Western licorice
More actions
| Summary | |
|---|---|
| Binomial | Glycyrrhiza glabra L. |
| Family | Fabaceae (Leguminosae) |
| Common names | licorice (American English), liquorice (British English), Western licorice, European licorice, Mediterranean licorice, mulethi (Hindi), yashtimadhu (Sanskrit, "sweet stick"), madhuyashti (Sanskrit alternative form), asl-us-sus or irq al-sus (Arabic), sus (Arabic short form), mahek (Persian); the Greek genus name glycyrrhiza is from glykys (sweet) + rhiza (root) |
| Native range | Mediterranean basin, Western Asia (eastern Mediterranean to Iran), and parts of southern Europe and North Africa; cultivated widely throughout the Mediterranean and in Spain, Italy, Greece, Turkey, Iran, Iraq, Syria, and the Caucasus |
| Cultivars / varieties | the principal commercial source is wild-harvested or semi-cultivated root from the Mediterranean, Caspian, and Central Asian populations; Spanish licorice (cultivated in Spain since the medieval period) and Italian licorice (Calabria) are the European commercial grades; Turkish and Iranian licorice supply the Middle Eastern and South Asian markets; related Glycyrrhiza uralensis (Chinese licorice, gan cao, the principal TCM licorice) and Glycyrrhiza inflata (Xinjiang licorice) are distinct species with their own articles |
| Parts used | root and underground stolon (the rhizome and runners), dried and (in some forms) deglycyrrhizinated; the leaves and aerial parts are not used medicinally |
| Cultivation | hardy perennial herb to 1.5 m at flowering; deep tap-rooted with extensive horizontal stolon network; propagated by stolon division or seed; harvested at three to four years for medicinal root, with deep mechanical or hand-digging required |
| Pharmacy | |
| Preparations | root powder 1 to 5 g daily for short-course use, with chronic high-dose use constrained by pseudohyperaldosteronism risk; decoction 1 to 4 g of root per cup; tincture 1:5 in 45 percent alcohol, 2 to 5 mL three times daily; deglycyrrhizinated licorice (DGL) 760 to 1500 mg before meals for peptic ulcer and gastritis (the modern Western-clinical preparation engineered to remove glycyrrhizic acid and avoid the pseudohyperaldosteronism risk while retaining demulcent and mucosal-protective activity); standardized glycyrrhizin extract for short-course anti-inflammatory use; topical creams and gels for atopic dermatitis (glabridin and licochalcone fractions are the active topical compounds) |
| Pregnancy | avoid medicinal doses; high glycyrrhizic acid intake associated with preterm birth in Finnish cohort studies; minor dietary use of licorice candy safe but to be limited |
| Legal status | unscheduled; food-use restrictions on glycyrrhizin content in many jurisdictions; the European Scientific Committee on Food (SCF) set an adult guidance upper limit of 100 mg glycyrrhizin per day for habitual consumption in 2003 |
| Pharmacology | |
| Active constituents | glycyrrhizin (glycyrrhizic acid) 2 to 12 percent of dry root by weight (variable by region and cultivar; the principal sweet compound at 50 times the sweetness of sucrose by mass, and the load-bearing pseudohyperaldosteronism compound); glycyrrhetinic acid (the aglycone of glycyrrhizin, produced by hydrolysis in the gut and the active intracellular form, the 11-beta-HSD2 inhibitor); flavonoids including liquiritin, isoliquiritin, and the isoflavones glabridin and licochalcone A (with antioxidant, anti-inflammatory, and antimicrobial activity); coumarins (small amounts); polysaccharides; saponins beyond glycyrrhizin; volatile oil (trace, contributing to the characteristic aroma) |
| Mechanism (summary) | glycyrrhetinic acid inhibits 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2), the renal and colonic enzyme that normally converts cortisol to inactive cortisone; with 11-beta-HSD2 inhibited, local cortisol concentrations rise and cortisol binds and activates the mineralocorticoid receptor (which it normally cannot, because the kidney's high 11-beta-HSD2 activity prevents access), producing functional mineralocorticoid agonism with sodium retention, potassium loss, hypertension, and edema -- the pseudohyperaldosteronism syndrome that is the principal safety concern of chronic high-dose licorice consumption; glycyrrhetinic acid also has anti-inflammatory activity through glucocorticoid receptor potentiation and through independent prostaglandin and leukotriene modulation; the flavonoid fraction (glabridin, licochalcone A) provides additional antioxidant, antimicrobial, and topical anti-inflammatory activity; the saponin fraction contributes the demulcent and expectorant effects; deglycyrrhizinated licorice (DGL) retains the flavonoid and saponin activity while removing the glycyrrhizin and its pseudohyperaldosteronism effect |
