Family

Fabaceae.

Related Species

Glycyrrhiza uralensis Fisch ex DC ( Gan cao ). The favored Chinese species, Gan cao is pharmacologically similar to Glycyrrhiza glabra . ¹

Habitat and Cultivation

A perennial shrub in the pea family, G. glabra is a Mediterranean native, but more than 20 related species are distributed throughout Europe, Asia, the Americas, and Australia. Glycyrrhiza uralensis and G. glabra are both widely cultivated in warmer zones throughout Eurasia.

Parts Used

Root, stolons.

Common Forms

• Dried Root   Whole dried root, and powdered dried root without bark.

• Tincture, Fluid Extract   15% to 20% alcohol.

• Standardized Extracts   Up to 20% glycyrrhizin.

• Deglycyrrhizinated Licorice (DGL)   0.5% to 2.0% flavonoids as liquiritigenin.

Overview

Licorice is one of the most ubiquitous herbs in Asian medicine and has been an important remedy in Western herbalism since Greco-Roman times. Licorice is a complex and clinically valuable herb that, without substantial justification, has acquired an uneven reputation in conventional medicine. In part, confusion arises from the many different forms of the herb, its constituents, concentrates, and derivatives, such as the antiulcer drug carbenoxolone sodium, deglycyrrhizinated licorice (DGL), or parenteral products such as SNMC (no longer available) from Japan. These preparations were developed after the emergence of scientific interest in the pharmacology of the herb because of its unusually broad range of effects, including multiple actions on steroid metabolism and inflammatory pathways; hepatoprotective, chemopreventive, and antitumorigenic properties; and pronounced antiviral activities (e.g., glycyrrhizin is the most potent SARS antiviral agent currently known). ^2,3

A significant proportion of “bad press” associated with licorice root is attributable to the use of concentrated glycyrrhizin in the processed food and tobacco industries as a flavoring agent because of its characteristic intense sweetness. “Licorice” is also used to describe a range of widely available popular confectionery products; notably, in the United States, these are more often flavored with anise rather than real licorice or glycyrrhizin. Reports in the medical literature of licorice-related adverse events are invariably associated with the use/abuse of such products, rather than therapeutic doses of the crude herb or its extracts in a clinical setting.

Therapeutic monographs on licorice root are available by the European Scientific Cooperative on Phytotherapy (ESCOP), ⁴ British Herbal Medical Association (BHMA), ⁵ World Health Organization (WHO), ⁶ and German Commission E. ⁷ The herb is official in the 2003 United States Pharmacopoeia – National Formulary, the European Pharmacopoeia, and the 1997 Pharmacopoeia of the People ' s Republic of China .

Historical/Ethnomedicine Precedent

Licorice has been used for food and medicine around the world since ancient Egyptian and Assyrian records were first written on papyri and clay tablets. It was one of the riches stored in King Tutankhamen's tomb. Scythians near the Sea of Azov knew the sweet root to be a successful treatment for people with asthma and dry cough. Documented in the third centuryBCEby the Greek Theophrastus, this use is still common with many herbalists today. Medicinal uses of licorice are recorded from every dynasty of Chinese history. The herb is one of the most frequently used in Chinese formulae, often included as an adjuvant in prescriptions to harmonize other herbs, and thus esteemed as the “Great Harmonizer”; it is primarily considered to tonify spleen ( Pi ) and stomach ( Wei ) qi deficiencies, moisten the lungs ( Fei ), relieve pain, clear “Heat” and “Toxins.” ⁸ The herb is also used widely in other Asian traditions, including Kampo and Ayurvedic medicine.

In Western use, licorice attracted medical interest when the Dutch physician Revers discovered at the end of World War II that some of his patients were using licorice as a home remedy to treat their ulcers successfully. This led to the development of semisynthetic antiulcer medication called carbenoxolone, long since replaced by newer classes of drug, such as histamine (H2) blockers and proton pump inhibitors. Deglycyrrhizinated licorice was a byproduct of carbenoxolone manufacture, and DGL is currently used to deliver high levels of anti-inflammatory licorice flavonoid compounds with significantly lower levels of glycyrrhetinic acid (GA), reducing the risk of GA-induced pseudoaldosteronism. The effects of the herb on glucosteroid metabolism simultaneously led to medical interest in its use for Addison's disease. ^9,10This is reflected in the incorporation of licorice into prescriptions for (functional) “adrenal insufficiency” and chronic fatigue conditions by modern herbalists and naturopathic physicians. In botanical medicine the herb continues to be valued for its general tonic properties as well as for its more specific indications (e.g., peptic ulcers).

