Real licorice can cause hypertension, hypokalemia, arrhythmias, edema, and preterm birth.

[LFODPKM ] Letter Key

Latin Name

Glycyrrhiza glabra L.

Family

Leguminosae/Fabaceae

Other Common Names

Sweet root

Description

• Licorice, a perennial herb with sweet-tasting roots, is native to the Mediterranean, the Mideast, Russia, and Asia. It is widely used as a flavoring, sweetener, and medicinal herb.

Part Used

Roots, rhizomes

Known Active Constituents

• Triterpenoid saponins, especially glycyrrhizin [also called glycyrrhizic or glycyrrhizinic acid (GL)], which is 50 times sweeter than sugar, and hydroxyglycyrrhizin. Glycyrrhizin concentration varies from 1% to 24% (usually 6% to 14%) (1). Also numerous flavonoids including liquiritin, isoliquiritin, and liquiritoside (2) and coumarin derivatives.

Mechanism/Pharmacokinetics

• GL is hydrolyzed to glycyrrhetinic acid (GA) in the intestine, apparently by intestinal bacteria. Licorice inhibits 11-hydroxysteroid dehydrogenase, which converts cortisol to cortisone. Cortisol has the same binding affinity as aldosterone (cortisone has a lower binding affinity), so inhibition of 11-hydroxysteroid dehydrogenase produces high renal levels of cortisol, leading to apparent mineralocorticoid excess (3).
• Peak serum concentration of GL occurs in less than 4 hours, then decreases rapidly. None is detectable at 96 hours. GA peaks at 24 hours, decreases gradually, and is still detectable in most people at 72 hours (1).
• Excretion of metabolites is most likely gastrointestinal; 2% of metabolites appear in urine.

[Outline]

• LLatin Name
• FFamily
• OOther Common Names
• DDescription
• PPart Used
• KKnown Active Constituents
• MMechanism/Pharmacokinetics

[CO ] Letter Key

Clinical Trials

• Hepatitis
  • A randomized controlled trial (RCT) in 57 patients with chronic hepatitis C found that glycyrrhizin (80, 160, or 240 mg intravenously three times per week), compared with placebo, significantly decreased serum alanine aminotransferase 26% versus 6%, p < 0.02. The effect was seen in 2 days, was not dose-related, and disappeared after cessation of therapy (4). There was no effect on viral clearance.
• Ulcers/gastrointestinal bleeding
  • A double-blind crossover study of nine volunteers tested 975 mg of aspirin with or without licorice (525 mg t.i.d.); licorice reduced the incidence of human fecal blood loss by 20% (5).
  • Once used conventionally to treat peptic ulcer, licorice was abandoned because of side effects (6). Numerous older studies found licorice effective for ulcers; two studies of deglycyrrhizinated licorice (DGL), which contains no GL and reputedly does not cause hypertension, found DGL equivalent to cimetidine (7,8).
• Endocrine effects
  • Licorice has glucocorticoid effects, an effect once exploited to treat Addison’s disease (9). In 10 volunteers, GA 500 mg/day decreased plasma cortisone (but not cortisol), elevated free cortisol and decreased free cortisone in urine (10). In 11 volunteers, licorice for 10 days increased urinary free cortisol, decreased urinary aldosterone, and decreased plasma renin activity, indicating significant suppression of the renin-angiotensin-aldosterone system (11). This suppression may last for several months (3).
  • A small study of seven men found that licorice (7 g, with 500 mg GL daily × 1 week) significantly decreased serum testosterone and 17-hydroxyprogesterone (12). However, a larger study tested 5 to 6 g licorice for 4 days in 20 men and a different brand of licorice in 21 participants (including 10 women) and found no effect of licorice on salivary testosterone (cortisol did increase) (13).
  • Licorice increases atrial natriuretic peptide levels (6).
  • A case of licorice-related hyperprolactinemia has been reported (14).