Western licorice is the dried root and underground stolon of Glycyrrhiza glabra L., a perennial leguminous herb of the Fabaceae (Leguminosae) native to the Mediterranean basin and Western Asia and one of the oldest continuously used medicinal plants of the Eurasian materia medica. The genus name glycyrrhiza is from the Greek glykys (sweet) and rhiza (root), reflecting the principal phytochemical feature of the plant: the sweet triterpene saponin glycyrrhizin (also called glycyrrhizic acid) reaches 2 to 12 percent of the dry root by weight and is approximately fifty times sweeter than sucrose by mass, making licorice the sweetest of the major medicinal roots and the source of the candy, tobacco-flavoring, and beverage uses that have run alongside the medicinal use for centuries. The medicinal indications of Western licorice converge across multiple traditions on a stable cluster: digestive complaint and peptic ulcer (the principal modern Western-clinical indication, addressed by the deglycyrrhizinated licorice formulation that removes the pseudohyperaldosteronism risk while retaining demulcent activity); chronic cough and respiratory complaint; chronic hepatic disease (where intravenous glycyrrhizin has been a Japanese clinical practice for chronic viral hepatitis for several decades); and a broadly tonic, harmonizing, or rasayana role across the traditions. The load-bearing modern safety story is the pseudohyperaldosteronism syndrome produced by chronic high-dose glycyrrhizin intake, which inhibits the renal 11-beta-hydroxysteroid dehydrogenase type 2 enzyme and produces functional mineralocorticoid agonism with hypertension, hypokalemia, sodium retention, and edema. The Chinese licorice (Glycyrrhiza uralensis) is the principal licorice of the Chinese materia medica, where it is known as gan cao and serves as the harmonizing ingredient in approximately sixty percent of all classical Chinese herbal formulas; the TCM material lives on the Chinese licorice page, with the present article covering the Western, Ayurvedic, and Unani historical centroid of G. glabra.
History and traditional use
The Mediterranean and Near Eastern origin of Western licorice is the historical centroid of the herb. Licorice root was recovered from the tomb of Tutankhamun (interred approximately 1323 BCE in the Valley of the Kings) among the grave goods, suggesting royal use in pharaonic Egypt; the herb appears in the Hippocratic corpus and earlier Greek references as glykyrrhiza, the sweet root, and Theophrastus in his Enquiry into Plants of about 300 BCE classed the plant as "the Scythian root" and noted its use for thirst-quenching, cough, and chest complaints, with the characteristic observation that Scythian horsemen could go ten or twelve days without drinking by chewing on the root (a folk-pharmacological reading of the demulcent and water-retaining effect that anticipates the modern pseudohyperaldosteronism mechanism).[1] Dioscorides in book three of his De Materia Medica of about 60 CE listed glykyrrhiza for thirst, dry cough, lung disease, stomach pain, urinary irritation, and as a sweetener and corrective for harsh-tasting medicines, the early documentation of the harmonizing role that would later be elaborated in Chinese medicine as the gan cao "harmonizer of formulas" role.[2] Pliny the Elder in book twenty-two of his Naturalis Historia continued the Greek tradition, naming the plant glycyrrhiza and listing it for cough, lung complaint, stomach disorders, and the sweetening of pharmaceutical preparations.[3]
The Islamic and Persian medical traditions documented licorice as asl-us-sus (Arabic, "root of the sus plant") or irq al-sus and as mahek (Persian), with the herb classed as warming in the second degree, moist in the second, sweet, and indicated for cough, hoarseness, chest complaint, gastric pain, urinary irritation, and as a corrective and sweetener in compound formulations. Avicenna in book two of his Canon of Medicine of about 1025 CE devoted an entry to asl-us-sus listing the indications and noting the harmonizing role of the herb in compound preparations of harsher simples;[4] the Unani tradition of South Asia incorporated licorice as one of the central simples and continues to use it in clinical practice to the present.
