Glycyrrhiza glabra, or Spanish licorice, grows wild in some areas of Europe and Asia. It is one of several important medicinal plant species belonging to the Glycyrrhiza genus. Numerous pharmacological studies conducted over the past 50 years show that licorice has therapeutic uses but not without adverse side effects.

Glycyrrhizin, one of the active components in licorice root, consists of glycyrrhizic acid in a mixture of potassium and calcium salts. Glycyrrhizin is 50 times sweeter than sugar and gives licorice its characteristic sweet taste. The active ingredient in licorice root is glycyrrhetinic acid, a triterpene glycoside with saponin-like properties formed from the hydrolysis of glycyrrhizin. Both glycyrrhizin and glycyrrhetinic acid are thought to be efficacious in treating peptic ulcers. However, both compounds can also cause mineralocorticoid side effects, including lethargy, headache, sodium and water retention, excess potassium excretion, and elevated blood pressure. Deglycyrrhizinated licorice (DGL) appears to be void of these adverse effects.

Spanish licorice is a perennial that grows three to seven feet in height. It has a root system comprised of taproots, branch rootstock, and runners, or underground woody stems that grow horizontally. The long, cylindrical roots are straight pieces of wrinkled, fibrous wood 14 to 20 m in length and 5 to 20 mm in diameter. The rootstock has a yellowish-brown exterior and yellow interior.

• Roots and stolons

Terpenoids (glycyrrhizic acid [yields glycyrrhetinic acid and glucuronic acid upon hydrolysis], glycyrrhetol, glabrolide, licoric acid, liquiritic acid, beta-amyrin); coumarins (glycyrin, heniarin, liqcoumarin, umbelliferone, GU-7); flavonoids (flavonols, isoflavones); volatile oil; amino acids, amines, sterols, gums, lignin.

Licorice products are made from both peeled and unpeeled dried roots, and the underground roots, stolons, and rhizomes of several varieties of Glycyrrhiza glabra. Commercial preparations consist of powdered root, finely cut roots, and dried and liquid extracts. DGL is usually manufactured as an extract.

Traditional herbal actions: expectorant, demulcent (soothing topical medication), antispasmodic, anti-inflammatory, laxative, adaptogen, antihepatatoxin, antiviral, antitumor, antipyretic, and to normalize immune function.

Clinical applications: allergies, autoimmune disorders (eg. lupus scleroderma), bronchitis, peptic ulcer disease (PUD), chronic gastritis and esophagitis, arthritis, primary adrenocortical insufficiency, asthma, antimicrobial and antiviral.

In vivo, glycyrrhizin has demonstrated antitoxic activity against diphtheria, tetanus, and tetrodotoxin as well as antimicrobial activity against numerous bacteria, fungi, and viruses. The isoflavonoid constituents account for antimicrobial effects in vitro against Staphylococcus aureus, Streptococcus mutans, Mycobacterium smegmatis, and Candida albicans.

Glycyrrhetinic acid significantly reduced tumor promoter activity both in vitro and in vivo, thereby, inhibiting the growth of particular cancer cell lines. Glycyrrhetinic acid also blocked free radical formation helping to curb liver-induced toxicity in animal studies.

Both glycyrrhizin and glycyrrhetinic acid have moderate binding affinity for glucocorticoid and mineralocorticoid receptors, as well as weak affinity for estrogen, sex-hormone-binding globulin, and corticosteroid-binding globulin. Licorice seems to inhibit estrogen metabolism when estrogen levels are high, yet enhances estrogen metabolism when estrogen levels are low. The estrogenic activity of licorice probably comes from isoflavones.

The steroid-like activity of glycyrrhizin and glycyrrhetic acid is responsible for the anti-inflammatory properties of licorice root. Licorice extends the half-life of cortisol by suppressing the metabolism of this hormone in the liver.

