Health Care Professional Information

Scientific Name
Glycyrrhiza glabra, Glycyrrhiza uralensis
Common Name

Gan cao, sweet root, glycyrrhiza, liquorice

Clinical Summary

Licorice, derived from the root of the plant, has been used as a flavoring and sweetening agent. This herb is also an important component of traditional Chinese medicine used to detoxify and to enhance or balance the effects of other components in herbal formulas; and as a tonic, expectorant and a demulcent in Ayurveda. A number of compounds including glycyrrhizin are thought to account for its biologic activity.
In vitro and animal data show that licorice has antibacterial (2) (27), antiviral (48), anticancer (3) (4) (28) (29), anti-inflammatory (30), and hepatoprotective (49) properties.
Licorice also demonstrated estrogenic effects (7) (8) (10), reduced cardiotoxicity associated with doxorubicin (31) and improved the antitumor effects of cyclophosphamide (32). However, these effects have not been confirmed in humans.

Licorice demonstrated effectiveness in reducing dyspepsia (1) and hyperlipidemia (33) in clinical studies.

Purported Uses
  • Bronchitis
  • Chest congestion
  • Constipation
  • GI disorders
  • Hepatitis
  • Inflammation
  • Menopausal symptoms
  • Microbial infection
  • Peptic ulcers
  • Primary adrenocortical insufficiency
  • Prostate cancer
Constituents
  • Triterpenoid Saponins: Glycyrrhizin
  • Flavonoids: Liquiritin, chalcones, glabridin, isoliquiritigenin
  • Isoflavone: Formononetin
  • Polysaccharides Sterols: B-sitosterol
    (4) (10) (11) (14)
Mechanism of Action

Glycyrrhizin has been reported to bind to glucocorticoid and mineralocorticoid receptors and exerts its effect via inhibition of 11b-hydroxysteroid dehydrogenase (12). Licorice can reduce serum testosterone by inhibiting 17-hydroxysteriod dehydrogenase (35) (36). Licorice contains isoflavones and other constituents that have estrogen receptor modulating activities (8) (10). The flavone and liquiritigenin components selectively activate ER-alpha (11).
Licorice demonstrated chemopreventive effects by modulating expression of the Bcl-2/Bax proteins, which act as apoptotic regulatory factors (3) and via inhibiting carcinogenesis (4).
In another study, licorice inhibited P-glycoprotein (P-gp), resulting in increased intracellular concentration of the chemo agent daunorubicin, which is a substrate of P-gp (34).
The most common side effect of licorice is hypokalemic hypertension, which occurs secondary to inhibition of 11beta-hydroxysteroid dehydrogenase, a renal enzyme, responsible for converting cortisol to cortisone. This inhibition results in enhancing the mineralocorticoid effects of cortisol (36) that include sodium retention and excretion of potassium.

Pharmacokinetics

Administration of licorice after meals delays the time (Tmax) to peak concentration, but does not affect maximum concentration (Cmax) or area-under-the-curve (AUC) (13). Elimination half-life is approximately 5 hours following intravenous administration (14). Primary route of excretion is via bile (15).

Warnings

Due to the adverse reaction profile of licorice, many studies have been performed using the deglycyrrhizinated licorice (DGL) extract that is free of glycyrrhizin.

Adverse Reactions

Reported: Hypertension (16) (45), lethargy, muscle pain, sodium retention, hypokalemia (17) (18) (19) (20) (26) (40) (41), adrenal crisis (21), ventricular fibrillation (22), cardiac arrythmias (23), carpal tunnel syndrome (24), glycyrrhizic acid poisoning (25), leukoderma (42) and thrombocytopenia (43) have been reported following use of licorice.

Herb-Drug Interactions

Cardiac glycosides: Licorice may potentiate toxicity (24).
Insulin: Licorice may have a synergistic effect possibly causing hypokalemia and sodium retention with concomitant use (38) .
Anticoagulants: Licorice may increase the metabolism and clearance of warfarin (19).
MAO-inhibitors (MAO-I): Licorice may potentiate activity of MAO-Is (37) (8)
P-Glycoprotein (P-gp) substrates: Licorice inhibited P-gp, resulting in increased intracellular concentration of the chemo agent daunorubicin, which is a substrate of P-gp (34).
Cytochrome P450 substrates: Glycyrrhizin, a major ingredient of licorice, induces CYP3A (39) and CYP2D6 (44), and can affect the intracellular concentration of drugs metabolized by this enzyme.
Cyclosporine: Licorice greatly reduced the oral bioavailability of cyclosporine by activating P-gp and CYP3A4 (46).
Cortisol acetate:Licorice increased cortisol availability in tissues in the hours following oral Cortisone acetate administration (47).

