Medically reviewed by Drugs.com. Last updated on Oct 22, 2018.
Scientific Name(s): Glycyrrhiza glabra (L.).
Common Name(s): Bois doux, Gan Cao, Glycyrrhizae extractum crudum, Glycyrrhizae radix, Kanzo, Lakrids, Lakritzenwurzel, Licochalcone-A, Licorice, Liquiriti radix, Russian licorice, Shao-yao-gan-cao-tang, Spanish licorice, Succens liquiritiae
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 for a variety of uses including cancer therapy as well as for their antiviral activity.
Licorice root has been used in daily doses from 760 mg 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. Negative effects on pubertal maturation, neuroendocrine function, cognition, and behavior of children born to women who consumed high amounts of licorice during pregnancy have been documented.
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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.
- Fabaceae (bean)
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 compounds can now be assayed in blood, urine, and bile.6
Uses and Pharmacology
Glycyrrhetic acid has shown anti-inflammatory and antiarthritic activity in animal studies, which may be due to prostaglandin E2 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
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 an undetermined mechanism. Inhibition of viral binding to host cell membranes and viral 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 A2 and 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
Interest in the potential for licorice extracts in the prevention of cancer continues, but in vitro and human clinical data 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
Carbenoxolone and a traditional licorice preparation Zhigancao may slow myocardial conduction.20, 21 An open-label, randomized, controlled trial (n = 50) assessed the hemodynamic effects of licorice supplementation (glycyrrhizin 290 to 370 mg/day) in normotensive volunteers. After 2 weeks, extracellular volume as well as systolic and diastolic blood pressure (periphery and central) increased significantly in the licorice group compared to the control group. Licorice ingestion also significantly decreased plasma aldosterone and potassium concentrations.57 A systematic review and meta-analysis of 26 clinical trials (N=985) published from 2002 to 2017 found an overall statistically significant increase in diastolic blood pressure (DBP; P<0.001) with short-term use of licorice compared to control; heterogeneity, however, was high. The effect was considered likely due to the significant hypernatremia induced by licorice. Subgroup analysis revealed a significant increase in systolic blood pressure (SBP) when the intervention duration was 2 and 8 weeks, and a significant increase in both SBP and DBP in healthy patients, women with polycystic ovary syndrome, and for each dosage of licorice/day. Pooled data reflected no significant effect on overall lipid parameters (ie, HDL, LDL, total cholesterol, triglycerides).91
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
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.2 A more recent randomized controlled study, however, conducted in 120 Helicobacter pylori-positive patients observed a significant increase in negative seroconversions among those who received supplemental licorice (380 mg twice daily × 2 weeks) as an adjunct to H. pylori triple therapy (83%) compared to triple therapy alone (62.5%; P=0.018). This response rate was significant only in patients with peptic ulcer disease and not in those with non-ulcer dyspepsia.68
Animal experiments and studies in liver cancer suggest a protective role for licorice in hepatotoxicity.2, 13 A small (n = 66), randomized, double-blind, 2-month study in adults with nonalcoholic fatty liver disease found that 2 g of aqueous extract of licorice root per day produced a significant reduction from baseline in ALT and AST levels.50 There was no histologic evaluation in this study.
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
A randomized, double-blind clinical trial enrolling 60 menopausal women compared the effect of licorice with hormone replacement therapy (HRT) for 90 days for hot flashes. Patients receiving licorice 1,140 mg/day experienced significant reductions in duration and number of hot flashes within the group compared with the HRT (conjugated estrogen 0.312/medroxyprogesterone 2.5 mg daily) group; however, the difference between groups was insignificant. On the other hand, HRT produced a significant reduction in severity of hot flashes compared with licorice (P = 0.008 and P = 0.019). No significant differences were identified based on contextual or demographic factors.53
A systematic review and meta-analysis of 26 clinical trials (N=985) published from 2002 to 2017 found an overall statistically significant reduction in body weight of −0.433 kg (less than 1 pound) and BMI of −0.15 kg/m2 (P=0.001 for each) with short-term use of licorice compared to controls; heterogeneity was moderate and high, respectively. Other significant effects included reductions in some liver enzymes (eg, ALP, γ-GTP) and BUN. Overall, lipid parameters were not changed significantly.91
Prevention Postoperative Sore Throat/Cough
In a double-blind, placebo-controlled trial enrolling 236 adult inpatients undergoing elective thoracic surgery, gargling for 1 minute with licorice solution (0.5 g per 30 mL water) approximately 5 minutes prior to anesthetic induction significantly reduced the incidence of postoperative sore throat and coughing compared with sugar water (5 g per 30 mL water).49 A dose-response randomized controlled study (n=144) found a 1 g licorice solution used to gargle 5 minutes prior to intubation to be significantly more effective than lower doses (ie, 0.5 g, 0.25 g) or controls for managing postoperative sore throat, postextubation coughing, and patient satisfaction (P<0.05 each).69
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 760 mg to 15 g for ulcer, gastritis, and nonalcoholic fatty liver disease. Higher doses given for extended periods may pose a risk of hyperkalemia. Deglycyrrhizinated licorice extracts are available.16, 17, 18, 50
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 A propsective cohort study from Korea suggest that licorice increased the risk of stillbirth, but investigators did not see a statistically significant increase in risk for major malformation.51
Despite herbal texts suggesting the use of licorice tea as a galactogogue, there is no clinical evidence.
