Licorice

Scientific Name(s): Glycyrrhiza glabra (L.) Family: Fabaceae (beans)

Common Name(s): Licorice , Spanish licorice , Russian licorice , gan Cao (Chinese), shao-yao-gan-cao-tang , bois doux (French), kanzo (Japanese), lakrids (Danish), lakritzenwurzel (German), licochalcone-A , Glycyrrhizae radix , Glycyrrhizae extractum crudum , Liquiriti radix , Succens liquiritiae

Uses

Used historically for GI complaints, licorice is primarily used as a flavoring agent in the tobacco and candy industries and to some extent in the pharmaceutical and beverage industries today. The chemical compounds found in licorice have been investigated as cancer therapy as well as for their antiviral activity.

Dosing

Licorice root has been used in daily doses from 2 to 15 g for ulcer and gastritis. Higher doses given for extended periods of time may pose a risk of hyperkalemia. The acceptable daily intake (ADI) for glycyrrhizin is suggested to be 0.2 mg/kg/day.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Use during pregnancy should be avoided. Licorice exhibits estrogenic activity and has reputed abortifacient effects. There is no clinical evidence to support the use of licorice tea as a galactogogue.

Interactions

Glycyrrhizin in licorice may alter prednisolone plasma concentrations and may increase the risk of digitalis toxicity.

Adverse Reactions

At lower dosages or normal consumption levels, few adverse reactions are evident. Ocular effects and hypersensitivity have been described. Hypertension and hypokalemia are recognized effects of excessive licorice consumption.

Toxicology

Toxicity from excessive licorice ingestion is well established. Mutagenicity and teratogenicity studies have generally shown no ill effects.

Botany

G. glabra is a 1.5 m shrub that grows in subtropical climates in rich soil. The name glycyrrhiza is derived from Greek words meaning “sweet roots.” The roots of the plant are harvested to produce licorice. Most commercial licorice is extracted from several varieties of G. glabra . The most common variety, G. glabra var. typica (Spanish or European licorice), is characterized by blue flowers, while the variety G. glabra var. glandulifera (Russian licorice) has violet blossoms. Turkey, Greece, Iran, and Iraq supply most commercial licorice. The variety grown in the United States is G. glabra var. lepidota , while that grown in Iran and Iraq is var. violacea . Chinese licorice is derived from the related species G. uralensis and G. pallidiflora . 1 , 2

History

Therapeutic use of licorice dates back to the Roman Empire. The Greek physician Hippocrates (460 BC) and botanist Theophratus (371 BC) extolled its uses, and Roman naturalist Pliny the Elder (23 AD) recommended it as an expectorant and carminative. Licorice also figures prominently in Chinese herbal medicine. It is used in modern medicinals chiefly as a flavoring agent that masks bitter agents, such as quinine, and in cough and cold preparations for its expectorant activity. Most licorice candy in the United States is actually flavored with anise, not licorice. A sample of licorice from 756 AD was analyzed and found to still contain detectable active principles after 1,200 years. 3

Chemistry

Licorice root contains a variety of compounds, including triterpenoids, polyphenols, and polysaccharides (starches, mannose, and sucrose). Polyphenols include certain phenolic acids, such as liquiritin, flavones and flavans; chalcones; and isoflavonoids, such as glabridin. 2 , 4 , 5 The bright yellow color of the root is attributed to the flavonoid content, especially liquiritin and isoliquiritin. Plant gums, resins, and essential oils have been extracted; however, the root is cultivated for the principle active glycoside glycyrrhizin. 2 , 6 The amount of glycyrrhizin varies from 7% to 10% or more depending on growing conditions. 6 Glycyrrhizin, glycyrrhizic acid, and glycyrrhizinate amount to 10% to 25% of the root extract. 2 The ammoniated salt of glycyrrhizin is manufactured to specifications from licorice extract and used as a flavoring agent. 2 Carbenoxolone, a synthetic analog of glycyrrhetic acid, has been used as a pharmacological agent in the management of peptic ulcers. 2 A process has been established to remove glycyrrhizic acid from licorice to eliminate the adverse metabolic effects of licorice. A high-pressure liquid chromotography method to compare the bioavailability of glycyrrhizic acid whether in licorice root or in pure glycyrrhiza extract has been published. These can now be tested in blood, urine, and bile. 6

