Glycyrrhiza glabra

Common Names: Licorice root, Sweet licorice, Sweet wood, Sweetwort, Liquorice.

Clinical Names: Glycyrrhiza glabra, Glycyrrhiza uralensis

Summary

botanical names: Glycyrrhiza glabra. The species favored in traditional Chinese medicine is Glycyrrhiza uralensis.

common names: Licorice root, Liquorice.

overview of interactions:
• herb affecting drug class performance: Corticosteroids

• herb affecting drug class toxicity: Thiazide Diuretics and Loop Diuretics

• herb theoretically affecting drug class toxicity: Monoamine Oxidase Inhibitors

• herb positively affecting drug toxicity: Acetylsalicylic Acid (Aspirin)

• herb theoretically affecting drug toxicity: Digoxin

• herb affecting drug performance: Interferon

• herb affecting drug performance: Spironolactone (Aldactone®)

• drug affecting herb bioavailability: Antibiotics

AHPA Botanical Safety Rating: 2b, 2d




Clinical

botanical names: Glycyrrhiza glabra. The species favored in traditional Chinese medicine is Glycyrrhiza uralensis.

common names: Licorice root, Sweet licorice, Sweet wood, Sweetwort, Liquorice.

part(s) used: Rhizome, root.

actions: Anti-inflammatory, immuno-stimulant, anti-viral, demulcent, expectorant, anti-catarrhal, anti-ulcer (PUD), hepatoprotective, spasmolytic, laxative.

dosage:
• Dried root: 1-4 g. three times daily. (Daily Maximum 12 g.).
• Tincture: (1:5) 5-15 ml. three times daily.
• Solid Extract: (4:1) 250-500 mg. three times daily.
(Manufacturer's preparations may vary)
• DGL Capsules :1-3 caps. three times daily.
(Manufacturer's preparations may vary; 300-380 mg/capsule is typical.)

therapy:
• internal: Adrenocortical insufficiency, allergies, arthritis, asthma, bronchitis, chronic fatigue, chronic gastritis, cough, hepatitis, hypoglycemia, hypotension, peptic ulcer disease, rheumatism, steroid drug withdrawal.
• external: Apthous stomatitis, dental caries, Herpes simplex lesions.

AHPA Botanical Safety Rating: 2b, 2d

toxicity:
• Maximum daily therapeutic dose range should not be exceeded. Idiosyncratic hypersensitivity reactions to licorice root are rare but have been reported.
• Prolonged consumption of licorice root in excess of the safe therapeutic dose may result in "pseudoaldosteronism" which mimics mineralocorticoid excess. See Commentary. This syndrome is characterized by potassium loss, sodium retention, edema, hypertension and weight gain.

contraindications:
• Contraindicated in overweight, hypertensive or cardiac patients, especially those on cardiotonic drugs or diuretics. (see drug interactions.)
• Contraindicated in severe renal insufficiency or high blood pressure due to the sodium and fluid retention .
• Contraindicated in hypokalemia due to increased potassium excretion from kidneys.
(Brinker F. 1998, 91; Bisset NG 1994, 301.)

constituents:
• Saponin triterpenes, including Glycyrrhizin, glycyrrhetinic acid [GA], liquiritic acid.
• Flavonoids and isoflavonoids, including liquiritin, formononetin.
• Other: coumarins, sugars, polysaccharides, asparagine, starch, bitter principle.

pharmacology
The pharmacology of licorice root extracts is well documented; for a review see Snow (1996). Recent work has focused on the hepatoprotective effects of Glycyrrhiza.

• Corticosteroid effects: The glycoside glycyrrhizin is the major triterpenoid constituent of licorice root, and is 50x sweeter than sugar. Glycyrrhizin inhibits hepatic and renal 11b-OHSD and 5a-reductase thereby blocking the inactivation of glucocorticoids and mineralocorticoids and elevating their serum titer. DGL is a preparation from which the glycyrrhizin molecule has been removed. DGL is preferred to carbenoxolone sodium, a synthetic licorice derived ulcer medication that causes side effects, in the treatment of peptic ulcer disease.