Consumption of high amounts of licorice during pregnancy has been shown to negatively affect the pubertal maturation, neuroendocrine function, cognition, and behavior of offspring. A follow-up study on the impact of maternal consumption of licorice on pubertal maturation of offspring was conducted subsequent to initial results compiled from a Finnish cohort (N=1,049) that revealed children born to women who consumed high amounts of licorice during pregnancy exhibited significantly worse intelligence, memory, risk of behavior problems, and physiological stress at the age of 8 years than children born to women who consumed little to no licorice during pregnancy. Of the 451 women who participated in the pubertal maturation follow-up study, 327 had consumed zero to low glycyrrhizin (up to 249 mg/week; mean 47 mg/week) and 51 had high maternal consumption (glycyrrhizin 500 mg/week or more; mean, 845 mg/week). After adjustments for covariates, significant variations in standard-deviation scores in the adolescents (mean age, 12.5 years) were observed in a number of pubertal maturation characteristics that were associated with high licorice consumption, including higher weight-for-age and body mass index-for-age as well as advanced pubertal stage in girls. However, in boys, a lower weight-for-age, height-for-age, and height were observed. Cognition problems (ie, lower general, verbal, and performance IQ scales) and risk of attention deficit/hyperactivity disorder problems were also significantly higher among adolescents in the high-exposure group.64
Agents with antiplatelet properties: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of agents with antiplatelet properties. Bleeding may occur. Consider therapy modification.31, 32, 33, 34
Antihypertensives: Herbs (hypertensive properties) may diminish the antihypertensive effect of antihypertensives agents. Monitor therapy.35
Cortisone: Licorice may increase cortisol serum levels. Monitor therapy.52
Estrogen derivatives: Herbs (estrogenic properties) may enhance the adverse/toxic effect of estrogen derivatives. Monitor therapy.36
Herbs (anticoagulant/antiplatelet properties): Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of other herbs (anticoagulant/antiplatelet properties). Bleeding may occur. Consider therapy modification.31, 32, 33, 34
Loop diuretics: Licorice may enhance the hypokalemic effect of loop diuretics. Monitor therapy.37
Nonsteroidal anti-inflammatory agents: Herbs (anticoagulant/antiplatelet properties) may enhance the adverse/toxic effect of nonsteroidal anti-inflammatory agents. Bleeding may occur. Consider therapy modification.31, 32, 33, 34
Thiazide diuretics: Licorice may enhance the hypokalemic effect of thiazide and thiazide-like diuretics. Monitor therapy.38
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 and has been demonstrated in a case of a 45-year-old perimenopausal woman who had been consuming up to 6 cups/day of licorice tea for 12 months.39, 59 A case of very early onset pre-eclampsia in an 18-year-old primigravida female was deemed likely aggravated by considerable licorice consumption.62 An open-label, randomized, controlled trial (n = 50) assessed the hemodynamic effects of licorice supplementation (glycyrrhizin 290 to 370 mg/day) in normotensive volunteers. After 2 weeks, extracellular volume as well as systolic and diastolic blood pressure (periphery and central) increased significantly in the licorice group compared to the control group. Licorice ingestion also significantly decreased plasma aldosterone and potassium concentrations.57 Licorice should be used cautiously in patients with hypertension because of potential for mineralocorticoid hypokalemic effects, including severe hypokalemia with secondary polymorphic ventricular tachycardia.40, 54, 56 A case of hypermineralcorticoidism subsequent to consumption of large amounts of licorice cough lozenges (160 lozenges/day; approximately 288 mg/day of glycyrrhizin) for 3 to 4 months resulted in hypokalemia and hypertension that resolved several weeks after cessation of the licorice lozenges. It was noted that although urinary cortisol was elevated during the toxic state, serum cortisol remained normal.61 Similarly, apparent mineralocorticoid excess as a result of drinking licorice tea 3 times daily was reported in a 65-year-old female who presented with frequent paroxysmal palpitations and hypokalemia.66 Mineralocorticoid excess compounded by excessive use of terbutaline (12 to 14 inhalations/day) and high water intake (4 to 5 L/day) was found to be likely related to an unspecified amount of licorice in a 54-year-old man with a history of asthma and hypertension.90