Other Claimed Benefits/Actions

• Chronic fatigue syndrome
• Expectorant
• Antitussive
• Antiinflammatory
• Bronchitis
• Gastrointestinal antispasmodic
• Laxative
• Apthous ulcers

[Outline]

• CClinical Trials
  • Hepatitis
  • Ulcers/gastrointestinal bleeding
  • Endocrine effects
• OOther Claimed Benefits/Actions

[AD ] Letter Key

Adverse Reactions

• Licorice toxicity causes pseudoprimary aldosteronism; symptoms may include edema, hypertension, and hypokalemia (15,16).
• Arrhythmias
  • Cardiac arrhythmias have been associated with licorice ingestion. A 44-year-old woman who had ingested 40 to 70 g licorice daily for 4 months developed repeated episodes of life-threatening torsades de pointes (17). Cardiac arrest, including two deaths, has been associated with licorice use.
• Hypertension (see questions and answers)
  • Excessive use of licorice can cause hypertension. Hypertension encephalopathy was reported in a 15-year-old 3 hours after eating 0.5 kg licorice (18); ingestion of 1 kg licorice by a 25-year-old woman with myeloid leukemia caused decerebrate rigidity, tetraparesis, and coma (19).
  • Ingestion of 100 g licorice daily × 4 weeks in 30 normotensive participants significantly increased systolic (6.5 mm Hg) but not diastolic blood pressure and decreased serum potassium 0.24 mmol/L. Effects were still apparent 4 weeks after discontinuing licorice (20). Women may be more susceptible; blood pressures were slightly higher for women than men, and 14/19 women gained weight (mean 0.59 kg; one women gained 6.8 kg), although men did not gain weight. In 13 different women given 50 g licorice, systolic blood pressure rose 5.6 mm Hg and diastolic blood pressure rose 3.4 mm Hg.
• Hypokalemia
  • Fifty-nine cases of licorice-associated hypokalemic myopathy have been reported; most patients had additional risk factors for hypokalemia, including alcoholism, diarrhea, or diuretic use (21).
  • Severe hypokalemia has caused several cases of rhabdomyolysis, including a 62-year-old man on diuretics who developed weakness and pain during Ramadan (during which observers fast during the day and often consume a licorice-containing soft drink during the evening meal). Apparently the fasting, diuretic use, and licorice consumption proved synergistic for hypokalemia (22).
  • Rhabdomyolysis and subsequent acute renal failure was reported in a 72-year-old man who had consumed 240 mg GL as an antacid for many years (23). After normalization of serum potassium, rechallenge with 40 mg GL administered intravenously daily caused moderate hypokalemia (2.3 mEq/L).
• Pulmonary edema/congestive heart failure
  • Pulmonary edema was reported in a 64-year-old healthy man who ate four packages (1,020 g) of Twizzlers (one of the few American "licorice" brands that contains real licorice) over 3 days; total GL consumed was approximately 3.6 g (9).
  • Three previous cases of licorice-associated congestive heart failure were reported (9).
• Preterm birth
  • A survey of 1,049 Finnish women who gave birth to singleton infants in 1998 examined the effect of licorice on birth outcome (24). Almost half of mothers surveyed (46%) reported weekly licorice consumption, and only 2.3% of respondents never consumed licorice during pregnancy. Compared with babies exposed to the lowest levels of maternal licorice (less than 250 mg GL/week), babies exposed to the highest levels (>=500 mg GL/week) were significantly more likely to be born before 38 weeks gestation [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.1, 5.5, p = 0.03]. Adjustments were made for sex, maternal age, parity, smoking, coffee consumption, and systolic blood pressure. Heavy licorice consumption shortened gestation by a mean of 2.52 days. Possible mechanisms include inhibition of cortisol metabolism (cortisol stimulates corticotropin-releasing hormone from the placenta and is thought to be a parturition trigger) or possibly increased uterine prostaglandin levels through inhibition of 15--hydroxyprostaglandin dehydrogenase (a homologue of 11--hydroxysteroid dehydrogenase).

