Licorice

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Glycyrrhiza spp.

Glycyrrhiza glabra L. (syn. G. glandulifera Walst. & Kit.), G. uralensis Fisch. Ex DC.

[Fam. Fabaceae]

Overview

Licorice root is presently one of the most widely used medicinal herbs, and has been used therapeutically for several thousand years in Western and Eastern medicine (Gibson, 1978; Leung and Foster, 1996; Wang et al., 2000). Licorice ranks as the 10th most important herb for Western medical herbalists and in Unani traditional medicine clinics in Pakistan (Bergner, 1994; American Institute of Unani Medicine, 1999). In Traditional Chinese Medicine (TCM), licorice root is the most commonly-used herb, though it is almost always used in combination with other herbs (Leung, 1999).

Description

Licorice root consists of the dried roots and rhizomes of Glycyrrhiza glabra L. (syn. G. glandulifera Walst. & Kit.) and its varieties or G. uralensis (WHO, 1999; McGuffin et al., 2001), or other species of Glycyrrhiza (US FDA, 1998), and contains no less than 4% glycyrrhizic acid (syn. glycyrrhizin) (Ph.Eur., 2001). Peeled roots contain no less than 20% water-soluble extractive, and unpeeled roots contain no less than 25% water-soluble extract (Blumenthal et al., 1998), and no less than 25% dilute ethanol-soluble extract (JP XII, 1991; JSHM, 1993).

Primary Uses

Crude Preparations

Catarrh of the upper respiratory tract (Blumenthal et al., 1998)

Deglycyrrhized Licorice Extract (DGL) Preparations

Aphthous, stomatitis (oral ulcers) (Das et al., 1989)

Gastric ulcers (Morgan et al., 1985)

Duodenal ulcer (Kassir, 1985; Larkworthy and Holgate, 1975)

Note: The German Commission E also approved licorice preparations containing glycyrrhizin for gastric and duodenal ulcers.

Other Potential Uses

Miscellaneous Preparations

Prevention of radiation complications in lungs during radiotherapy (Palagina et al., 1999) [extract]

Chronic hepatitis (Chang and But, 1986; Huang, 1999) [decoction]

Sore throat, as a demulcent (IP, 1996; WHO, 1999) [form not specified]

Cough with viscid expectoration (Schilcher, 1997) [extract, tea, or juice]

Dyspepsia (WHO, 1999) [form not specified]

Purified Licorice Derivatives

Hepatic failure, subacute (Acharya et al., 1993) [Note: i.v. preparation]

Reduced risk of liver carcinogenesis in hepatitis C patients (Arase et al., 1997)

Uses in TCM

Bronchitis, pharyngitis, laryngitis, bronchial asthma, chronic hypocorticoidism (PPRC, 1992)

Combination Preparations

Infantile colic—with chamomile flower (Matricaria spp.), fennel seed (Foeniculum vulgare), vervain herb (Verbena hastata), and lemon balm leaf (Melissa officinalis) (Weizman et al., 1993; Zand et al., 1994)

Productive cough in children—with marshmallow root (Althaea officinalis), anise seed (Pimpinella anisum), and cowslip flower (Primula veris) (Schilcher, 1997)

Dosage

Internal

Crude Preparations

Decoction: 1.0–1.5 g licorice root placed in approximately 150–250 ml cold water. Boiled, simmered for 10–15 minutes, then strained, 2–3 times daily (Meyer-Buchtela, 1999; ÖAB, 1991; Wichtl and Bisset, 1994).

Infusion: Approximately 150 ml boiling water poured over 4.5 g licorice root and steeped 10–15 minutes; 2–3 times daily (Braun et al., 1997).

Fluid extract BP [1:1 (g/ml), 16–20% ethanol (v/v)]: 2–5 ml, 3 times daily (BP, 1980; Bradley, 1992).

Powdered root: Approximately 5–15 g root daily, equivalent to 200–600 mg glycyrrhizin (Blumenthal et al., 1998), 2–4 g single dose (API, 1989). Note: After decocting for 10 minutes, approximately 50% of the available glycyrrhizin, and approximately 45% of the liquiritin are released into the tea. After 30 minutes, approximately 80% of the glycyrrhizin, and 75% of the liquiritin are released, respectively (Meyer-Buchtela, 1999).

