gov/23185686/
3. Ceccuzzi G, Rapino A, Perna B, Costanzini A, Farinelli A, Fiorica I, Marziani B, Cianci A, Rossin F, Cesaro AE, Spampinato MD, De Giorgio R, Guarino M (2023). Liquorice Toxicity: A Comprehensive Narrative Review. Nutrients. https://pubmed.ncbi.nlm.nih.gov/37764649/
4. Penninkilampi R, Eslick EM, Eslick GD (2017). The association between consistent licorice ingestion, hypertension and hypokalaemia: a systematic review and meta-analysis. Journal of Human Hypertension. https://pubmed.ncbi.nlm.nih.gov/28660884/
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