Licorice

• How It Works

  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. Studies show that 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 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
    Evidence is lacking to support this claim
  • To relieve constipation
    Evidence is lacking to support this claim
  • 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 including fluid accumulation, low potassium, and high blood pressure were reported.
  • To treat hepatitis
    Clinical trials 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 clinical data are lacking.
  • 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 antimicrobial activity, but human data are lacking.
  • To treat prostate cancer
    Evidence is lacking to support this claim. Licorice is an ingredient in PC-SPES, which has been studied in patients with prostate cancer.
• Do Not Take If
  • You are taking cardiac glycosides: Licorice may increase their effects and cause toxicity.
  • You are taking insulin: Licorice may increase the sugar lowering effect.
  • You are taking diuretic drugs: Licorice may lower the blood potassium level.
  • You are taking warfarin or other blood thinners: Licorice may increase the risk of bleeding.
  • You are taking MAO-inhibitors (MAOIs): Licorice may have additive effects.
  • You are taking daunorubicin: Licorice intake can result in increased intracellular concentration of daunorubicin, which may increase its toxic effects.
  • You are taking cytochrome P450 substrates: Licorice may affect the actions 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.
  • You are taking metformin: Pre-administration of licorice juice reduced the efficacy of metformin, in a rat model. Whether similar effect occurs in humans is not known
  • You are taking antihypertensives: Because of its hypertensive effects, licorice may interfere with antihypertensive medications.
• Side Effects
  • High blood pressure
  • Lethargy
  • Muscle pain
  • Cardiac arrhythmias
  • High sodium retention
  • Low blood levels of potassium
  • Decreased libido in men
  • Suppression of scalp sebum secretion
  • Low blood platelet count
  • Hypertensive retinopathy
  • Hypertensive nephropathy
  • Licorice has been associated with intracranial hemorrhagic stroke and cerebral microbleeds^.
  • A systematic review showed an association between heavy licorice use and early preterm births.
• Special Point

  Due to the adverse reaction profile of licorice, many researchers have used the deglycyrrhizinated licorice (DGL) extract that is free of glycyrrhizin.

• Scientific Name

  Glycyrrhiza glabra, Glycyrrhiza uralensis

• Clinical Summary

  Derived from the root of the plant, licorice has been used as a flavoring and sweetening agent. It is also an important component of traditional Chinese medicine used to detoxify and enhance or balance the effects of other components in herbal formulations; and as a tonic, expectorant and a demulcent in Ayurveda. A number of compounds including glycyrrhizin are thought to be responsible for its biological effects.

  Preclinical studies have shown that licorice has antibacterial ^(2) (27), antiviral ⁽⁴⁸⁾, anticancer ^{(3) (4) (28) (29)}, anti-inflammatory ⁽³⁰⁾, and hepatoprotective ⁽⁴⁹⁾ properties. It also demonstrated estrogenic effects ⁽¹⁰⁾, reduced cardiotoxicity associated with doxorubicin ⁽³¹⁾, and improved the antitumor effects of cyclophosphamide ⁽³²⁾.

  Clinical data suggest utility of licorice in lowering dyspepsia ⁽¹⁾, hyperlipidemia ⁽³³⁾, and concurrent intake of a glycyrrhizin-containing product during alcohol consumption was shown to afford hepatoprotection ⁽⁵⁰⁾. When combined with fermented milk containing Lactobacillus paracasei, licorice was shown to reduce bacterial density and to improve histologic inflammation in patients with H. pylori infection ⁽⁶²⁾. Further, preoperative gargling with licorice solution affected significant reductions in postoperative sore throat when compared to gargling with sugar water ⁽⁵¹⁾. A systematic review also suggests benefits of preoperative use of topical licorice for preventing postoperative sore throat ⁽⁶³⁾. Additional studies reported that licorice solution improves xerostomia in hemodialysis patients ⁽⁵²⁾; and had comparable efficacy as triamcinolone in the management of oral mucositis during radiotherapy ⁽⁵³⁾.

  It is important to note that chronic ingestion of even moderate doses of licorice has been associated with hypertension and hypokalemia ⁽⁵⁴⁾.