Drug Interactions

• Corticosteroids
  • Licorice potentiates corticosteroids. Oral administration of GL increases the plasma concentration of prednisolone. GA, but not GL, potentiates the effect of hydrocortisone in human lung tissue. Topical GA potentiates the action of hydrocortisone (25).
• Oral contraceptives
  • Combined oral contraceptives may increase sensitivity to GL. Hypokalemia and hypertension were reported in two oral contraceptive users who used licorice chewing gum; daily doses of GL were 120 mg and 50 mg (notable because adverse effects usually occur at much higher doses) (26).
• Nitrofurantoin
  • DGL may increase nitrofurantoin bioavailability > 50% (1).
• Thiazide diuretics
  • Concurrent use increases the risk of hypokalemia.
• Laxatives
  • Licorice may potentiate the effect of other laxatives.
• Insulin
  • Glycyrrhizin may act synergistically with insulin in suppressing renin and aldosterone (1).

[Outline]

• AAdverse Reactions
  • Arrhythmias
  • Hypertension
  • Hypokalemia
  • Pulmonary edema/congestive heart failure
  • Preterm birth
• DDrug Interactions
  • Corticosteroids
  • Oral contraceptives
  • Nitrofurantoin
  • Thiazide diuretics
  • Laxatives
  • Insulin

Common Dosage Forms

• Powdered dried root: 1 to 5 g q.d. to t.i.d.
• Infusion or decoction: 1 to 5 g t.i.d. Infusion may be made by pouring boiling water over herb and steeping for 30 minutes or by boiling herb for a few minutes and then letting it steep 15 minutes.
• Liquid extract: 2 to 5 mL t.i.d.
• DGL: 0.4 to 1.6 t.i.d. (for ulcers).

• What is a safe range of licorice ingestion?
• Is licorice toxicity common?
• Is licorice in Chinese medicine dangerous?
• Is licorice a laxative?
• What is licorice used to flavor?

Q: What is a safe range of licorice ingestion?

A: Individuals vary in susceptibility to licorice; 100 mg GL daily (about 50 g or 1.75 oz of candy) is enough to produce adverse effects in some people, and most people who consume more than 400 mg GL daily will experience symptoms (3). Some individuals, however, are hypersensitive to glycyrrhizin; doses as low as 20 mg/day GL have produced severe hypokalemia (23).

• A safety study in 39 healthy women tested oral GL (1, 2, and 4 mg/kg body weight) for 8 weeks (27). The authors proposed a no-effect level of 2 mg/kg and extrapolated an acceptable daily intake (ADI) of 0.2 mg/kg body weight. If licorice contains 0.2% of GL, a 60-kg person should ingest no more than 6 g licorice (containing 12 mg GL) a day.

Q: Is licorice toxicity common?

A: Although the prevalence of licorice toxicity is unknown, it is not common; many people consume licorice without ill effects. In Denmark, average licorice consumption is 2 kg per person per year, and no epidemics of licorice toxicity have been reported. One study of Danish schoolchildren (6 to 18 years old) found no linear relationship between licorice consumption and blood pressure (28). No common characteristics of susceptible individuals have been identified (although women seem more susceptible than men).

Q: Is licorice in Chinese medicine dangerous?

A: Almost all reported cases of licoriceinduced problems have been from licorice-containing liqueurs, candies, gum, laxatives, or chewing tobacco rather than from the use of licorice as medicine. In Chinese medicine licorice is always used as part of a mixture, and the synergistic effects of mixtures, as well as perhaps dose differences, may prevent problems.

Q: Is licorice a laxative?

A: Yes. Glycyrrhizin is a surfactant, increasing the wettability of bowel contents. It is often combined with anthraquinone-containing herbs (29).

Q: What is licorice used to flavor?

A: Licorice is commonly used to flavor and sweeten herbal teas. It may be added to chewing gum, cigarettes, snuff, chewing tobacco, beer, porter, stout, or root beer. Most "licorice" candies manufactured in the United States are actually flavored with anise; imported candies usually contain real licorice.

