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 of Licorice
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.
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 have not yet been identified.
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.
Glycyrrhizin in licorice may alter prednisolone plasma concentrations and may increase the risk of digitalis toxicity.
Licorice 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.
Toxicity from excessive licorice ingestion is well established. Mutagenicity and teratogenicity studies have generally shown no ill effects.
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
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
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
Licorice Uses and PharmacologyAntiviral
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
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. 2Cancer
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. 4GI
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. 2Other effects
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. 19Cardiac
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. 2Diabetes
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
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
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.
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
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
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
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