The Ayurvedic tradition is one of the two principal historical centroids of Glycyrrhiza glabra outside the Mediterranean, with the herb documented as yashtimadhu (Sanskrit, "sweet stick") in the Charaka Samhita and Sushruta Samhita and used continuously from the early centuries of the common era to the present.[5] Yashtimadhu is classed as sweet (madhura rasa), cooling (sheeta virya), unctuous (snigdha), heavy (guru), kapha-vata-shamaka (pacifying the cold-and-damp and cold-and-windy doshas, although somewhat increasing kapha at large dose), and is classed as a medhya rasayana (mind-and-intellect rejuvenative) and as one of the foundational Ayurvedic rasayanas (tonic rejuvenatives).[6] Classical indications include cough (kasa), respiratory complaint, throat irritation, gastric pain (amlapitta), peptic disease, mental fatigue and memory weakness (the medhya rasayana role), and as a corrective sweetener in many compound formulations. Yashtimadhukadi Ghrita is a classical ghee-based compound of yashtimadhu with other herbs, used for chronic respiratory and digestive complaint; yashtimadhu also appears in numerous churnas (powders) and kashayas (decoctions).
The Chinese tradition uses Glycyrrhiza uralensis (Chinese licorice) rather than G. glabra as the principal licorice of the materia medica; G. uralensis is the gan cao of the companion article, where the TCM "harmonizer of formulas" role is documented in detail.[7] G. glabra has appeared in Chinese herbal practice as an import substitute for gan cao where uralensis was unavailable, and modern Chinese herbal pharmacies sometimes carry both species under the gan cao name without species discrimination, but the historical centroid of the Chinese tradition is firmly on uralensis.
The medieval European tradition received licorice as the standard Mediterranean apothecary commodity and incorporated the herb into the European herbal pharmacopoeia continuously from the Greek inheritance through the medieval monastic and Renaissance traditions to the modern. Nicholas Culpeper in The English Physitian of 1652 wrote of licorice as warming and moistening, prescribed for "hoarseness, wheezing, shortness of breath, and all the diseases of the breast and lungs," for thirst in fevers, and as a corrective sweetener in unpleasant-tasting compound preparations; Culpeper's description tracks the Greek and Islamic indications closely. The German Commission E approved Western licorice for catarrh of the upper respiratory tract and for gastric and duodenal ulcer (at doses of 5 to 15 g daily of root, providing 200 to 600 mg glycyrrhizin, for a duration not exceeding four to six weeks because of the pseudohyperaldosteronism risk at longer courses).[8]
The modern Western-clinical era of licorice begins with the mid-twentieth-century investigation of the herb for peptic ulcer disease and the resulting development of two related interventions: the synthetic derivative carbenoxolone (glycyrrhetinic acid succinate disodium) was developed in the late 1950s and approved for peptic ulcer in the United Kingdom and several other countries through the 1960s and 70s, with substantial trial evidence of ulcer-healing benefit at the cost of pronounced pseudohyperaldosteronism toxicity that ultimately limited its clinical use as proton pump inhibitors replaced it as the standard of care;[9] and deglycyrrhizinated licorice (DGL) was developed as a parallel intervention that removed the glycyrrhizin (and thus the pseudohyperaldosteronism risk) while retaining the flavonoid and saponin fractions believed to mediate the mucosal-protective and ulcer-healing effects. DGL has remained in modern Western-clinical herbal practice as a chronic-use safe alternative to whole licorice for peptic ulcer, gastritis, and gastroesophageal reflux disease, with a substantial clinical evidence base for the indication and an essentially benign safety profile compared with whole licorice.[10]
The Japanese clinical practice for chronic viral hepatitis has used intravenous glycyrrhizin as Stronger Neo-Minophagen C (SNMC, a formulation of glycyrrhizin, glycine, and L-cysteine) since the 1970s for chronic hepatitis B and C, with substantial reported trial evidence of reduced ALT and slowed progression to cirrhosis, although the formulation is not widely used outside Japan and the pseudohyperaldosteronism risk constrains long-term use.[11] The Western-medical adoption of SNMC has been limited despite the Japanese clinical experience; in the United States and Europe, oral DGL and the indirect anti-inflammatory roles of licorice are the dominant clinical uses.