Literature Summary and Critique

Madisch A, et al. Treatment of Functional Dyspepsia with a Herbal Preparation. A Double- Blind, Randomized, Placebo-Controlled, Multicenter Trial. Digestion 2004;69:45-52.
This study was aimed at determining the efficacy and safety of STW 5-II, an herbal preparation which contains icorice root as one of the major ingredients as well as matricaria flower, peppermint leaves, caraway, lemon balm, and bitter candy tuft. One hundred and twenty patients with functional dyspepsia were randomly assigned to 4 treatment groups and treated over a 12-week period. Patients received either STW 5-II or placebo for 8 weeks. Treatment during the last 4-week period was determined based on symptom relief in patients. The primary outcome measure was the standardized gastrointestinal symptom score (GIS). There was a significant decrease in GIS in patients treated with STW 5-II compared to those on placebo during the first 4 weeks. Symptoms improved further in patients who continued treatment during the second 4 weeks. After 8 weeks, 43.3% patients on active treatment and 3.3% patients on placebo reported total symptom relief. The authors suggest that STW 5-II significantly improves symptoms of dyspepsia as compared to a placebo. However, since STW 5-II contains other herbs, the extent to which licorice contributes to relieving dyspeptic symptoms is not clear from this study.

Dosage (Inside MSKCC Only)
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References
  1. Madisch A, Holtmann G, Mayr G, et al. Treatment of functional dyspepsia with a herbal preparation. A double-blind, randomized, placebo-controlled, multicenter trial. Digestion. 2004;69(1):45-52.
  2. Gupta VK, Fatima A, Faridi U, et al. Antimicrobial potential of Glycyrrhiza glabra roots. J Ethnopharmacol. Mar 5 2008;116(2):377-380.
  3. Jo EH, Hong HD, Ahn NC, et al. Modulations of the Bcl-2/Bax family were involved in the chemopreventive effects of licorice root (Glycyrrhiza uralensis Fisch) in MCF-7 human breast cancer cell. J Agric Food Chem. Mar 24 2004;52(6):1715-1719.
  4. Takahashi T, Takasuka N, Iigo M, et al. Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development. Cancer Sci. May 2004;95(5):448-453.
  5. De Smet PAGM. Adverse Effects of Herbal Drugs. Vol 3. New York: Springer: 1997.
  6. Lin SH, Yang SS, Chau T, et al. An unusual cause of hypokalemic paralysis: chronic licorice ingestion. Am J Med Sci. Mar 2003;325(3):153-156.
  7. Brinker F. Herb Contraindications and Drug Interactions. 2nd ed. Sandy (OR): Eclectic Medical Publications; 1998.
  8. Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health-Care Professionals. 1st ed. London: Pharmaceutical Press; 1996.
  9. Blumenthal M, Goldberg A, Brinckmann J, et al. Herbal Medicine, Expanded Commission E Monographs. Austin: American Botanical Council; 2000.
  10. Somjen D, Knoll E, Vaya J, et al. Estrogen-like activity of licorice root constituents: glabridin and glabrene, in vascular tissues in vitro and in vivo. J Steroid Biochem Mol Biol. Jul 2004;91(3):147-155.
  11. Mersereau JE, Levy N, Staub RE, et al. Liquiritigenin is a plant-derived highly selective estrogen receptor beta agonist. Mol Cell Endocrinol. Feb 13 2008;283(1-2):49-57.
  12. Tyler V. Herbs of Choice, the Therapeutical Use of Phytomedicinals. Binghamton: Pharmaceutical Press; 1994.