• Anti-inflammatory and anti-allergenic effects: Glycyrrhetinic acid inhibits PGE2, arachadonic acid release, and has a activity similar to that of hydrocortisone in rat models of arthritis. Glycyrrhetinic acid also suppresses dexamethasone-induced histamine release, and mast cell degranulation in vivo according to animal studies.
(Snow J. Protoc.J.Bot.Med., 1996, 1,3:9-14)

• Anti-viral effects: Glycyrrhetinic acid inhibits Herpes simplex type 1, Varicella zoster (VZV), decreases Hepatitis B surface antigen, and inhibits HIV-1 (but not via reverse transcriptase.)
(Snow J. Protoc.J.Bot.Med., 1996, 1,3:9-14)

• Hepatoprotective effects: Glycyrrhetinic acid reduces key liver enzymes SGOT and SGTP and induces interferon according to animal studies.
(Abe, N, et al. Microbiol Immunol 1982;26(6):535-539; Abe, Y, et al. Nippon Rinsho 1994 Jul;52(7):1817-1822; Fujisawa K. Trop Gastroenterol 1991 Oct-Dec;12(4):176-179; Shinada M, et al. Proc Soc Exp Biol Med 1986 Feb;181(2):205-210; Eisenburg, J. Fortschr Med 1992 Jul 30;110(21):395-398.)

clinical trials:
Several clinical studies have shown DGL to be effective in in reducing size and symptoms of peptic ulcers without side effects, and of reducing surgery requirements and providing safe and long term maintenance in patients with healed ulcers. One study has shown that GL increases titers of prednisolone. A concentrated commercial preparation (SNMC) has been used to treat hepatiis, sub acute hepatic failure and improved symptoms in HIV haemophilia patients.
(Acharya SK, et al. Indian J Med Res 1993 Apr;98:69-74.Chen MF, et al . Endocrinol. Japon. 1990.37:331-341; Chen MF, et al. Endocrinol Jpn 1991 Apr;38(2):167-174;Hikono H, Kiso Y. Economic and Medical Plant Research 1988.Vol II: 39-72; Mori K, et al. 1990. Tohoku J. Exp. Med. 162: 183-193.)



Interactions

herb affecting drug performance: Corticosteroids

• mechanism: Glycyrrhiza potentiates prednisone and corticosteroids by prolonging steroid biological half-life. The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-DH) oxidizes cortisol to inactive cortisone. Some kinds of licorice contain glycyrrhetic acid which inhibits the action of 11 beta-DH (e.g. in the kidney). Thus, licorice consumption can induce a mineralocorticoid excess state, most likely due to an acquired inhibition of this key enzyme, decreased transformation of cortisol into cortisone, and resultant increased cortisol levels at the mineralocorticoid receptor. In states of 11 beta-DH deficiency such as the syndrome of apparent mineralocorticoid excess (AME) and licorice ingestion, cortisol acts as a potent mineralocorticoid. Furthermore, this increased mineralocorticoid action of cortisol can cause a drop in serum potassium and an increase in serum sodium concentration, together with a metabolic alkalosis, and lead to water retention, weight gain, and increased risk of hypertension.

• research: In a 1979 in vitro study using rat livers Tamura et al. found that two key components of licorice, glycyrrhetinic acid and glycyrrhizin, significantly suppressed the action of 5 beta-reduction. They further noted that 5 beta-reductase plays an important role in the regulation of cortisol and aldosterone metabolism in humans. In conclusion they "presumed" that the suppression of 5 beta-reductase activity by glycyrrhetinic acid or glycyrrhizin administration may delay the clearance of corticosteroids and prolong the biological half-life of cortisol resulting in the synergism of these steroids and glycyrrhetinic acid or glycyrrhizin. The simultaneous use of licorice, in concentrated or very large amounts for extended periods of time, could thus conceivably result in unintentionally high levels of circulating corticosteroids and increased incidence of drug-related side effects. In a single dose study involving six healthy men Chen et al found that the intravenous administration of a concentrated licorice extract, glycyrrhizin, together with prednisolone resulted in prolonged duration of action by the prednisolone in comparison to that in other subjects administered an equivalent dose of prednisolone without the glycyrrhizin. While such synergism could have beneficial uses, the authors cautioned that the enhanced activity of the prednisolone could result in increased side effects from the drug. Regardless, these findings may have only minimal relevance to the action of licorice used as an herb by the general public or as prescribed by trained medical herbalists of Western or Oriental traditions. Likewise, the practice of administering intravenous glycyrrhizin is relatively rare as it can only be administered legally by physicians in the United States and very few of them have the inclination or training to provide such treatments.
(Tamura Y, et al. Arzneimittelforschung 1979;29(4):647-64; Chen MF, et al. Endocrinol Jpn 1990 Jun;37(3):331-341; Lee YS, et al. Clin Pharmacol Ther 1996 Jan;59(1):62-71; Pratesi C, et al. J Hypertens Suppl 1991 Dec;9(6):S274-275; Nanahoshi M. Nippon Naibunpi Gakkai Zasshi 1967 Mar 20;42(12):1312-1319.)