Ocular effects have been described and may be due to the cyclooxygenase-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.41 Additionally, a case of hypertensive retinopathy resulting in acute visual impairment in the presence of pseudohyperaldosteronism in a 57-year-old man was determined to be the result of consumption of at least 900 g/week of liquorice over the last 3 to 4 months. He had an unremarkable medical history and presented with a blood pressure of 250/110 mm Hg and severe hypokalemia. A total of 7 medications were needed to improve his vision at the time of discharge and even after 3 months of not eating any liquorice, he still required 2 antihypertensive medications to maintain a normal blood pressure.63 A better outcome was achieved for a 47-year-old female who developed glycyrrhizin-induced hypertensive retinopathy and nephropathy after long-term consumption of glycyrrhizin 225 mg/day for 3 years. The initial hypertension (230/100 mm Hg), renal dysfunction, and ophthalmodynia that were present upon admission returned to normal within 6 months of discontinuing the compound glycyrrhizin tablets.70
Hypersensitivity reactions to glycyrrhiza-containing products have also been noted.2
In the 2016 Scientific Statement by the American Heart Association regarding drugs that may cause or exacerbate heart failure, licorice has been recognized as a product with antiplatelet and anticoagulant effects, which may increase bleeding risk when used with anticoagulants. Additionally, it exhibits possibly harmful cardiovascular effects, such as hypertension and fluid retention (pseudohyperaldosteronism), which may be harmful in patients with heart failure. The guidelines noted that naturoceuticals are not recommended for the management of heart failure symptoms or for the secondary prevention of cardiovascular events, and that nutritional supplements are not recommended for the treatment of heart failure [Low-quality; Limited].60
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.42, 43, 44, 45, 46, 47, 48, 55, 67 A rare case of licorice-induced thyrotoxic periodic paralysis was reported in a 43-year-old man recently diagnosed with Graves’ disease who presented with hypokalemia, a hyperthyroid state, and paralysis. His symptoms were suspected to have been induced secondarily to excess licorice consumption (400 mL/day licorice tea for the previous 12 days). Paralysis symptoms resolved completely upon stabilizing his potassium levels.67
Although several cases of posterior reversible encephalopathy syndrome-induced licorice hypertension in adults have been reported,58, 65 one case in a 10-year-old child has been documented. The boy was hospitalized following a cluster of generalized unexplained tonic-clonic seizures. General, neurological, and lab tests were unremarkable except for elevated blood pressure (135/88 mm Hg) and low blood potassium (3.5 mmol/L). Persistently high cortisol levels with normal circadian rhythm were also observed and suggested an association between an endocrine disorder and hypertension. Medical history and observation of black teeth during a follow-up examination revealed the boy had been eating 20 licorice sweets a day for a period of 4 months; consuming an estimated 2,400 mg licorice per day (corresponding to 72 mg of glycyrrhizic acid/day; equivalent to 2.88 mg/kg). Blood pressure normalized and vasogenic edema was reduced considerably within 2 weeks after stopping the licorice.58
The mechanism by which the glycyrrhizinates exert their effect on the renin-angiotensin-aldosterone system has been elucidated.2, 39, 40, 46 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 due to its involvement in surfactant synthesis. In the highest dosage group, a reduction in the enzyme was observed but with no increase in fetal malformation or fetal death rate.2
- G. glabra var. typica
- G. glabra var. glandulifera
- G. glabra var. lepidota
- G. glabra var. violacea
- G. pallidiflora
- G. uralensis
- European Licorice
- Spanish Licorice
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