Uses and Pharmacology

Antiviral

Historically, licorice and its extracts have been used in China and Japan to treat chronic viral hepatitis. 2 In in vitro experiments, glycyrrhizin inhibited certain pathogenic viruses by a mechanism that is unclear. Inhibition of viral binding to cell membranes and replication, as well as interference with cellular signal transduction have been suggested. Animal and human studies suggest a more complex mechanism involving induction of interferon production via effects of T-cell function. 2

Although the mechanism is unclear, glycyrrhizic acid inhibited the reactivation of latent Kaposi sarcoma-associated herpes virus, 7 , 8 and showed efficacy against SARS-associated coronavirus. 9

Increased survival times for mice have been demonstrated with glycyrrhizin administration for influenza virus A 2 herpes simplex. 2

In clinical trials in chronic hepatitis, Stronger Neo-Minophagen C (an intravenous [IV] glycyrrhizin solution produced in Japan) normalized serum transaminase levels and improved liver function but demonstrated no effect on hepatitis C RNA levels. 2

Cancer

Interest in the potential for licorice extracts in the prevention of cancer continues, but in vitro and human clinical trials are lacking.

Chemical compounds including glabridin, liquiritin, isoliquiritin, glycyrrhizin, glycyrrhizinic acid, and carbenoxolone have been studied for their effects on mice, rat, and human cancer cell lines, with most studies indicating a dose-dependent action on cell/tumor proliferation and apoptosis. Prostate, breast, colon, liver, and lung cancer cell lines have been investigated. 2 , 4 , 5 , 10 , 11 , 12 , 13 , 14

Various mechanisms of action have been suggested for licorice compounds, including antioxidant activity, DNA-protective activity, suppressive action, cyclooxygenase inhibition, and phytoestrogenic and progesterone antagonist activity. 2 , 4 In one experiment, glabridin demonstrated growth-promoting activity at low concentrations but inhibitory activity at higher concentrations. 11 The authors suggest the various chemical compounds in licorice extracts may act to modulate one another's effects. Another experiment compared activity of different esters of glycyrrhetinic acid indicating structure activity relationships for licorice compounds. 14

In a large retrospective study in Japan (N = 1,249), difference in progression to hepatocellular carcinoma was found in patients with chronic hepatitis C unresponsive to interferon treatment. After adjustment for many variables, those patients who received IV glycyrrhizinic acid 4 mg showed a decrease in the rate of progression to liver cancer, possibly irrespective of length of treatment. 15 The same authors had earlier demonstrated a protective effect of long-term glycyrrhizin administration in hepatocellular cancer. 4

GI

As a result of licorice's extensive folk use for gastric irritation, multiple studies in the 1970s and 1980s explored the efficacy of licorice, glycyrrhizinated compounds, deglycyrrhizinated licorice, and carbenoxlone in gastric/peptic ulcers. 2 , 16 , 17 , 18 The studies largely showed inconclusive results and efficacy lower than other pharmaceutical agents, such as cimetidine. Due to insufficient evidence in the management of ulcers, licorice is now largely limited to a flavoring ingredient in over-the-counter preparations. 2

Other effects
Anti-inflammatory

Glycyrrhetic acid has shown anti-inflammatory and antiarthritic activity in animal studies, which may be caused by prostaglandin E 2 inhibitory qualities demonstrated by several glycyrrhizin analogs. Japanese researchers found that licorice could aid in the clearance of excess immune complexes in mice with systemic lupus erythematosus. 19

Cardiac

Carbenoxolone and a traditional licorice preparation Zhigancao may slow myocardial conduction. 20 , 21

Dental

Glycyrrhizin may reduce the growth and acid production of oral bacteria, but results have varied. Other experiments suggest that inhibition of bacterial adherence and inhibition of the enzyme required for plaque formation may be alternative mechanisms for the anticariogenic action of licorice. 2

Diabetes

Carbenoxolone and glycyrrhizin have been investigated in animal experiments for use in diabetes. Results have varied and the mechanism by which they might act is unclear. 22 , 23 , 24

Hepatoprotection

Animal experiments and studies in liver cancer suggest a protective role for licorice in hepatotoxicity. 2 , 13

Hormonal effects

Reductions in serum testosterone have been demonstrated in several studies in healthy men consuming glycyrrhizin 0.5 g/day for 7 days. Another trial did not find a reduction; however, methodology between the 2 studies varied. 2 , 25

In women, licorice has been used in conjunction with spironolactone in the treatment of polycystic ovary syndrome. 26 The estrogenic activity of licorice, as well as compounds glabridin and glabrene, has been documented. 26 , 27