The pseudohyperaldosteronism syndrome is the load-bearing modern safety story for whole licorice consumption and has been documented in a substantial case-report literature dating from the 1950s onward. The classical presentation is the licorice-candy headache and edema syndrome in heavy consumers of glycyrrhizin-containing licorice candy (or, less commonly, chronic medicinal use of whole licorice root preparations): hypertension, hypokalemia, sodium retention, edema, and in severe cases hypokalemic muscle weakness, paralysis, or cardiac arrhythmia. The Walker 1994 and van Uum 2005 reviews are standard references for the mechanism and the case literature.[12][13] The European Scientific Committee on Food set an adult guidance upper limit of 100 mg glycyrrhizin per day for habitual consumption in 2003, equivalent to approximately 1 to 5 g of licorice root depending on cultivar and preparation; chronic intake above this threshold approaches the pseudohyperaldosteronism range in susceptible individuals and intake at multiple times this level reliably produces clinical syndromes in case-report populations.[14] Pregnancy carries a real preterm-birth signal at high glycyrrhizic acid intake: Finnish cohort studies have documented associations between heavy licorice candy consumption in pregnancy and preterm birth, with a dose-response pattern.[15]
Botany and identification
Glycyrrhiza glabra is a perennial herbaceous legume of the Fabaceae reaching 1 to 1.5 m at flowering. The deep tap root extends 1 to 2 m into the soil and produces an extensive horizontal stolon network from which new aerial stems emerge; the harvested medicinal "root" is in fact a mixture of true root and underground stolon. The leaves are pinnate with 9 to 17 elliptic leaflets 3 to 6 cm long, smooth and somewhat sticky-glandular on the lower surface. The flowers are small (8 to 12 mm), pale lilac to violet, in axillary racemes, papilionaceous in the typical Fabaceae form; the fruit is a small flat oblong pod 1.5 to 3 cm long containing two to eight reniform brown seeds. The dried root of commerce is the cured peeled rhizome and stolon: yellow-brown to greyish-yellow, fibrous, somewhat woody, with a characteristic sweet aroma and intensely sweet taste. Distinguished from Glycyrrhiza uralensis (the Chinese licorice) by smaller leaflet size and a less branched root system; from Glycyrrhiza inflated (Xinjiang licorice) by the smooth (rather than inflated) seed pod. Whole-stick licorice is light yellow-brown internally and dark brown externally; powdered licorice is light yellow-brown. Whole and powdered preparations are largely indistinguishable from G. uralensis without species-specific chemical or microscopic analysis, with the consequence that "licorice" of unspecified species is often unidentifiable as glabra or uralensis after processing.
Active constituents
The principal medicinally active constituents of Western licorice are the glycyrrhizin fraction (the triterpene saponin) and the flavonoid fraction.
Glycyrrhizin (glycyrrhizic acid, the triterpene saponin) is 2 to 12 percent of the dried root by weight (variable by region, cultivar, and harvest age, with Iranian and Turkish roots typically at the higher end). Glycyrrhizin is the principal sweet compound, approximately fifty times sweeter than sucrose by mass, and the source of licorice's characteristic taste and of its candy and tobacco-flavoring uses. On oral administration glycyrrhizin is hydrolyzed in the intestinal lumen and colonic flora to its aglycone, glycyrrhetinic acid (also called enoxolone or glycyrrhetic acid), which is the active intracellular form. Glycyrrhetinic acid is the molecule that inhibits 11-beta-hydroxysteroid dehydrogenase type 2 and produces the pseudohyperaldosteronism effect, as well as the anti-inflammatory and other systemic effects of licorice. The pharmaceutical derivative carbenoxolone (glycyrrhetinic acid hydrogen succinate disodium) is a semisynthetic derivative produced by succinylation of glycyrrhetinic acid; carbenoxolone was approved for peptic ulcer in several countries in the 1960s and 70s and remains a research tool for 11-beta-HSD2 pharmacology.
The flavonoid fraction is approximately 1 to 2 percent of the dried root and includes the chalcone isoliquiritin and its aglycone isoliquiritigenin, the flavanone liquiritin and its aglycone liquiritigenin, and the isoflavones glabridin and licochalcone A (with glabridin distinctive of G. glabra and licochalcone A more characteristic of G. inflata). The flavonoids contribute the antioxidant, antimicrobial, and topical anti-inflammatory activity of licorice; glabridin and licochalcone A are the principal constituents of the modern licorice-derived topical preparations for atopic dermatitis. The flavonoid fraction is retained in deglycyrrhizinated licorice (DGL) preparations, providing the basis of DGL's gastroprotective and anti-ulcer activity in the absence of glycyrrhizin.
The non-active fractions include polysaccharides (contributing to the demulcent and immunomodulatory activity), asparagine and other amino acids (the licorice "honey-stick" sweetness extends beyond the glycyrrhizin contribution), coumarins (small amounts; not the warfarin class, no anticoagulant activity), and trace volatile oil (contributing to the characteristic aroma).