Deglycyrrhized Licorice (DGL) Preparations

DGL native dry extract BP [0.5–2.0% total flavonoids, calculated as liquiritigenin]: 0.4–1.6 g, 3 times daily (BP, 1986; Bradley, 1992).

DGL chewable tablets [380 mg DGL 4:1]: For acute cases of gastric or duodenal ulcers; 2–4 tablets chewed before each meal. For chronic cases, 1–2 tablets chewed before each meal (Pizzorno and Murray, 1999).

Standardized Preparations

Fluid extract DAB [2.0–4.0% glycyrrhizin, 52–65% ethanol (v/v)]: 5–15 ml daily, (or 2–5 ml, 3 times daily) corresponding to Commission E dosage of 5–15 g of root daily (Blumenthal et al., 1998).

Fluid extract PPRC  [minimum 7.0% glycyrrhizin, 20–25% ethanol (v/v)]: 2–5 ml, 3 times daily (PPRC, 1992).

Native dry extract [4–5:1 (w/w), minimum 20% glycyrrhizin]: 0.33–0.8 g, after meals 3 times daily.

Duration of Administration

No longer than four to six weeks internally without medical advice. There is no objection to using licorice root as a flavoring agent up to a maximum daily dosage equivalent to 100 mg glycyrrhizin (Blumenthal et al., 1998). A diet rich in potassium (e.g., bananas) is recommended during treatment period (Bruneton, 1999).

Chemistry

Licorice root contains triterpenoid saponins, mainly glycyrrhizin (glycyrrhizic acid, glycyrrhizinic acid) (Tang and Eisenbrand, 1992; Ph. Eur. minimum 4%) with the sapogenin glycyrrhetic acid (glycyrrhetin, glycyrrhetinic acid). Glycyrrhetic acid is a triterpene with an oleanan skeleton (Tang and Eisenbrand, 1992). Licorice also contains approximately 1% flavonoids, mainly flavanones (e.g., liquiritin), chalcones (e.g. isoliquiritin), and isoflavonoids (e.g., formononetin); polysaccharides (arabinogalactans); and sterols (b-sitosterol, stigmasterol) (Bradley, 1992; Tang and Eisenbrand, 1992).

Pharmacological Actions

Human

Crude Preparations

Anti-inflammatory; expectorant; demulcent; adrenocorticotropic (Bradley, 1992); reduces serum testosterone in men (Armanini et al., 1999); antioxidant (Fuhrman et al., 1997).

Deglycyrrhized Licorice (DGL) Preparations

Protects LDL against lipid peroxidation (Fuhrman et al., 1997).

Purified Licorice Derivatives

Accelerates the healing of gastric ulcers in controlled clinical
studies of glycyrrhizic acid and the aglycone of glycyrrhizic acid (Blumenthal et al., 1998).

Animal

Secretolytic and expectorant effects in rabbits; antispasmodic action in isolated rabbit ileum has been observed (Blumenthal et al., 1998); antioxidant and oxygen radical-scavenging in rats (Yokozawa et al., 2000); may have cancer chemopreventive effects (Wang et al., 2000); induces liver microsomal cytochrome P450 in mice (Hu et al., 1999); inhibits decline in immune complex (IC) clearance in carrageenan-injected mice (Matsumato et al., 1996); prevents gastric mucosal damage in rats (Goso et al., 1996); protects mitochondrial function against oxidative stresses (Haraguchi et al., 2000); anti-arrhythmic action of total licorice flavonoids (e.g. liquiritigenin and isoliquiritigenin) in mice and guinea pigs (Hu et al., 1999); protects liver (Nose et al., 1994; Shim et al., 2000); inhibits generation of suppressor T-cells in thermally injured mice (Kobayashi et al., 1993). Phytosterols, beta-sitosterol, and stigmasterol are estrogenic in castrated mice (Van Hulle, 1970).