Dosage

Licorice has a poor oral bioavailability, requiring 10 hours to reach maximum glycyrrhizic acid concentrations in healthy volunteers from the ammoniated salt and 12 hours for licorice extract. The lipophilic components of licorice extract have been shown to reduce the gastric emptying rate and absorption of glycyrrhizic acid, and neither glycyrrhizin nor the acid accumulate in tissues. Extensive saturable albumin binding has been demonstrated in humans. Plasma clearance is decreased in patients with chronic hepatitis C and liver cirrhosis. 2

Licorice root has been used in daily doses from 2 to 15 g for ulcer and gastritis. Higher doses given for extended periods may pose a risk of hyperkalemia. Deglycyrrhizinated licorice extracts are available. 16 , 17 , 18

A No-Observed Effects Level has been proposed as purified glycyrrhizin 2 mg/kg/day, and the ADI for glycyrrhizin is suggested at 0.2 mg/kg/day. 2

Pregnancy/Lactation

Use during pregnancy should be avoided. Licorice exhibits estrogenic activity and has reputed abortifacient effects. 28 , 29 Glycyrrhetic acid has been demonstrated to cross the placental barrier in rats. 2 Research suggests a risk factor for preterm delivery when excessive licorice is consumed; however, the data used to support this observation were heterogeneous and retrospectively gathered via questionnaire. 30

Despite herbal texts suggesting the use of licorice tea as a galactogogue, there is no clinical evidence to support this case.

Interactions

Digoxin

Congestive heart failure and digitalis toxicity occurred in an 84-year-old man during concurrent ingestion of digoxin 0.125 mg and an herbal laxative containing licorice ( G. glabra ). 31 The mechanism for digitalis toxicity was attributed to possible electrolyte imbalance resulting from the mineralocorticoid activity of licorice.

Prednisolone

Glycyrrhizin may inhibit the metabolism of prednisolone, elevating prednisolone plasma concentrations and increasing the pharmacologic effects and adverse reactions. Ingestion of 3 different herbal products containing glycyrrhizin increased, decreased, or had no effect on prednisolone plasma levels, depending on which herbal preparation was ingested. 32 In 2 studies of glycyrrhizin effects on the pharmacokinetics of IV prednisolone, pretreatment with glycyrrhizin 50 mg every 4 hours for 4 doses increased the area under the curve of total 33 and free prednisolone, decreased total plasma clearance, and prolonged the mean residence time of prednisolone. 33 , 34

Adverse Reactions

At “usual” dosages or normal consumption levels, few adverse reactions are evident. Reports of adverse reactions in the literature are generally due to licorice intoxication or chronic excessive intake, and these effects are described in Toxicology below.

Consumption of as little as 50 g/day can produce mineralocorticoid hypertension. 35 Caution is advised in elderly patients with hypertension due to the potential for mineralocorticoid hypokalemic effects. 36

Ocular effects have been described and may be due to the syslooxygenase-inhibitory effect of glabridin; however, large amounts of licorice are required for this effect. Vasospasm of the optic nerve blood vessels resulting in visual disturbances mimicking ocular migraine (but with no headache) has been reported. 37

Hypersensitivity reactions to glycyrrhiza-containing products have also been noted. 2

Toxicology

Many case reports of hypokalemic paralysis, pseduoaldosteronism, and cardiac myopathy due to hypokalemia are found in the literature. Symptoms including severe hypokalemia, mineralocorticoid hypertension, cardiac arrhythmias, paralysis of the extremities, metabolic alkalosis, hypoxemia, and hypercapnea have been reported. Several authors suggest that licorice intoxication might be a more commonplace cause for these states considering the widespread availability of licorice-containing traditional and herbal medicines. 38 , 39 , 40 , 41 , 42 , 43 , 44

The mechanism by which the glycyrrhizinates exert their effect on the renin-angiotensin-aldosterone system has been elucidated. 2 , 35 , 36 , 42 Competitive (and reversible) inhibition of the enzyme 11-beta-hydroxysteroid dehydrogenase results in the suppression of cortisol conversion to inactive cortisone. Consequent suppression of plasma renin activity and aldosterone levels is evident. Exchangeable sodium levels increase and cortisol occupation of mineralocorticoid receptors in the distal kidney tubules is enhanced. The condition responds to administration of spironolactone, potassium supplementation, and discontinuation of licorice.