In other human research, glycyrrhizin products taken intravenously resolved at least some liver function damage in approximately 40% of hepatitis patients. Both oral and topical licorice preparations have been shown to be effective in treating canker sores, eczema and psoriasis, herpes simplex, premenstrual syndrome, and Addison's Disease. Other studies reveal that the efficacy of DGL in treating gastric ulcers can be comparable to that of cimetidine and ranitidine; DGL has also been used as a successful adjunct with H2 blockers. The pharmacological activity of DGL is thought to be due to flavonoids.

Licorice achieves its anti-ulcer effect by accelerating the secretion rate of mucus by the gastric mucosa. Glycyrrhetic acid helps maintain high levels of prostaglandin in the stomach by blocking the activity of two crucial enzymes involved in the metabolism of prostaglandins E and F2-alpha. This is a key mechanism since elevated prostaglandin levels in the stomach protect the gastric mucosa.

Recommended dosage:

• Dried root: 1 to 5 g as infusion or decoction tid 
• Licorice tincture (1:5): 2 to 5 ml tid 
• DGL extract: 0.4 to 1.6 g tid for peptic ulcer 
• DGL extract (4:1): in chewable tablet form 300 to 400 mg 20 minutes before meals for peptic ulcer 

Oral intake of more than 20 g/day of licorice can cause adverse effects. Excessive consumption of glycyrrhizin causes pseudoaldosteronism, which produces the mineralocorticoid symptoms of headache, lethargy, hypertension, sodium and water retention, elevated potassium secretion, and sometimes even cardiac arrest. Symptoms usually manifest within one week if the daily ingestion of licorice is over 100 g. The adverse effects of licorice resemble symptoms associated with injections of deoxycorticosterone (ACTH) given in large doses. Again, DGL is virtually free of adverse mineralocorticoid side effects.

Death occurs only rarely from ingesting licorice, but side effects such as lethargy and muscular weakness may occur with excess consumption. Muscle pain occurs about one third of the time, and numbness in the extremities is seen about one fourth of the time with moderate intake. Other side effects include weight gain and, on rare occasions, myoglobinuria.

Persons who consume large quantities of licorice, chew tobacco, or use other licorice-flavored products are at risk for licorice toxicity. Adverse reactions to ingesting licorice products have been reported for individuals who have hypertension, kidney or heart disorders, hypokalemia, cirrhosis of the liver or cholestatic liver diseases, and hypertonia. Licorice is also contraindicated for pregnant women. High doses of licorice products should not be used for longer than four to six weeks.

ACE inhibitors enhance the dehydrogenase activity of 11b-hydroxysteroiddehydrogenase (11b-HSD), which is thought to contribute to their ability to cause sodium excretion by the kidneys (Kerstens and Dullaart 1999). Licorice reduces the action of 11b-HSD; in so doing, licorice may oppose some of the antihypertensive effects of ACE inhibitors.

Deglycyrrhizinated licorice (DGL) (100 mg, 300 mg, or 500 mg) administered with aspirin (60 mg po) reduced ulcer formation and blood loss in rats (Rees et al. 1979). The effects of licorice on aspirin-induced gastric mucosal injury also were evaluated in a double-blind cross-over study with nine healthy male volunteers. Less blood loss was associated with aspirin ingestion (325 mg tid) when administered concurrently with DGL (175 mg). It has also been shown that licorice-coated aspirin significantly reduced the number and size of ulcers in the gastric mucosa of animals compared to aspirin alone (Dehpour et al. 1994).

In rats, low doses of cimetidine taken with DGL (50 mg) provided greater protection against aspirin-induced gastric mucosal damage than either deglycyrrhizinated licorice or cimetidine alone (Bennett et al. 1980).

Licorice not only induces high blood pressure in some patients but also causes clinically significant hypokalemia, resulting in myopathy and arrhythmia (Sailler et al. 1993; Shintani et al. 1992). Patients with hypokalemia may be predisposed to development of digoxin toxicity due to sensitization of the myocardium to digoxin in the setting of low serum potassium (Physicians' Desk Reference 1999). Although licorice-induced hypokalemia and its subsequent effects on digoxin are not well documented, the known effect described raise a theoretical concern.