In vitro

Binds estrogen receptors (Zava et al., 1998); antimicrobial (Li et al., 1998; Okada et al., 1989); antioxidant (Okada et al., 1989); decreases arylamine N-acetyltransferase (NAT) activity in Helicobacter pylori cultures from peptic ulcer patients (Chung, 1998); anti-tumor necrosis factor (TNF) activity (Yoshikawa et al., 1997).

Mechanism of Action

Glycyrrhizin is metabolized to its aglycone 18-b-glycyrrhetinic acid in the intestine by human intestinal bacteria, which is then absorbed into the blood

Protects liver through 18-b-glycyrrhetinic acid and glycyrrhizin (Shim et al., 2000)

Relieves gastric inflammation, possibly by inhibiting prostaglandin synthesis and lipoxygenase (Inoue et al., 1986; Tamura et al., 1979)

Antigastric ulcer activity is due to the FM 100 fraction (licorione), which lowers gastric acidity, reduces pepsin activity, and inhibits gastric secretion (Huang, 1999)

Inhibits human 11-b-hydroxysteroid dehydrogenase, the enzyme that catalyzes the conversion of cortisol to cortisone, and bacterial 3-alpha, 20-beta-hydroxysteroid dehydrogenase (Duax et al., 2000)

Inhibits 11-b-hydroxysteroid dehydrogenase, which minimizes the binding of cortisol to mineralocorticoid receptors, creating a mineralocorticoid-like effect (Farese et al., 1991)

Inhibits peripheral metabolism of corticol, which binds to mineralocorticoid receptors in the same way as aldosterone (Heikens et al., 1995)

May also inhibit both 17-b-hydroxysteroid dehydrogenase and 17,20-lyase, which catalyzes conversion of 17-hydroxy-progesterone to androstenedione (Armanini et al., 1999)

Modulates the cell-mediated immune system, which may be due to glycyrrhizin stimulating the induction of contrasuppressor cells (Kobayashi et al., 1993)

Demulcent and expectorant actions due to stimulating tracheal mucous secretion (Hikino, 1985)

Antioxidant action may be related to absorption and binding of licorice’s flavonoids (e.g., glabridin) to the LDL particle, thereby protecting the LDL from oxidation (Fuhrman et al., 1997)

Contraindications

The German Commission E states that licorice is contraindicated in cholestatic liver disorders, liver cirrhosis, hypertension, hypokalemia, and severe kidney insufficiency (Blumenthal et al., 1998). Licorice is also contraindicated in diabetes by the Belgian Pharmaceutical Association (Van Hellemont, 1986), although this was not confirmed in a subsequent monograph by the World Health Organization (WHO, 1999).

Pregnancy and Lactation: Not recommended during pregnancy (Braun et al., 1997; McGuffin et al., 1997; WHO, 1999). The effect of glycyrrhizin was studied on 1,049 Finnish women and their infants. Heavy exposure to glycyrrhizin (<500 mg/wk) did not affect birth weight, but did double the risk of birth before 38 weeks (Strandberg et al., 2001). No known restrictions during lactation.

Adverse Effects

No adverse effects have been associated with licorice used within proper dosage and treatment period limits (Schulz et al., 1998; WHO, 1999). With prolonged use (longer than six weeks), and higher doses (greater than 50 g/day), sodium and water retention and a loss of potassium may occur, accompanied by hypertension, edema, hypokalemia, and in rare cases, myoglobinuria (Blumenthal et al., 1998; WHO, 1999). With short-term treatment for cough, these mineralocorticoid effects did not develop (Schilcher, 1997). Within several weeks of discontinuing use, any symptoms of hyperaldosteronism should disappear (Mantero, 1981). Side effects are less likely with aqueous licorice root extract than with isolated glycyrrhizin, due to lower intestinal absorption when consumed as a component of the total extract (Cantelli-Forti et al., 1994). There has been one case report of pulmonary edema following an acute overdose (approximately 1,020 g, containing ~3.6 g glycorrhizic acid in three days) of Hershey Twizzlers^® black licorice-flavored candy (Chamberlain and Abolnik, 1997). There is one case report of life-threatening ventricular tachycardia due to hypokalemia induced by overdose (approximately 40–70g daily for four months) of a licorice candy (Eriksson et al., 1999), though the brand of the candy, and the actual quantity of licorice or licorice derivatives contained in the candy are missing from the report.