• Purported Uses
  • Bronchitis
  • Chest congestion
  • Constipation
  • GI disorders
  • Hepatitis
  • Inflammation
  • Menopausal symptoms
  • Microbial infection
  • Peptic ulcers
  • Primary adrenocortical insufficiency
  • Prostate cancer
• Mechanism of Action

  Glycyrrhizin, one of the bioactive compounds of licorice, has been shown to bind to glucocorticoid and mineralocorticoid receptors, and to exert its effects via inhibition of 11b-hydroxysteroid dehydrogenase ⁽¹²⁾. Licorice can reduce serum testosterone by inhibiting 17-hydroxysteriod dehydrogenase ^(35) (36). It also contains isoflavones and other constituents that have estrogen receptor-modulating activities ⁽¹⁰⁾. The flavone and liquiritigenin components selectively activate ER-beta ⁽¹¹⁾.

  Liquiritigenin was shown to have neuroprotective effects in scopolamine-induced mice likely via increasing expression of brain-derived neurotrophic factor (BDNF), and phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding (CREB) in the hippocampus ⁽⁵⁵⁾. In addition, glycyrrhizic acid, a triterpene glycoside, demonstrated anti-allergic property by restoring the immune balance of subsets 1 and 2 of T helper cells in a dose-dependent manner. It also significantly reduced B cells producing allergen-specific IgE and IgG₁ ⁽⁵⁶⁾.

  Licorice demonstrated chemo-preventive effects by modulating expression of Bcl-2/Bax proteins, which act as apoptotic regulatory factors ⁽³⁾; and via inhibiting carcinogenesis ⁽⁴⁾. Other mechanisms include inducing apoptosis in human oral squamous cell carcinoma cells by regulation of the JAK2/STAT3 signaling pathway ⁽⁶⁰⁾; and by modulating cyclin B1-CDK1 for G2/M arrest in prostate cancer cells ⁽⁶¹⁾.

  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 potassium excretion.

• Warnings

  Due to the adverse reaction profile of licorice, many researchers used the deglycyrrhizinated licorice (DGL) extract that is free of glycyrrhizin.

• Adverse Reactions
  • Hypertension ^{(16) (45) (57) (59) (66)}, hypertensive retinopathy and nephropathy ⁽⁵⁹⁾, lethargy, muscle pain, sodium retention, hypokalemia ^{(17) (18) (19) (20) (26)  (41) (59)}, 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 ingestion of licorice or licorice containing products.
  • Licorice has been associated with intracranial hemorrhagic stroke and cerebral microbleeds ⁽⁶⁴⁾.
  • A systematic review showed an association between heavy licorice use and early preterm births ⁽⁶⁵⁾.
• Herb-Drug Interactions

  Cardiac glycosides: Licorice may potentiate toxicity ⁽²⁴⁾.
  Diuretics: Licorice may increase the risk of hypokalemia ^(17) (18).
  Insulin: Licorice may increase insulin sensitivity ⁽³⁸⁾ .
  Anticoagulants: Licorice may increase the metabolism and clearance of warfarin ⁽¹⁹⁾.
  MAO-inhibitors (MAOIs): Licorice may potentiate activity of MAOIs ⁽³⁷⁾
  P-Glycoprotein (P-gp) substrates: Licorice inhibited P-gp, resulting in increased intracellular concentration of the chemotherapy agent daunorubicin, which is a substrate of P-gp ⁽³⁴⁾.
  Cytochrome P450 substrates: Glycyrrhizin, a major constituent of licorice, induces CYP3A ⁽³⁹⁾ and CYP2D6 ⁽⁴⁴⁾, and can affect the intracellular concentration of drugs metabolized by this enzyme. However, other constituents, like glabridin, glycycoumarin and licochalcone A from different species of licorice can inhibit these enzymes ⁽⁴⁰⁾.
  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⁾.
  Metformin: Pre-administration of licorice juice reduced the efficacy of metformin, in a rat model ⁽⁵⁸⁾. The clinical relevance in humans has yet to be determined.
  Antihypertensives: Because of its hypertensive effects, licorice may interfere with antihypertensive medications ⁽⁶⁶⁾.

• References

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  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.

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  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.

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  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.

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