Preparations
The traditional therapeutic forms are the whole root (chewed directly, the traditional "licorice stick"); the decoction (1 to 4 g of root per cup of water, simmered 15 to 20 minutes, taken one to three times daily for short-course respiratory or gastric complaint, with chronic high-dose use constrained by the pseudohyperaldosteronism risk); the powdered root (1 to 5 g daily, in honey or warm water, or as an ingredient in compound formulations); the tincture (1:5 in 45 percent alcohol, 2 to 5 mL three times daily, the traditional Western herbalist's form). The modern Western-clinical and supplement forms are the standardized glycyrrhizin extract (used at low dose for short-course anti-inflammatory or hepatoprotective indication, with the pseudohyperaldosteronism risk in proportion to the glycyrrhizin dose); deglycyrrhizinated licorice (DGL) tablets, typically chewed before meals at 380 to 760 mg three times daily for peptic ulcer, gastritis, or gastroesophageal reflux disease (the principal modern Western-clinical chronic-use preparation, engineered to remove glycyrrhizin while retaining demulcent and mucosal-protective activity); topical glabridin or licochalcone creams for atopic dermatitis; intravenous glycyrrhizin formulations (Stronger Neo-Minophagen C, SNMC) in Japanese clinical practice for chronic hepatitis B and C. Licorice candy and confectionery use is the consumer product form most likely to produce inadvertent chronic high glycyrrhizin exposure in patients not in formal medicinal use.
Pharmacokinetics
Glycyrrhizin is poorly absorbed from the intestine in its intact saponin form; the principal absorption mechanism is intestinal-microbial hydrolysis to glycyrrhetinic acid, which is then absorbed and reaches the systemic circulation. Plasma glycyrrhetinic acid peaks 8 to 12 hours after oral administration of whole licorice or glycyrrhizin preparations and has an elimination half-life of approximately 8 hours; chronic dosing produces accumulation over days. Glycyrrhetinic acid is highly protein-bound in plasma (greater than 99 percent) and is metabolized via hepatic glucuronidation and sulfation, with biliary excretion and enterohepatic recycling. The 11-beta-HSD2 inhibition by glycyrrhetinic acid is competitive and reversible, with the magnitude of pseudohyperaldosteronism effect closely tracking plasma glycyrrhetinic acid concentration; the inter-individual variability in pseudohyperaldosteronism response at a given dose is substantial, with genetic variation in 11-beta-HSD2 and in the intestinal microbial conversion of glycyrrhizin to glycyrrhetinic acid contributing to the variation.
Intravenous glycyrrhizin (the Japanese SNMC formulation) bypasses the intestinal-hydrolysis step and delivers glycyrrhizin directly to the circulation, with hydrolysis to glycyrrhetinic acid then occurring in hepatic tissue and in plasma esterases; the pharmacokinetic profile is somewhat different from oral whole licorice but converges on glycyrrhetinic acid as the active species.
Deglycyrrhizinated licorice (DGL) preparations contain less than 3 percent of the glycyrrhizin of whole licorice (typically 1 to 2 mg glycyrrhizin per 380 mg DGL tablet) and accordingly produce negligible pseudohyperaldosteronism even at chronic high dose; the flavonoid and saponin fractions retained in DGL have separate absorption profiles and contribute to the mucosal-protective effect without producing the safety burden of whole licorice.
Pharmacodynamics
The principal pharmacodynamic effect of glycyrrhizin and glycyrrhetinic acid is the inhibition of 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2), the renal and colonic enzyme that normally protects the mineralocorticoid receptor from cortisol by converting cortisol to inactive cortisone in the immediate vicinity of the receptor. With 11-beta-HSD2 inhibited by glycyrrhetinic acid, local cortisol concentrations rise and cortisol (which has comparable affinity to aldosterone for the mineralocorticoid receptor and circulates at concentrations approximately one hundred times higher) binds and activates the receptor, producing functional mineralocorticoid agonism. The downstream effects are sodium retention with consequent water retention, potassium loss through the renal collecting duct, hypertension, edema, and (in severe cases) hypokalemic muscle weakness or paralysis and cardiac arrhythmia. The plasma renin and aldosterone are suppressed (the syndrome is called "pseudo-hyperaldosteronism" because the clinical picture mimics primary hyperaldosteronism while renin and aldosterone levels are low rather than elevated). The pseudohyperaldosteronism is the principal safety concern of whole licorice and the principal reason DGL exists as a preparation.