Drug Interactions

Licorice may potentiate the side effects of potassium depleting thiazide diuretics (e.g., chlorothiazide, chlorthalidone, hydrochlorothiazide, and metolazone) (Austin et al., 2000; Blumenthal et al., 1998; Shintani et al., 1992). With potassium loss, sensitivity to digitalis glycosides increases (Blumenthal et al., 1998; Van Hellemont, 1986). The 1998 French Explanatory Note warns not to combine with corticoid treatment (Bruneton, 1999). When decocted in combination with toxic herbs such as prepared aconite root (Aconitum carmichaelii Debeaux), a detoxified preparation used in TCM, the yield of anti-arrhythmic licorice flavonoids is significantly higher than when decocted alone. This mitigated the toxic effects (e.g., arrhythmia) induced by aconitine (Hu et al., 1999; Leung, 1999) in mice and guinea pigs.

American Herbal Products Association (AHPA) Safety Rating

Class 2b: Not to be used during pregnancy (McGuffin et al., 1997).

Class 2d: Not for prolonged use or in high doses except under supervision of a qualified health practitioner (McGuffin et al., 1997).

Regulatory Status

Austria: Unpeeled dried root is official in the Austrian Pharmacopoeia (Meyer-Buchtela, 1999; Wichtl, 1997).

Belgium: Traditional Herbal Medicine (THM) permitted for specific indications (Bradley, 1992; WHO, 1998).

Canada: Approved active ingredient in THM products and in Homeopathic products, both requiring pre-marketing authorization with Drug Identification Number (DIN) assigned (Health Canada, 2001). Food if no claim statement is made.

China: Dried root and rhizome, prepared (stir-fried with honey) root and rhizome, alcoholic fluid extract and dry aqueous native extract, containing not less than (NLT) 20.0% glycyrrhetic acid, are official drugs of the Pharmacopoeia of the People’s Republic of China (PPRC, 1997).

European Union: Dried unpeeled or peeled, root and stolons containing NLT 4.0% glycyrrhizic acid and standardized ethanolic fluid extract containing NLT 3.0% and NMT 5.0% glycyrrhizic acid are official in European Pharmacopoeia (Ph.Eur. 2001).

France: THM permitted for specific indications, internal or locally (mouth and throat). Official in French Pharmacopoeia (Bradley, 1992; Bruneton, 1999; WHO, 1998).

Germany: Dried root or dry extract for infusion, decoction, liquid or solid dosage forms, are approved non-prescription drugs in the Commission E monographs (Blumenthal et al., 1998). Licorice root tea is approved as an over-the-counter (OTC) drug in the German Standard License monographs (Braun et al., 1997). Peeled dried root containing NLT 4.0% glycyrrhizic acid, and standardized ethanolic fluid extract containing NLT 5.0% and NMT 7.0% glycyrrhizic acid are official in German Drug Codex supplement to German Pharmacopoeia (DAC, 1990 & 1995). Standardized ethanolic fluid extract containing NLT 2.0% and NMT 4.0% glycyrrhizic acid are official in German Pharmacopoeia (DAB, 1999).

India: Dried unpeeled roots and stolons containing NLT 4.0% glycyrrhizinic acid are official in Indian Pharmacopoeia (IP, 1996). Dried unpeeled stolon and root are official in the Government of India Ayurvedic Pharmacopoeia of India (API, 1989). Prepared mature root (min. 4 years) is an official single-drug and/or component of multiple-ingredient drugs dispensed in Unani system of medicine (CCRUM, 1986 & 1997). A monograph for dried root occurs in the Indian Herbal Pharmacopoeia (IHP I, 1998).

Italy: Listed in the Italian Pharmacopoeia (Newall et al., 1996).

Japan: Traditional Kampo medicine. Dried peeled or unpeeled root and stolon are official in the Japanese Pharmacopoeia (JSHM, 1993).

Russian Federation: Official in the State Pharmacopoeia of the Union of Soviet Socialist Republics, Ph.USSR X (Bradley, 1992; Newall et al., 1996).

Sweden: Classified as foodstuff. As of January 2001, no licorice products are listed in the Medical Products Agency (MPA) “Authorised Natural Remedies” (MPA, 2001).