  13. Miyamura M, Ono M, Kyotani S, et al. [Properties of glycyrrhizin in Kampo extracts including licorice root and changes in the blood concentration of glycyrrhetic acid after oral administration of Kampo extracts]. Yakugaku Zasshi. Mar 1996;116(3):209-216.
  14. Stormer FC, Reistad R, Alexander J. Glycyrrhizic acid in liquorice—evaluation of health hazard. Food Chem Toxicol. Apr 1993;31(4):303-312.
  15. Ichikawa T, Ishida S, Sakiya Y, et al. Biliary excretion and enterohepatic cycling of glycyrrhizin in rats. J Pharm Sci. Jul 1986;75(7):672-675.
  16. Breidthardt T, Namdar M, Hess B. A hypertensive urgency induced by the continuous intake of a herbal remedy containing liquorice. J Hum Hypertens. 2006 Jun;20(6):465-6.
  17. Yasue H, Itoh T, Mizuno Y, Harada E. Severe hypokalemia, rhabdomyolysis, muscle paralysis, and respiratory impairment in a hypertensive patient taking herbal medicines containing licorice. Intern Med. 2007;46(9):575-8.
  18. Mumoli N, Cei M. Licorice-induced hypokalemia. Int J Cardiol. 2008 Mar 14;124(3):e42-4.
  19. Mu Y, Zhang J, Zhang S, Zhou HH, Toma D, Ren S, et al. Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J Pharmacol Exp Ther. 2006 Mar;316(3):1369-77.
  20. Templin C, Westhoff-Bleck M, Ghadri JR. Hypokalemic paralysis with rhabdomyolysis and arterial hypertension caused by liquorice ingestion. Clin Res Cardiol. 2009 Feb;98(2):130-2.
  21. Isaia GC, Pellissetto C, Ravazzoli M, Tamone C. Acute adrenal crisis and hypercalcemia in a patient assuming high liquorice doses. Minerva Med. 2008 Feb;99(1):91-4.
  22. Gerritsen KG, Meulenbelt J, Spiering W, et al. An unusual cause of ventricular fibrillation. Lancet. 2009 Mar 28;373(9669):1144.
  23. Tacconi P, Paribello A, Cannas A, Marrosu MG. Carpal tunnel syndrome triggered by excessive licorice consumption. J Peripher Nerv Syst. 2009 Mar;14(1):64-5.
  24. Yorgun H, Aksoy H, Sendur MA, et al. Brugada syndrome with aborted sudden cardiac death related to liquorice-induced hypokalemia. Med Princ Pract. 2010;19(6):485-9.
  25. Caubet-Kamar N, Tubery M, Garrouste C, Lauque D, Kamar N. Harmful effect of saline infusion in a patient with glycyrrhizic acid poisoning. CJEM. 2010 May;12(3):224-5.
  26. Støving RK, Lingqvist LE, Bonde RK, Is glycyrrhizin sensitivity increased in anorexia nervosa and should licorice be avoided? Case report and review of the literature. Nutrition. 2010 Aug 24. [Epub ahead of print]
  27. Badr AE, Omar N, Badria FA. A laboratory evaluation of the antibacterial and cytotoxic effect of Liquorice when used as root canal medicament. Int Endod J. 2010 Aug 31.
  28. Kim YH, Shin EK, Kim DH, et al. Antiangiogenic effect of licochalcone A. Biochem Pharmacol. 2010 Oct 15;80(8):1152-9.
  29. Park SY, Lim SS, Kim JK, et al. Hexane-ethanol extract of Glycyrrhiza uralensis containing licoricidin inhibits the metastatic capacity of DU145 human prostate cancer cells. Br J Nutr. 2010 May 21:1-11.
  30. Chandrasekaran CV, Deepak HB, Thiyagarajan P, et al. Dual inhibitory effect of Glycyrrhiza glabra (GutGard™) on COX and LOX products. Phytomedicine. 2010 Sep 21.
  31. Choi HJ, Seon MR, Lim SS, et al. Hexane/ethanol extract of Glycyrrhiza uralensis licorice suppresses doxorubicin-induced apoptosis in H9c2 rat cardiac myoblasts. Exp Biol Med (Maywood). 2008 Dec;233(12):1554-60.