A study conducted with volunteers and patients with psoriasis and eczema demonstrated that application of glycyrrhetinic acid enhanced vasoconstriction and glucocorticoid activity in skin by local inhibition of 11b-HSD (Teelucksingh et al. 1990). This report also noted that in vitro studies in nude mice confirmed the inhibition of this enzyme in skin. The report also suggested that topical application of glycyrrhetinic acid significantly enhanced the anti-inflammatory activity of topical hydrocortisone compared to hydrocortisone alone.

Systemic administration of glycyrrhizin with prednisolone to humans was shown to alter the pharmacokinetic parameters of prednisolone by significantly increasing the concentrations of both total and free prednisolone in plasma (Chen et al. 1990; Chen et al. 1991). These results suggest that ingestion of licorice could interact with corticosteroid treatment. Similarly, in early animal studies of rats and rabbits, glycyrrhizin exhibited an ability to enhance the immunosuppressive effects of cortisone (Kumagai et al. 1967).

When licorice-containing substances were combined with diuretics, patients were at increased risk of developing glycyrrhizin-induced hypokalemic myopathy (GIHM) (Shintani et al. 1992). In 96.6% of the cases studied, GIHM resolved completely by supplementing with potassium and discontinuing the glycyrrhizin.

Ingestion of licorice (200 g/day) for 10 weeks concurrent with a thiazide diuretic for two weeks resulted in the development of severe hypokalemia, arterial hypertension, edema, and rhabdomyolysis in a 38-year-old man (Folkersen et al. 1996). A hypertensive 70-year-old man who ingested licorice candy (100 g/day) for 4 to 5 years became pathologically hypokalemic when treated with thiazide diuretics (Farese et al. 1990). (Note: these doses greatly exceed the amounts of licorice recommended to avoid side effects and toxicity; see sections entitled "Dosage Ranges and Duration of Administration" and "Side Effects/Toxicology.")

A healthy female volunteer taking oral contraceptives developed hypertension, hypokalemia, and peripheral edema after four weeks of ingestion of dried, aqueous extract of licorice root at doses up to 814 mg (Bernardi et al. 1994). There are two other case reports cited in the literature involving women who also developed hypokalemia and hypertension when they used licorice chewing gum while on oral contraceptives (de Klerk et al. 1997). Symptoms resolved upon discontinuation of the licorice chewing gum.

The U.S. FDA classifies licorice root as a dietary supplement. The German Commission E approves the herb for use in catarrhs of the upper respiratory tract and for gastric/duodenal ulcers.

Acharya SK, Dasarathy S, Tandon A, Joshi YK, Tandon BN. A preliminary open trial on interferon stimulator (SNMC) derived from Glycyrrhiza glabra in the treatment of subacute hepatic failure. Indian J Med Res. 1993;98:69-74.

Arase Y, et al. The long term efficacy of glycyrrhizin in chronic hepatitis C. Cancer. 1997;79:1494-1500.

Bannister B, Ginsberg R, Scneerson J. Cardiac arrest due to liquorice-induced hypokalemia. BMJ. 1977;17:738-739.

Bennett A, Clark-Wibberley T, Stamford IF, Wright JE. Aspirin-induced gastric mucosal damage in rats: cimetidine and deglycyrrhizinated liquorice together give greater protection than low doses of either drug alone. J Pharm Pharmacol. 1980;32(2):150.

Bernardi M, D'Intino PE, Trevisani F, et al. Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. Life Sci. 1994;55(11):863-872.

Blumenthal M, ed. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, Mass: Integrative Medicine Communications; 1998:161-162.

Bradley P, ed. British Herbal Compendium. Vol. 1. Dorset, England: British Herbal Medicine Association; 1992:145-148.

Chen MF, Shimada F, Kato H, Yano S, Kanaoka M. Effect of glycyrrhizin on the pharmacokinetics of prednisolone following low dosage of prednisolone hemisuccinate. Endocrinol Jpn. 1990;37(3):331-341.