Known or Potential Therapeutic Uses

Addison's disease, adrenal insufficiency, asthma, bronchitis, cancer chemoprevention, chronic fatigue, constipation, cough, hepatoprotection against toxicity, herpes simplex infection (topically), human immunodeficiency virus (HIV) infection, inflammations of the gastric and urinary tracts, joint inflammation, mouth ulcers, peptic ulcers, polycystic ovarian syndrome, sudden acute respiratory syndrome (SARS), sore throat, stress, viral hepatitis.

Key Constituents

Triterpene saponins, principally glycyrrhizin 2% to 6% (aglycone = glycyrrhetin or glycyrrhetinic acid).

Polysaccharides, flavonoids (approximately 1.0%) including liquiritin, chalcones including isoliquiritin, isoflavonoids, sterols.

Note: Nomenclature for the glycyrrhizin and its aglycone varies. This monograph adopts the abbreviation “GL” for the glycoside (glycyrrhizin, glycyrrhizic acid, glycyrrhizinic acid) and “GA” for the aglycone (glycyrrhetinic acid).

Therapeutic Dosing Range

• Dried Root   By decoction, 3 to 10 g/day; typical maximum Chinese dose: 15 to 30 g/day.

• Tincture/Fluid Extract   Based on 1:1, 2 to 5 mL three times daily.

• Standardized Extract   Up to 20% glycyrrhizin, equivalent to 5 to 15 g/day DGL—0.5% to 2.0% flavonoids, chewable tablets approximately 380 mg three times daily.

Strategic Considerations

The major therapeutic monographs for licorice root vary slightly in their accounts of potential interactions between licorice root preparations and prescription drugs, but the general theme is consistent. The German Commission E maintains that “potassium loss due to other drugs may be increased,” and suggests that “with potassium loss, sensitivity to digitalis glycosides may be increased.” ⁷ The same warning is repeated by ESCOP, ⁴ who include other “antiarrhythmic drugs or drugs which induce reversion to sinus rhythm such as quinidine” in their precautions about hypokalemia, as well as repeating the warnings of Commission E about combining licorice with potassium depleters, including stimulant laxatives and loop or thiazide diuretics. ESCOP also notes a possible alteration of prednisolone pharmacokinetics (i.e., glucocorticoid-sparing effect) with licorice. The WHO monograph ⁶ includes a further precaution about combining aldosterone antagonists such as spironolactone or amiloride with licorice.

These warnings are representative of most discussions on licorice's interactions with prescription drugs. Strictly speaking, these are better classified as drug “contraindications” based on the known pharmacological property of GL to induce a syndrome known as pseudoaldosteronism or “apparent mineralocorticoid excess.” The first report of licorice-induced hypokalemia was unwittingly made by London physician de Cayley in 1950, who recorded the three cases of hypokalemic arrhythmia associated with p-aminosalicylic acid (PAS) therapy for tuberculosis. ¹¹ De Cayley did not detect the connection to licorice, but the following year, Strong ¹² realized that PAS was in fact flavored with licorice root extract. In 1979, Ulick et al. ¹³ used “apparent mineralocorticoid excess” (AME) to describe the congenital pediatric syndrome of hypertension, hypokalemia, suppressed renin-angiotensin-aldosterone axis, and increased urinary ratio of 11β-hydroxy to 11-oxo metabolites of cortisol (suggesting a failure of conversion of cortisol to cortisone). ^14,15

Subsequently, the ability of licorice extracts to inhibit the enzyme 11β-hydroxysteroid dehyhydrogenase (11β-HSD) became established through in vitro, animal, and human experiments, and the resultant effects are usually termed licorice-induced “pseudoaldosteronism” to distinguish it from congenital AME. ^16-19Renal 11β-HSD-2 normally serves to “protect” local mineralocorticoid receptors from activation by cortisol by metabolizing the endogenous glucocorticoid locally to its inactive form. That is, the enzyme confers aldosterone specificity on intrinsically nonspecific renal mineralocorticoid receptors. When this enzyme is inhibited, the resulting excess cortisol stimulates both the glucocorticoid and the “unprotected” renal mineralocorticoid receptors, promoting potassium loss. If unchecked, this can lead to sodium retention and hypokalemia, with possible sequelae of hypertension, myopathy, rhabdomyolysis with potential renal failure from myoglobinemia, and cardiac rhythm disturbances. ^17-27The corollary impression that licorice is thus associated with potentially life-threatening toxicities pervades secondary accounts of the herb and reports of its interactions.