The majority of mutagenicity studies in animals show no genotoxic effects for licorice or glycyrrhizinates. 2 Teratogenicity studies in mice, rats, hamsters, and rabbits at a range of doses show no treatment-related effects. 2 A study on fetal rat lung development explored the effect of glycyrrhizinates on 11-beta-hydroxysteroid dehydrogenase, because it is involved in surfactant synthesis. In the highest dose group, a reduction in the enzyme was observed but with no increase in fetal malformation or fetal death rate. 2

Bibliography

1. Glycyrrhiza glabra L. USDA, NRCS. 2007. The PLANTS Database ( http://plants.usda.gov , Dec 2007). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Isbrucker RA , Burdock GA . Risk and safety assessment on the consumption of Licorice root ( Glycyrrhiza sp.), its extract and powder as a food ingredient, with emphasis on the pharmacology and toxicology of glycyrrhizin . Regul Toxicol Pharmacol . 2006;46(3):167-192.
3. Shibata S . Int J Pharmacog . 1994 ; 32 ( 1 ): 75-89 .
4. Wang ZY , Nixon DW . Licorice and cancer . Nutr Cancer . 2001 ; 39 ( 1 ): 1-11 .
5. Chin YW , Jung HA , Liu Y , et al. Anti-oxidant constituents of the roots and stolons of licorice ( G. glabra ) . J Agric Food Chem . 2007 ; 55 ( 12 ): 4691-4697 .
6. Raggi MA , Bugamelli F , Nobile L , et al. HPLC determination of glycyrrhizin and glycyrrhetic acid in biological fluids, after licorice extract administration to humans and rats . Bollettino Chimico Farmaceutico . 1994 ; 133 ( 11 ): 704-708 .
7. Curreli F , Friedman-Kien AE , Flore O , et al. Glycyrrhizic acid alters Kaposi sarcoma-associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes . J Clin Invest . 2005 ; 115 ( 3 ): 642-652 .
8. Cohen JI . Licking latency with licorice . J Clin Invest . 2005 ; 115 ( 3 ): 591-593 .
9. Cinatl J , Morgenstern B , Bauer G , et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus . Lancet . 2003 ; 361 ( 9374 ): 2045-2046 .
10. Jung JI , Lim SS , Choi HJ , et al. Isoliquiritigenin induces apoptosis by depolarizing mitochondrial membranes in prostate cancer cells . J Nutr Biochem . 2006 ; 17 ( 10 ): 689-696 .
11. Dong S , Inoue A , Zhu Y , et al. Activation of rapid signaling pathways and the subsequent transcriptional regulation for the proliferation of breast cancer MCF-7 cells by the treatment with an extract of Glycyrrhiza glabra root . Food Chem Tox . 2007 ; 45 ( 12 ): 2470-2478 .
12. Adams LS , Seeram NP , Hardy ML , Carpenter C , Heber D . Analysis of the interactions of botanical extract combinations against the viability of prostate cancer cell lines . eCAM . 2006 ; 3 ( 1 ): 117-124 .
13. Lee CK , et al. Effects of the licorice extract against tumor growth and cisplatin-induced toxicity in a mouse xenograft model of colon cancer . Bio Pharm Bull . 2007 ; 30 ( 11 ): 2191-2195 .
14. Chintharlapalli S , Papineni S , Jutooru I , et al. Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor [gamma] agonists in colon cancer cells . Mol Cancer Ther . 2007 ; 6 ( 5 ): 1588-1598 .
15. Ikeda K , Arase Y , Kobayashi M , et al. A long-term glycyrrhizin injection therapy reduces hepatocellular carcinogenesis rate in patients with interferon-resistant active chronic hepatitis C: a cohort study of 1249 patients . Dig Dis Sci . 2006 ; 51 ( 3 ): 603-609 .
16. Kassir ZA . Endoscopic controlled trial of four drug regimens in the treatment of chronic duodenal ulceration . Ir J Med . 1985 ; 78 : 153-156 .
17. Morgan AG , McAdam WA , Pacsoo C , Damborough A . Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy . Gut . 1982 ; 23 ( 6 ): 545-551 .
18. Morgan AG , Pacsoo C , McAdam WA . Maintenance therapy: a two year comparison between Caved-S and cimetidine treatment in the prevention of symptomatic gastric ulcer recurrence . Gut . 1985 ; 26 ( 6 ): 599-602 .
19. Chen R , Yuan C . China Journal of Chinese Materia Medica . 1991 ; 16 ( 10 ): 617-619 .