Glycyrrhetinic acid also potentiates exogenous corticosteroid effect through the same 11-beta-HSD2 inhibition mechanism and through some direct glucocorticoid receptor modulation, with clinical relevance in patients on chronic prednisone or similar corticosteroid medicines. The anti-inflammatory effect of licorice in respiratory and gastric complaint is partly attributable to this endogenous-cortisol-potentiation mechanism and partly to direct flavonoid anti-inflammatory activity. Glycyrrhizin and glycyrrhetinic acid have documented in vitro and limited in vivo antiviral activity against hepatitis B virus, hepatitis C virus, and herpes simplex virus, the empirical basis of the Japanese SNMC clinical practice. The flavonoid fraction (glabridin, licochalcone A, liquiritin) provides antioxidant activity, antimicrobial activity against several oral and gastric pathogens including Helicobacter pylori, and topical anti-inflammatory effects on atopic dermatitis lesions. The saponin and polysaccharide fractions contribute to the demulcent and expectorant effects.
Experience
Log in to add your own experience.
Problems
Peptic ulcer disease, gastritis, and gastroesophageal reflux disease (the principal modern Western-clinical indication, addressed with DGL rather than whole licorice for chronic use). Catarrh of the upper respiratory tract; chronic cough and bronchitis (the Commission E and traditional Western herbal indication). Sore throat (the lozenge form). Chronic hepatitis B and C (the Japanese SNMC IV practice; oral preparations have a thinner evidence base). Atopic dermatitis, eczema (topical glabridin or licochalcone preparations). Mild adrenal-insufficiency support (folk and complementary practice; the pseudohyperaldosteronism is the flip-side of mild Addisonian supplementation, with the cortisol-sparing effect rationalizing the use; clinical evidence is anecdotal). Functional dyspepsia (mild). Traditional Ayurvedic indications: cough, throat irritation, gastric complaint, mental fatigue (medhya rasayana role), debility. Traditional Unani indications: cough, gastric pain, urinary irritation, harmonizing role in compound formulations. Folk and historical: snake bite (no modern evidence), wound healing.
Titration and dosing
Whole root powder: 1 to 5 g daily, for short-course use (typically four to six weeks maximum). Decoction: 1 to 4 g of root per cup, three times daily, for short-course use. Tincture 1:5 in 45 percent alcohol: 2 to 5 mL three times daily. DGL (deglycyrrhizinated licorice): 380 to 760 mg chewed before meals three times daily (the standard modern peptic ulcer dose), indefinite duration; the principal advantage of DGL is that the pseudohyperaldosteronism dose limit does not apply. Standardized glycyrrhizin extract: dose-limited by the 100 mg/day glycyrrhizin guidance from the European SCF for habitual chronic use; short-course higher-dose use can deliver up to 200 to 400 mg glycyrrhizin daily for limited periods. Topical glabridin or licochalcone cream: per manufacturer specification, applied to affected skin twice daily. Carbenoxolone (the semisynthetic pharmaceutical derivative, available in some countries): 50 to 100 mg three times daily for peptic ulcer, with the pseudohyperaldosteronism dose limit closely monitored.
Effects
No effects listed yet, be the first to suggest one.
Interactions
The clinically significant interactions of whole Western licorice (Glycyrrhiza glabra root and glycyrrhizin-containing preparations) are dominated by the pseudohyperaldosteronism mechanism and produce a cluster of medicine-class interactions that share the common feature of being amplified by licorice-induced hypokalemia or sodium retention.
Potassium-depleting diuretics (loop diuretics such as furosemide and bumetanide; thiazide diuretics such as hydrochlorothiazide and chlorthalidone): the combined hypokalemia is the principal risk, with case reports of severe hypokalemic muscle weakness and cardiac arrhythmia in patients on long-term diuretic therapy who add chronic licorice consumption. The combination is contraindicated at therapeutic-dose chronic licorice consumption; DGL avoids the interaction.
Cardiac glycosides (digoxin): licorice-induced hypokalemia increases the risk of digoxin toxicity, with case reports of arrhythmia in digoxin-treated patients on chronic licorice. The combination is contraindicated; potassium monitoring is the conservative practice if licorice consumption is unavoidable in a digoxin-treated patient; DGL avoids the interaction.