In practice, the situation is less clear-cut. First, the theoretical potential of licorice and its derivatives (except DGL) to induce pseudoaldosteronism is well known to practitioners of natural medicine who regularly use the herb and has been documented in conventional medical literature for over half a century. Coadministration of licorice with potassium-depleting drugs such as thiazide or loop diuretics, especially in patients vulnerable to electrolyte disturbance or using narrow-therapeutic-index antiarrhythmics, is a contraindication and clear departure from the standard of care. If two separate agents possessing similar toxicities are coadministered, there is risk of additive toxicity. This is not strictly speaking an interaction, unless there is evidence for unexpected “synergistic” or nonlinear increases in toxicity resulting from the combination. In botanical medicine settings, high doses of licorice are never prescribed for prolonged periods, and when used at normal therapeutic doses for 6 to 8 weeks, the adverse sequelae of pseudoaldosteronism are rarely observed. Blood pressure is usually monitored during higher-dose licorice prescription. There are no published reports of licorice-induced pseudoaldosteronism arising from practitioner-administered use of licorice; all published reports relate to either unwitting or deliberate consumption of products such as licorice candy, chewing tobacco, or flavored and sweetened beverages and laxatives. The risks of adverse events from self-administration are small but finite, given the public availability of these products, but it is appropriate to distinguish these concerns from clinical practice. ²⁸

Second, inhibition of renal 11β-HSD-2 by licorice and resulting mineralocorticoid receptor–mediated effects do not appear to account fully for the known features of the pseudoaldosteronism syndrome, particularly the varying individual expressions of both hypertension and edema. There is evidence of central nervous system (CNS) involvement unrelated to the renin-angiotensin axis, as well as local renovascular nitric oxide (NO)–mediated endothelial effects in addition to direct mineralocorticoid effects. ^29,30

The impact of licorice on steroid metabolism is complex and not fully understood. Inactivation of cortisol by 11β-HSD-2 is reversible because the enzyme is a bidirectional oxidoreductase. There are at least two isoforms of the enzyme; 11β-HSD-1 is widely distributed in peripheral tissues and the brain and acts predominantly as a reductase (i.e., reactivating glucocorticoids); 11β-HSD-2 is also bidirectional, but a higher-affinity enzyme that predominantly inactivates glucocorticoids, and it is co-localized with mineralocorticoid receptors (e.g., in the kidney). ³¹ Evidence for a third isoform, found in choriocarcinoma cells, has also been presented. ³² Glucocorticoid receptors are also subject to polymorphisms that contribute to individual variability in responses. There appears to be pronounced sexual dimorphism in humans between the relative contributions to cortisol inactivation by the A-ring reductases and 11β-HSD-1. ^33,34Licorice and GA also inhibits the A-ring reductases (5α- and 5β-reductase); both these enzymes irreversibly inactivate glucocorticoids. ^35,36The relationship between relative activities of the irreversible A-ring reductases and bidirectional oxidoreductases appears to vary widely and independently, depending on metabolic conditions. ^37,38

Data from animal studies used to explore the steroid biology must be extrapolated with caution to humans because definite species differences exist in the enzymatic determinants of steroid metabolism, which have diverged throughout mammalian evolution. ^36,39-42Pharmacokinetic variation in the bioavailability of GA has been demonstrated, and given the dependence of GL hydrolysis and release of GA on intestinal flora, this factor may be highly significant. ^43-46(See later discussion on the interaction between licorice and antibiotics.) Other compounds in food or herbal medicines may also inhibit 11β-HSD-1, notably grapefruit juice. ^47,48

In the final analysis, the inhibition of 11β-HSD isoenzymes by licorice arguably underlies only one clinically significant drug interaction, which is the consequent ability of licorice to “spare” prescription glucocorticoids (see licorice-prednisone/corticosteroid interaction). This interaction is not emphasized by secondary sources or the general literature. Licorice dosage required to effect a sustained inhibition of 11β-HSD have been estimated in a human pharmacokinetic study by Krahenbul et al. ⁴⁹ to be 1000 to 1500 mg GA per day, whereas dose levels of less than 500 mg GA/day did not appear to be able to sustain levels of inhibition. Similar results were established by Bernardi et al., ⁵⁰ who found mild adverse effects only at the highest dose (814 mg GL/day) in a trial of healthy volunteers taking different daily doses for 2 weeks, although measurable renin depression occurred at lower-dose groups of 217 and 380 mg GL daily. ⁵⁰