herb affecting class drug toxicity: Thiazide Diuretics and Loop Diuretics

• mechanism: Loop and thiazide diuretics: potassium-depleting diuretics may potentiate the effects of glycyrrhizin, a saponin found in licorice, and thereby increase its toxic effects.
(Farese RV, et al. N Engl J Med 1991 Oct 24;325(17):1223-1227; Shintani S, et al. Eur Neurol 1992;32(1):44-51; Bannister B, et al. Br Med J 1977 Sep 17;2(6089):738-739.)

• herbal concerns: Most healthcare practitioners trained in botanical medicine now use deglycyrrhizinated licorice (DGL) in cases where there is significant risk of high blood pressure or other complications. DGL is safe to use with all diuretics. Nevertheless an individual with hypertension or taking any diuretic should only use licorice, in any form, within the context of appropriate medical supervision.

herb positively affecting drug toxicity: Acetylsalicylic Acid (Aspirin)

• mechanism: Glycyrrhiza reduces acetylsalicylic acid toxicity: DGL (deglycyrrhizinated licorice) is a concentrated extract of licorice root containing flavonoids that are especially effective in countering the irritating effects aspirin has on the stomach and intestines.

• research: One study found that when 350 mg of chewable DGL was taken at the same time as each dose of aspirin gastrointestinal, bleeding caused by the aspirin was significantly reduced. DGL also helps to heal mucous membranes and repair ulcers throughout the stomach and intestines, including those due to aspirin or other nonsteroidal anti-inflammatory drugs, such as indomethacin. According to one animal study, the combined action of DGL and Tagamet together was more effective in preventing harmful effects of aspirin than either medicine alone.
(Bennett A, et al. J Pharm Pharmacol 1980;32:151; Morgan AG, et al. Gut 1982,23:545-551; Morgan AG, et al. Gut 1985 Jun;26(6):599-602; Rees WDW, et al. Scand J Gastroenterol 1979;14:605-607.)

herb theoretically affecting drug toxicity: Digoxin

• mechanism: Licorice root potentiates the cumulative toxicity of cardiac glycosides including digoxin due to hypokalemic effects.
(Brinker F.1998, 91; Bisset NG (ed.), 1994, 303.)

• herbal concerns: A product known as DGL (Deglycyrrhizinated Licorice) is available which retains the anti-inflammatory and anti-ulcer actions of whole licorice root without pseudo-aldosterone side effects.

herb affecting drug performance: Interferon

• research: Synergy with Interferon: Intravenous application of concentrated derivatives of licorice root have been found to be efficacious in the treatment of hepatitis, in part due to its apparent stimulation of endogenous interferon. Several studies have found that the combination of glycyrrhizin and interferon can be more effective than synthetic interferon therapy alone. However, at this time, no human studies have been published using orally administered licorice extracts in conjunction with synthetic interferon.
(Abe, N, et al. Microbiol Immunol 1982;26(6):535-539; Abe, Y, et al. Nippon Rinsho 1994 Jul;52(7):1817-1822; Fujisawa K. Trop Gastroenterol 1991 Oct-Dec;12(4):176-179; Abe, Y, et al. Nippon Rinsho 1994 Jul;52(7):1817-1822; Shinada M, et al. Proc Soc Exp Biol Med 1986 Feb;181(2):205-210; Eisenburg, J. Fortschr Med 1992 Jul 30;110(21):395-398.)