  32. Gol'dberg ED, Amosova EN, Zueva EP, et al. Licorice preparations improve efficiency of chemotherapy and surgical treatment of transplanted tumors. Bull Exp Biol Med. 2008 Feb;145(2):252-5.
  33. Hasani-Ranjbar S, Nayebi N, Moradi L, et al. The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; a systematic review. Curr Pharm Des. 2010;16(26):2935-47.
  34. Nabekura T, Yamaki T, Ueno K, Kitagawa S. Inhibition of P-glycoprotein and multidrug resistance protein 1 by dietary phytochemicals. Cancer Chemother Pharmacol. 2008 Oct;62(5):867-73.
  35. Armanini D, Mattarello MJ, Fiore C, et al. Licorice reduces serum testosterone in healthy women. Steroids. 2004 Oct-Nov;69(11-12):763-6.
  36. Armanini D, Bonanni G, Mattarello MJ, et al. Licorice consumption and serum testosterone in healthy man. Exp Clin Endocrinol Diabetes. 2003 Sep;111(6):341-3.
  37. Hatano T, Fukuda T, Miyase T, Noro T, Okuda T. Phenolic constituents of licorice. III. Structures of glicoricone and licofuranone, and inhibitory effects of licorice constituents on monoamine oxidase. Chem Pharm Bull (Tokyo). 1991 May;39(5):1238-43.
  38. Eu CH, Lim WY, Ton SH, bin Abdul Kadir K. Glycyrrhizic acid improved lipoprotein lipase expression, insulin sensitivity, serum lipid and lipid deposition in high-fat diet-induced obese rats. Lipids Health Dis. 2010 Jul 29;9:81.
  39. Tu JH, He YJ, Chen Y, et al. Effect of glycyrrhizin on the activity of CYP3A enzyme in humans. Eur J Clin Pharmacol. 2010 Aug;66(8):805-810.
  40. Yorgun H, Aksoy H, Sendur MA, et al. Brugada syndrome with aborted sudden cardiac death related to liquorice-induced hypokalemia. Med Princ Pract. 2010;19(6):485-9.
  41. Pant P, Nadimpalli L, Singh M, Cheng JC. A case of severe hypokalemic paralysis and hypertension. Licorice-induced hypokalemic paralysis. Am J Kidney Dis. 2010 Jun;55(6):A35-7.
  42. Madhogaria S, Ahmed I. Leucoderma after use of a skin-lightening cream containing kojic dipalmitate, liquorice root extract and Mitracarpus scaber extract. Clin Exp Dermatol. 2010 Jun;35(4):e103-5.
  43. Celik M, Karakus A, Zeren C, et al. Licorice induced hypokalemia, edema, and thrombocytopenia. Hum Exp Toxicol. 2012 Dec;31(12):1295-8.
  44. Pandit S, Ponnusankar S, Bandyopadhyay A, Ota S, Mukherjee PK. Exploring the possible metabolism mediated interaction of Glycyrrhiza glabra extract with CYP3A4 and CYP2D6.Phytother Res. 2011 Oct;25(10):1429-34.
  45. Ruiz-Granados ES, Shouls G, Sainsbury C, Antonios T. A salty cause of severe hypertension. BMJ Case Rep. 2012 Feb 25;2012. doi:pii: bcr1220115336. 10.1136/bcr.12.2011.5336.
  46. Hou YC, Lin SP, Chao PD. Liquorice reduced cyclosporine bioavailability by activating P-glycoprotein and CYP 3A. Food Chem. 2012 Dec 15;135(4):2307-12.
  47. Methlie P, Husebye EE, Hustad S, Lien EA, Løvås K. Grapefruit juice and licorice increase cortisol availability in patients with Addison's disease.Eur J Endocrinol. 2011 Nov;165(5):761-9.
  48. Kuo KK, Chang JS, Wang KC, Chiang LC. Water extract of Glycyrrhiza uralensis inhibited enterovirus 71 in a human foreskin fibroblast cell line. Am J Chin Med. 2009;37(2):383-94.
  49. Huo HZ, Wang B, Liang YK, Bao YY, Gu Y. Hepatoprotective and Antioxidant Effects of Licorice Extract against CCl(4)-Induced Oxidative Damage in Rats. Int J Mol Sci. 2011;12(10):6529-43.