Corticosteroids (prednisone, hydrocortisone, dexamethasone, and other systemic and topical corticosteroid medicines): glycyrrhetinic acid potentiates exogenous corticosteroid effect through 11-beta-HSD2 inhibition and direct receptor modulation. The clinical effect is dose-dependent and modest at culinary licorice exposure but potentially substantial at therapeutic-dose chronic licorice with high-dose corticosteroid use; the historical clinical observation by Dutch endocrinologists in the 1950s that licorice extracted patients on hydrocortisone replacement therapy could reduce their hydrocortisone dose led directly to the identification of the licorice cortisol-sparing mechanism.
Antihypertensive medicines (ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-blockers, and others): the sodium-retention effect of chronic high-dose licorice opposes blood-pressure control and can produce treatment-resistant hypertension in patients on otherwise effective antihypertensive regimens. The clinical management is to reduce or eliminate chronic licorice consumption (or substitute DGL where the indication is gastric); the combination is not an absolute contraindication but the licorice intake should be a routine inquiry in any patient presenting with apparently resistant hypertension.
Anticoagulants: the coumarin fraction of licorice is small and is not the 4-hydroxycoumarin warfarin class; no direct anticoagulant interaction is established. Older sources sometimes flagged a theoretical concern that has not been substantiated in case reports or pharmacokinetic studies.
Other interactions: licorice modestly induces some CYP3A4 activity at high dose; the clinical effect is generally modest but can be relevant for medicines with narrow therapeutic windows and known CYP3A4 substrate dependence.
DGL (deglycyrrhizinated licorice) avoids essentially all of the above interactions and is the preparation of choice for any chronic use, particularly in patients on diuretics, digoxin, corticosteroids, or antihypertensive medicines.
Pregnancy and lactation
Culinary amounts of licorice (an occasional candy stick, small culinary use in baked goods or savory dishes) are considered safe in pregnancy at the same intake levels considered safe in the general adult population. Chronic high-dose licorice candy consumption in pregnancy has been associated with preterm birth in Finnish cohort studies, with a dose-response pattern that becomes clinically meaningful at the multi-gram-per-day glycyrrhizin intake range typical of heavy licorice candy consumers in northern European populations.[15] The mechanism may involve cortisol-mediated effects on the fetal hypothalamic-pituitary-adrenal axis or direct uterine effects via the mineralocorticoid pathway. Therapeutic-dose medicinal licorice and chronic high-dose supplementation should be avoided in pregnancy; DGL preparations, which have negligible glycyrrhizin content, are reasonable for short-course gastric complaint in pregnancy where indicated, although formal safety data in pregnancy is limited.
Monitoring
For patients on chronic medicinal licorice consumption (whole root or standardized glycyrrhizin preparations at more than a few hundred milligrams glycyrrhizin daily for more than two to four weeks), blood pressure monitoring and serum potassium monitoring at baseline and every two to four weeks during continued use is the conservative practice; any rise in blood pressure or fall in potassium should prompt dose reduction or substitution with DGL. For patients on diuretics, digoxin, or corticosteroids who add even short-course licorice consumption, the same monitoring applies, with a lower threshold to discontinue licorice. DGL preparations do not require monitoring beyond the routine clinical follow-up of the underlying gastric indication.
Patient counseling
The most important counseling distinction for licorice is the form of the preparation, particularly the distinction between whole-licorice (or any glycyrrhizin-containing preparation) and DGL (deglycyrrhizinated licorice). The two preparations are clinically distinct medicines despite originating in the same plant: whole licorice carries the pseudohyperaldosteronism risk at chronic high intake and is appropriate only for short-course use (typically four to six weeks maximum) at moderate dose; DGL has negligible glycyrrhizin, no meaningful pseudohyperaldosteronism risk, and is appropriate for indefinite chronic use for peptic ulcer or gastritis. This is analogous in clinical practice to the distinction between Ceylon and cassia cinnamon (the same plant family, two clinically relevant forms, one carrying the chronic-use safety burden and one engineered around it). Patients seeking licorice for chronic gastric or anti-ulcer use should generally use DGL; patients seeking licorice for short-course respiratory or anti-inflammatory use can reasonably use whole licorice at the European SCF guidance dose of up to 100 mg glycyrrhizin per day.
Licorice candy is a substantial source of inadvertent chronic glycyrrhizin exposure in patients who may not be in formal medicinal use. Traditional European licorice candy (the salt-licorice or sweet-licorice products of Scandinavia, the Netherlands, Germany, and the United Kingdom) typically contains 1 to 10 mg glycyrrhizin per gram of candy, and heavy consumers (multiple ounces daily) can readily exceed the 100 mg/day European SCF guidance. Patients presenting with apparently resistant hypertension, unexplained hypokalemia, or unexplained edema should be asked about licorice candy consumption as a routine part of the clinical history; the syndrome is well-documented and not infrequent in heavy candy consumers, particularly in northern European populations where licorice candy is a common confectionery item.