1. Chandler RF. Glycyrrhiza glabra. In: De Smet PAGM, Keller K, Hansel R et al, eds. Adverse effects of herbal drugs. Berlin: Springer-Verlag, 1997:67–88.
2. Robbers JE, Speedie MK, Tyler VE. Pharmacognosy and pharmacobiotechnology. Baltimore: Williams & Wilkins, 1996.
3. Størmer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquorice—evaluation of health hazard. Food Chem Toxicol 1993;31:303–312.
4. van Rossum TGJ, Vulto AG, Hop WCJ et al. Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebo-controlled phase I/II trial. J Gastroenterol Hepatol 1999;14:1093–1099.
5. Rees WDW, Rhodes J, Wright JE et al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol 1979;14:605.
6. Schambelan M. Licorice ingestion and blood pressure regulating hormones. Steroids 1994;59:127–130.
7. Kassir ZA. Endoscopic controlled trial of four drug regimens in the treatment of chronic duodenal ulcers. Ir Med J 1985;78:153–156.
8. Morgan AG, McAdam WAF, Pacsoo C et al. Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982;23:545–551.
9. Chamberlain JJ, Abolnik IZ. Pulmonary edema following a licorice binge. West J Med 1997;167:184–185.
10. MacKenzie MA, Hoefnagels WHL, Jansen RWMM et al. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers. J Clin Endocrinol Metab 1990;70:1637–1643.
11. Stewart PM, Wallace A, Valentino R et al. Mineralocorticoid activity of liquorice: 11-beta hydroxysteroid dehydrogenase deficiency comes of age. Lancet 1987;2:821–824.
12. Armanini D, Bonanni G, Palermo M. Reduction of serum testosterone in men by licorice. N Engl J Med 1999;341:1158.
13. Josephs RA, Guinn JS, Harper ML. Liquorice consumption and salivary testosterone concentrations. Lancet 2001;358:1613–1614.
14. Werner S, Brismar K, Olsson S. Hyperprolactinaemia and licorice. Lancet 1979;1:319.
15. Farese RV, Biglieri EG, Shackleton CHL et al. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991;325:1223–1227.
16. Epstein MT, Espiner EA, Donald RA et al. Effect of eating liquorice on the renin-angiotensin aldosterone axis in normal subjects. BMJ 1977;1:488–490.
17. Eriksson JW, Carlberg B, Hillörn V. Life-threatening ventricular tachycardia due to liquorice-induced hypokalaemia. J Int Med 1999;245:307–310.
18. Van der Zwan A. Hypertension encephalopathy after liquorice ingestion. Clin Neurol Neurosurg 1993;95:35–37.
19. Hupperets P, de Pauw BE, Holdrinet RSG et al. Reversible coma due to hypokalaemia in a patient treated for acute leukaemia. Neth J Med 1983;26:21–22.
20. Sigurjonsdottir HA, Ragnarsson J, Franzson L et al. Is blood pressure commonly raised by moderate consumption of liquorice? J Hum Hypertens 1995;9:345–348.
21. Shintani S, Murase H, Tsukagoshi H et al. Glycyrrhizin (licorice)-induced hypokalemic myopathy. Eur Neurol 1992;32:44–51.
22. Achar KN, Abduo TJ, Menon NK. Severe hypokalemic rhabdomyolysis due to ingestion of liquorice during Ramadan. Aust N Z J Med 1989;19:365–367.
23. Chubachi A, Wakui H, Asakura K et al. Acute renal failure following hypokalemic rhabdomyolysis due to chronic glycyrrhizic acid administration. Int Med 1992;31:708–711.
24. Strandberg TE, Järvenpää A-L, Vanhanen H et al. Birth outcome in relation to licorice consumption during pregnancy. Am J Epidemiol 2001;153:1085–1088.
25. Teelucksingh S, Mackie ADR, Burt D et al. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990;335:1060–1063.
26. De Klerk GJ, Nieuwenhuis G, Beutler JJ. Hypokalaemia and hypertension associated with use of liquorice flavoured chewing gum. BMJ 1997;314:731–732.
27. Van Gelderen CE, Bijlsma JA, van Dokkum W et al. Glycyrrhizic acid: the assessment of a no effect level. Hum Exp Toxicol 2000;19:434–439.
28. Ibsen KK. Liquorice consumption and its influence on blood pressure in Danish school-children. Dan Med Bull 1981;28:124–126.
29. Bisset NG, Wichtl M. Herbal drugs and phytopharmaceuticals: a handbook for practice on a scientific basis with reference to German Commission E monographs. Boca Raton, FL: CRC Press, 1994.