20. Kojodjojo P , Kanagaratnam P , Segal OR , Hussain W , Peters NS . The effects of carbenoxolone on human myocardial conduction: a tool to investigate the role of gap junctional uncoupling in human arrhythmogenesis . J Am Coll Cardiol . 2006 ; 48 ( 6 ): 1242-1249 .
21. Matsumoto T , Tanaka M , Yamada H , Cyong JC . Effect of licorice root on Carrageenan-induced decrease in immune complex clearance in mice . J Ethnopharm . 1996 ; 53 ( 1 ): 1-4 .
22. Sandeep TC , Andrew R , Homer NZ , et al. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone . Diabetes . 2005 ; 54 ( 3 ): 872-879 .
23. Tomlinson JW , Sherlock M , Hughes B , et al. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis . J Clin Endocrinol Metab . 2007 ; 92 ( 3 ): 857-864 .
24. Andrews RC , Rooyackers O , Walker BR . Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes . J Clin Endocrinol Metab . 2003 ; 88 ( 1 ): 285-291 .
25. Arimanini D , Mattarello MJ , Fiore C , et al. Licorice reduces serum testosterone in healthy women . Steroids . 2004 ; 69 ( 11-12 ): 763-766 .
26. Armanini D , Castello R , Scaroni C , et al. Treatment of polycystic ovary syndrome with spironolactone plus licorice . Eur J Obstet Gynecol Reprod Biol . 2007 ; 131 ( 1 ): 61-67 .
27. Oerter Klein K , Janfaza M , Wong JA , Chang RJ . Estrogen bioactivity in fo-ti and other herbs used for their estrogen-like effects as determined by a recombinant cell bioassay . J Clin Endocrinol Metab . 2003 ; 88 ( 9 ): 4077-4079 .
28. Newall CA , Anderson LA , Phillipson JD , eds. Herbal Medicines: A Guide for Health-Care Professionals . London: Pharmaceutical Press; 1996 .
29. Ernst E . Herbal medicinal products during pregnancy: are they safe? BJOG . 2002 ; 109 : 227-235 .
30. Strandberg TE , Andersson S , Järvenpää AL . Risk factors for preterm delivery . Lancet . 2003 ; 361 ( 9355 ): 436 .
31. Harada T , Ohtaki E , Misu K , Sumiyoshi T , Hosoda S . Congestive heart failure caused by digitalis toxicity in an elderly man taking a licorice-containing Chinese herbal laxative . Cardiology . 2002 ; 98 ( 4 ): 218 .
32. Homma M , Oka K , Ikeshima K , et al. Different effects of traditional Chinese medicines containing similar herbal constituents on prednisolone pharmacokinetics . J Pharm Pharmacol . 1995 ; 47 ( 8 ): 687-692 .
33. Chen MF , Shimada F , Kato H , Yano S , Kanaoka M . Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone . Endocrinol Japon . 1991 ; 38 ( 2 ): 167-174 .
34. 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 Japon . 1990 ; 37 ( 3 ): 331-341 .
35. Quinkler M , Stewart PM . Hypertension and the cortisol-cortisone shuttle . J Clin Endocrinol Metab . 2003 ; 88 ( 6 ): 2384-2392 .
36. 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 ): 575-578 .
37. Santaella RM , Fraunfelder FW . Ocular adverse effects associated with systemic medications: recognition and management . Drugs . 2007 ; 67 ( 1 ): 75-93 .
38. Sigurjonsdottir HA , Ragnarsson J , Franzson L , Sigurdsson G . Is blood pressure commonly raised by moderate consumption of liquorice? J Human Hyperten 1995 ; 9 ( 5 ): 345-348 .
39. Bielenberg J . Pharm Ztg . 1989 ; 134 ( 12 ): 9-12 .
40. Farese RV , Biglieri EG , Shackleton CH , Irony I , Gomez-Fontes R . Licorice-induced hypermineralocorticoidism . N Engl J Med . 1991 ; 325 ( 17 ): 1223-1227 .
41. Hsu YJ , Lin YF , Chau T , et al. Electrocardiographic manifestations in patients with thyrotoxic periodic paralysis . Am J Med Sci . 2003 ; 326 ( 3 ): 128-132 .
42. Elinav E , Chajek-Shaul T . Licorice consumption causing severe hypokalemic paralysis . Mayo Clin Proc . 2003 ; 78 ( 6 ): 767-768 .
43. Schapera CH . Potential causes of secondary hypertension . Am Fam Physician . 2003 ; 68 ( 1 ): 42 .
44. Lin SH , Yang SS , Chau T , Halperin ML . An unusual cause of hypokalemic paralysis: chronic licorice ingestion . Am J Med Sci . 2003 ; 325 ( 3 ): 153-156 .

Copyright © 2009 Wolters Kluwer Health

Hide
(web3)