Consumer Information

How It Works

Bottom Line: Licorice may be helpful in treating peptic ulcers, but it has not been shown effective in treating cancer.

In traditional Chinese medicine, licorice is often used in herbal formulas to harmonize the effects of other herbs. Experiments in animals and humans show licorice can mimic the effects of steroid hormones such as aldosterone and estrogen. The substance in licorice that scientists think is responsible for these effects is called glycyrrhizin. However, because glycyrrhizin causes undesirable side effects, it is often removed from licorice products during processing.

Physiologic activity has also been reported for several other compounds in licorice. Isoflavone compounds also mimic estrogens in the human body, and can kill several strains of bacteria and viruses on contact. Other compounds act as blood thinners and inhibit the process of inflammation. In humans, the compound, carbenoxolone, has been used to treat stomach and esophageal ulcers with positive effects. Scientists think that it increases blood flow to and amount of mucus lining the stomach.

Purported Uses
  • To treat bronchitis and chest congestion
    No scientific evidence supports this use.
  • To relieve constipation
    This claim is not backed by research.
  • To treat gastrointestinal disorders such as peptic ulcers
    A substance in licorice called carbenoxolone decreased pain and heartburn and increased healing in patients with peptic ulcers, but major side effects (e.g., edema or fluid accumulation, low potassium, and high blood pressure) were reported.
  • To treat hepatitis
    Clinical trials in Japan have used a licorice extract (containing glycyrrhizin) to treat hepatitis B and C, and have shown that glycyrrhizin reduces liver disease. However, there is no proof that deglycyrrhizinated licorice would have the same effect.
  • To reduce inflammation
    Studies in animals support this use, but there is no proof from clinical trials that this effect occurs in humans.
  • To relieve menopausal symptoms
    Studies in animals show that licorice has estrogenic effects, and some of the components of licorice bind estrogen receptors. Human data are lacking.
  • To treat microbial infections
    Studies in animals suggest that licorice has anti-microbial activity, but human data are lacking.
  • To treat prostate cancer
    No scientific evidence supports this use. Licorice is an ingredient in PC-SPES, which has been studied in patients with prostate cancer.
Research Evidence

Dyspepsia:
This study was done to find out the efficacy and safety of STW 5-II, an herbal preparation, in releiving dyspepsia. The formula contains extracts of licorice root, matricaria flower, peppermint leaves, caraway, lemon balm, and bitter candy tuft. One hundred and twenty patients with functional dyspepsia were randomly assigned to 4 treatment groups and treated over a 12-week period. Patients received either STW 5-II or placebo for 8 weeks. Treatment during the last 4-week period was determined based on symptom relief in patients. Results showed that STW 5-II greatly improved symptoms of dyspepsia compared to a placebo. However, since STW 5-II contains other herbs, the extent to which licorice contributes to relieving dyspeptic symptoms is not clear from this study.

Do Not Take If
  • You take cardiac glycosides (Licorice may increase their effects and cause toxicity).
  • You take insulin (Licorice may have additive effects, possibly causing low blood levels of potassium and high levels of sodium retention in the body).
  • You take warfarin or other blood thinners (Licorice may increase the risk of bleeding).
  • You take MAO-inhibitors (MAO-Is) (Licorice may have additive effects).
  • You take daunorubicin: Licorice intake can result in increased intracellular concentration of daunorubicin, which may increase its toxic effects.
  • You are taking drugs that are substrates of Cytochrome P450 3A and 2D6 (Licorice may increase the risk of side effects of these drugs).
  • You are taking Cyclosporine: Licorice greatly reduced the oral bioavailability of cyclosporine by activating P-gp and CYP3A4, which can make it less effective.
  • You are taking Cortisol acetate:Licorice increased cortisol availability in tissues, which may increase its side effects.
Side Effects
  • High blood pressure
  • Lethargy
  • Muscle pain
  • Cardiac arrhythmias
  • Sodium retention
  • Hypokalemia (low blood levels of potassium)
  • Pseudo-hyperaldosteronism (causing low blood levels of potassium and high sodium retention)
  • Decreased libido in men
  • Suppression of scalp sebum secretion
  • Thrombocytopenia (low blood platelet count)
Special Point

Due to the adverse reaction profile of licorice, many studies have been performed using the deglycyrrhizinated licorice (DGL) extract that is free of glycyrrhizin.

E-mail your questions and comments to aboutherbs@mskcc.org.