Chen MF, Shimada F, Kato H, Yano S, Kanaoka M. Effect of oral glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn. 1991;38(2):167-174.

de Klerk GJ, Nieuwenhuis C, Beutler JJ. Hypokalemia and hypertension associated with use of liquorice flavoured chewing gum. BMJ. 1997;314:731-732.

De Smet PAGM, Keller K, Hänsel R, Chandler RF, eds. Adverse Effects of Herbal Drugs. Berlin: Springer-Verlag; 1997:67-87.

Dehpour AR, Zolfaghari ME, Samadian T. The protective effect of liquorice components and their derivatives against gastric ulcer induced by aspirin in rats. J PharmPharmacol. 1994;46(2):148-149.

Farese RV, Biglieri EG, Shakelton CHL, et al. Licorice-induced hypermineralcorticoidism. N Engl J Med. 1990;325(17):1223-1227.

Folkersen L, Knudsen NA, Teglbjaerg PS. [Licorice. A basis for precautions one more time!]. Ugeskr Laeger. 1996;158(51):7420-7421.

Gruenwald J, Brendler T, Jaenicke C, et al., eds. PDR for Herbal Medicines. Montvale, NJ: Medical Economics Co.; 1998:875-879.

Hattori T, et al. Preliminary evidence for inhibitory effect of glycyrrhizin on HIV replication in patients with aids. Antiviral Res. 1989;II:255-262.

Heinerman J. Heinerman's Encyclopedia of Fruits, Vegetables and Herbs. Englewood Cliffs, NJ: Prentice Hall; 1988.

Kerstens MN, Dullaart R. 11 Beta-hydroxysteroid dehydrogenase: characteristics and the clinical significance of a key enzyme in cortisol metabolism [in Dutch]. Ned Tijdschr Geneeskd. 1999;143(10):509-514.

Kinghorn A, Balandrin M, eds. Human Medicinal Agents from Plants. Washington DC: American Chemical Society; 1993; chap 3.

Kumagai A, Nanaboshi M, Asanuma Y, Yagura T, Nishino K, Yamamura Y. Effects of glycyrrhizin on thymolytic and immunosuppressive action of cortisone. Endocrinol Jpn. 1967;14(1):39-42.

Mori K, et al. Effects of glycyrrhizin (SNMC: stronger neo-minophagen C) in hemophilia patients with HIV-I infection. Tohoku J Exp Med. 1990;162:183-193.

Murray MT. The Healing Power of Herbs: The Enlightened Person's Guide to the Wonders of Medicinal Plants. 2nd ed. Rocklin, Calif: Prima Publishing; 1998:228-239.

Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health-care Professionals. London: Pharmaceutical Press; 1996:183-186.

Ohuchi K, et al. Glycyrrhizin inhibits prostaglandin E2 formation by activated peritoneal macrophages from rats. Prostagland Med. 1981;7:457-463.

Physicians' Desk Reference. 53rd ed. Montvale, NJ: Medical Economics Company, Inc.; 1999.

Rees WD, Rhodes J, Wright JE, Stamford LF, Bennett A. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol. 1979;14:605-607.

Sailler L, Juchet H, Ollier S, Nicodeme R, Arlet P. Potassium loss may increase effects, especially of digitalis and related glycosides. [Generalized edema caused by licorice: a new syndrome. Apropos of 3 cases.] Rev Med Interne. 1993;14(10):984.

Shintani S, Murase H, Tsukagoshi H, Shiigai T. Glycyrrhizin (licorice)-induced hypokalemic myopathy. Eur Neuro. 1992;32:44-51.

Snow JM. Glycyrrhiza glabra L. (Leguminaceae). Protocol J Botan Med. 1996;1:9-14.

Teelucksingh S, Mackie ADR, Burt D, McIntyre MA, Brett L, Edwards CR. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet. 1990;335:1060-1063.

Turpie A, Runcie J, Thomson T. Clinical trial of deglycyrrhizinated liquorice in gastric ulcer. Gut. 1969;10:299-303.

Tyler VE. Herbs of Choice: The Therapeutic Use of Phytomedicinals. Binghamton, NY: Pharmaceutical Products Press; 1994:197-199.