The modulation by licorice of multiple steroid-metabolizing enzymes has some impact on sex hormones as well as glucocorticoids. Reports have suggested mild antitestosterone effects and weak estrogen receptor (ER) binding by licorice, and pronounced biphasic phytoestrogenic activity for the flavonoid compounds isoliquiritigen and glabidrin. ^51-63Speculations about interactions between licorice and prescription steroid sex hormones have inevitably been made but are currently unsupported by clinical data. The only available trial was a small, open-label study with 15 women and 21 men that examined the effects of 4 weeks’ daily consumption of 9 g licorice (150 mg GA) on steroidal hormone levels. Negligible effects were found in the androgens, but in men a slight decrease in dehydroepiandrosterone sulfate (DHEAS) was observed ⁶⁴ (see Theoretical, Speculative, and Preliminary Interactions Research).

Effects on Drug Metabolism and Bioavailability

Effects of licorice on the major drug-metabolizing and xenobiotic-metabolizing enzymes and effects of its compounds have not been fully characterized. Kent et al. ⁶⁵ tested recombinant human cytochrome P450 (CYP450) enzymes in vitro for inhibition by whole-licorice-root extract and the licorice flavonoid glabidrin and found significant inhibition of 3A4 and 2B6 by both licorice extract and glabidrin. The effects were mechanism based and dose dependent but were demonstrated at plausible concentrations of licorice extract, with 6.9 micromolar (µM) achieving more than 50% inhibition of 3A4. CYP 2C9 was competitively inhibited by the licorice flavonoid glabidrin, whereas 2D6 and 2E1 did not appear to be affected by either licorice extract or isolated glabidrin. ⁶⁵ Using a live rodent model, however, Jeong et al. ⁶⁶ demonstrated that CYP450 2E1 inhibition was a component part of the mechanism underlying carbon tetrachloride hepatotoxicity prevention by oral pretreatment with GA. ⁶⁶

Paolini et al. ^67,68found that single doses of licorice extract or GL had no effect on mixed oxidases in a murine model. However, prolonged administration of 240 or 480 mg/kg GA resulted in significant increases of CYP450 3A4 activity, also shown to result from changes in messenger ribonucleic acid (mRNA), denoting increased induction of the enzyme. Smaller increases in 2A1, 2B1, 1A2, and 2B9 were also noted. A much-quoted in vitro fluorometric screening assay by Budzinski et al. ⁶⁹ of several commercial herbal extracts and compounds on human 3A4 suggests that licorice extract was a moderate inhibitor of 3A4. However, the concentrations used were effectively in the 5-millimolar range, far in excess of attainable in vivo levels. Also, the relationship between in vitro fluorometric data and in vivo activity has not been demonstrated to have any consistent correlation.

The current picture of licorice effects on phase I drug metabolism remains incomplete. Clinical studies are required to establish how the preliminary and inconclusive experimental data may translate into significant drug-herb interactions. One rodent study suggests a possible enhancement effect of licorice on the phase II conjugase enzyme uridine diphosphate (UDP) glucuronosyltransferase (UGT1A), which did not appear to be an induction (mRNA) effect. ⁷⁰ Additional evidence suggests possible effects of licorice on drug transporters of the organic anion peptide subfamily. ⁷¹ Finally, some animal data suggest that steroid drug distribution may be affected by licorice modulating steroid-binding globulins; however, the clinical significance of these data is not known. ^72,73

In conclusion, preliminary evidence exists that licorice may exert pharmacokinetic interaction effects on phases I, II, and III of drug metabolism, as well as some aspects of drug distribution. A preliminary report based on Chinese licorice (Gan cao) suggests the possibility that Glycyrrhiza uralensis compounds may bind to the pregnane X receptor (PXR). ⁷⁴ If corroborated for licorice root, such effects might indicate a more significant potential for pharmacokinetic interactions than has been established to date. At present, however, clinical reports suggestive of pronounced pharmacokinetic interactions between licorice and pharmaceutical drugs are absent, and the complex effects on steroid-metabolizing enzymes dominate the considerations of the herb from an interactions perspective.

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