Switzerland: Official in Swiss Pharmacopoeia, Ph.Helv.VII (Bradley, 1992; WHO, 1998; Wichtl, 1997). Licorice is an approved component of multi-ingredient phytomedicines listed in the Swiss Codex 2001/02 available in juice, syrup, tea infusion, and tincture dosage forms (Ruppanner and Schaefer, 2000) with positive classification (List D) by Interkantonale Konstrollstelle für Heilmittel (IKS) and corresponding sales Category D with sale limited to pharmacies and drugstores, without prescription (Morant and Ruppaner, 2001).

U.K.: Herbal medicine on the General Sale List, Schedule 1 (requires full Product License), Table A (internal or external use) (GSL, 1994). Dried unpeeled roots and stolons containing NLT 4.0% glycyrrhizinic acid, ethanolic fluid extract, and DGL dry aqueous extract containing 0.5~2.0% total flavonoids, calculated as liquiritigenin, are official in the British Pharmacopoeia (BP, 1986).

U.S.: Dietary supplement or food depending on label claim statement (USC, 1994). Licorice root and derivatives are affirmed as Generally Recognized as Safe (GRAS) for use as a flavoring agent or flavor enhancer in vitamin or mineral dietary supplements, herb and seasoning products and nonalcoholic beverages, including tea (US FDA, 1998). Dried roots, rhizome and stolons, powdered root, and powdered dry extract are subjects of botanical monographs in development for the US National Formulary. Previews of the standards development were published in Pharmacopeial Forum (USP, 2002).

Clinical Review

Ten studies are outlined in the following table, “Clinical Studies on Licorice,” including a total of 2,544 participants. Eight studies including a total of 1,505 participants. All but one of these studies (Armanini et al., 1999) demonstrated positive effects for indications such as treatment of various types of ulcers, chemoprevention, and use as an antioxidant. Three studies were conducted on licorice root extract (Armanini et al., 1999; Armanini et al., 1996; Palagina et al., 1999), four studies were on DGL extract (Fuhrman et al., 1997; Das et al., 1989; Kassir, 1985; Morgan et al., 1985), and two studies were conducted on isolated glycyrrhizin preparations (Arase et al., 1997; Acharya et al., 1993). These include an open (O) study on the effects of licorice root tablets on gonadal function (Armanini et al., 1999), a comparison (Cm) study on pulmonary metabolism during radiotherapy (Palagina et al., 1999), an O study on pseudohyperaldosteronism (Armanini et al., 1996), a placebo-controlled (PC) study on LDL cholesterol (Fuhrman et al., 1997), an O, uncontrolled study on aphthous ulcer (Das et al., 1989), a Cm, randomized (R) study on chronic duodenal ulceration (Kassir, 1985), and a single-blind, controlled, R study on benign gastric ulcers (Morgan et al., 1985). Isolated glycyrrhizin has been investigated as a chemopreventive in one retrospective Cm (Arase et al., 1997) and one O study on the treatment of subacute hepatic failure (Acharya et al., 1993). One study on birth outcome found that licorice did not affect birth weight but did double the risk of birth before 38 weeks (Strandberg et al., 2001).

Branded Products

Caved-S^®: Tillots Pharma AG / Hauptstrasse 27 / CH–4417 Zeifen / Switzerland / Tel: +41-61-935-2626 / Fax: +41-61-935-2625. Each tablet contains 380 mg deglycerized licorice extract. This product is no longer available.

Saila Licorice Root Tablets: Saila S.p.A. / 83 Viale Garibladi / Silvi Marina, Teramo / Italy. One tablet contains 500 mg glycyrrhizin.

Stronger Neo Minophagen-C (SNMC); Minophagen Pharmaceutical Co. / No. 3 Tomizawa Bldg. / 2-7, Yotsuya 3-chome / Shinjuku, Tokyo 160 / Japan / Tel: +81-3-3355-6561 / Fax: +81-3-3355-6565. Standardized to contain 0.2% glycyrrhizin, 0.1% cysteine, and 2.0% glycine in physiologic saline, intravenous. This product is no longer available.

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