Patients with established hypertension, congestive heart failure, hypokalemia, renal disease, hepatic cirrhosis with ascites, or chronic corticosteroid use should avoid chronic medicinal licorice or limit themselves to DGL preparations for any therapeutic use. Patients planning elective surgery should be counseled to discontinue therapeutic-dose whole licorice supplementation two to four weeks before surgery (the duration is set by the glycyrrhetinic acid pharmacokinetic profile rather than by platelet turnover); culinary licorice and short-term licorice candy use do not require preoperative discontinuation.
Patients seeking the cortisol-sparing or mild adrenal-supportive use of licorice (a folk and complementary indication, not a primary clinical intervention) should be counseled that the effect is real but is the same mechanism that produces the pseudohyperaldosteronism syndrome at higher intake, and that the clinical management of any indication for adrenal supplementation should involve formal endocrine evaluation rather than empirical herbal supplementation.
Relevant anecdote
No anecdotes yet, share a relevant one.
Relevant Literature
No literature entries yet.
Log in to submit relevant literature.
See also
Chinese licorice, Glycyrrhiza uralensis, Ginger, Marshmallow, Slippery elm, Comfrey, Mullein, Thyme
References
- ↑ Hort AF (translator). Theophrastus: Enquiry into Plants, Volume II, Books VI-IX. Loeb Classical Library. Cambridge, MA: Harvard University Press; 1916 (translation of c. 300 BCE original).
- ↑ Beck LY (translator). Pedanius Dioscorides of Anazarbus: De Materia Medica. Hildesheim: Olms-Weidmann; 2005 (translation of c. 60 CE original).
- ↑ Bostock J, Riley HT (translators). Pliny the Elder: The Natural History. London: Taylor and Francis; 1855.
- ↑ Gruner OC (translator). A Treatise on the Canon of Medicine of Avicenna, Incorporating a Translation of the First Book. London: Luzac and Co.; 1930.
- ↑ Sharma PV (translator). Charaka Samhita: Text with English Translation. Varanasi: Chaukhambha Orientalia; 1981.
- ↑ Williamson EM. Major Herbs of Ayurveda. Edinburgh: Churchill Livingstone; 2002.
- ↑ Bensky D, Clavey S, Stoger E. Chinese Herbal Medicine: Materia Medica, 3rd ed. Seattle: Eastland Press; 2004.
- ↑ Blumenthal M, Goldberg A, Brinckmann J (editors). Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications; 2000.
- ↑ Doll R, Hill ID, Hutton CF. Treatment of gastric ulcer with carbenoxolone sodium and oestrogens. Gut. 1965 Feb;6(1):19-24. PMID 14259418.
- ↑ Morgan AG, Pacsoo C, McAdam WA. Maintenance therapy: a two year comparison between Caved-S and cimetidine treatment in the prevention of symptomatic gastric ulcer recurrence. Gut. 1985 Jun;26(6):599-602. PMID 4007604. (Caved-S is a deglycyrrhizinated licorice preparation; one of the foundational DGL maintenance trials.)
- ↑ Iino S, Tango T, Matsushima T, Toda G, Miyake K, Kumada H, et al. Therapeutic effects of stronger neo-minophagen C at different doses on chronic hepatitis and liver cirrhosis. Hepatology Research. 2001 Jan 1;19(1):31-40. PMID 11137478.
- ↑ Walker BR, Edwards CR. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinology and Metabolism Clinics of North America. 1994 Jun;23(2):359-377. PMID 8070427.
- ↑ van Uum SH. Liquorice and hypertension. The Netherlands Journal of Medicine. 2005 Apr;63(4):119-120. PMID 15869038.
- ↑ European Commission Scientific Committee on Food. Opinion of the Scientific Committee on Food on Glycyrrhizinic Acid and its Ammonium Salt. SCF/CS/ADD/EDUL/225 Final. Brussels: European Commission Health and Consumer Protection Directorate-General; 10 April 2003. (Sets 100 mg/day adult upper guidance for habitual glycyrrhizin intake.)
- ↑ 15.0 15.1 Strandberg TE, Järvenpää AL, Vanhanen H, McKeigue PM. Birth outcome in relation to licorice consumption during pregnancy. American Journal of Epidemiology. 2001 Jun 1;153(11):1085-1088. PMID 11390327.