herb affecting drug performance: Spironolactone (Aldactone®)

• mechanism: Glycyrrhiza can offset the pharmacological effect of spironolactone. 11 beta-hydroxysteroid dehydrogenase (11 beta-DH) is the enzyme that oxidizes cortisol to inactive cortisone and prevents cortisol from acting like a mineralocorticoid at the aldosterone receptor site in the kidney. Some kinds of licorice contain glycyrrhetic acid which inhibits the action of 11 beta-DH (e.g. in the kidney) and causes cortisol to behave like aldosterone. Thus, licorice consumption can induce a mineralocorticoid excess state, most likely due to an acquired inhibition of this key enzyme, decreased transformation of cortisol into cortisone, and resultant increased cortisol levels at the mineralocorticoid receptor. In states of 11 beta-DH deficiency such as the syndrome of apparent mineralocorticoid excess (AME) and licorice ingestion, cortisol acts as a potent mineralocorticoid. Thus, by acting to enhance aldosterone effects licorice would oppose the therapeutic intent of spironolactone as an aldosterone antagonist or aldosterone-inhibiting agent. Furthermore, this increased mineralocorticoid action of cortisol can cause a drop in serum potassium and an increase in serum sodium concentration, together with a metabolic alkalosis, and lead to water retention, weight gain, and increased risk of hypertension.
(Miller LG. Arch Intern Med 1998 Nov 9;158(20):2200-2211; Lee YS, et al. Clin Pharmacol Ther 1996 Jan;59(1):62-71; Pratesi C, et al. J Hypertens Suppl 1991 Dec;9(6):S274-275; Nanahoshi M. Nippon Naibunpi Gakkai Zasshi 1967 Mar 20;42(12):1312-1319.)

• herbal concern: The research cited above has focussed on concentrated extracts and intravenous forms of licorice. Common "licorice" candy usually contains no actual Glycyrrhiza, other than perhaps a minute amount as flavoring. No solid conclusions can be drawn as to how much these findings relate to the use of licorice in the forms commonly used by practitioners of Western and Chinese herbal medicine. A product known as DGL (Deglycyrrhizinated Licorice) is available which retains the anti-inflammatory actions of whole licorice root without pseudo-aldosterone side effects. Individuals using spironolactone should consult with their prescribing physician and/or a qualified practitioner of herbal medicine about the potential risks involved in using any form of licorice.

herb theoretically affecting drug toxicity: Monoamine Oxidase Inhibitors

• research: MAOI activity of licorice extracts has been noted in vitro but at concentrations orders of magnitude higher than would be achieved by therapeutic dose. Interactions with neurotransmitter modulating drugs are not reported.

drug affecting herb bioavailability: Antibiotics

• mechanism: Hydrolysis of glycyrrhizin into glycyrrhetinic acid is performed by bowel flora. This will be adversely affected by antibiotic therapy, although this is not a potentially dangerous pharmacokinetic interaction.

commentary: licorice root toxicity confusion:

• Enthusiastic medical reports of licorice toxicity fail to mention that the form of licorice responsible for causing side effects is invariably a commercial product such as chewing tobacco, laxatives, or confectionery containing concentrated licorice extracts, often in combination with loop diuretics rather than the medicinal form of the herb, i.e., whole licorice root. Medical reports of whole licorice root consumption causing side effects are conspicuously absent from the literature. For an excellent overview of the licorice root toxicity controversy see Daniel Mowrey.
(Mowrey DB.1986, Appendix A 294.)

• Commission E suggests Glycyrrhiza is contraindicated in cholestatic hepatic disease. Licorice root is hepatoprotective, antihepatotoxic, and has been used succesfully in clinical trials to treat viral hepatitis. These facts suggest the Comission E is unduly conservative in this regard. Nevertheless, when severe liver disease is accompanied by ascites, licorice would be contrandicated due to its mineralocorticoid effects

• Two reports of fatalities due to massive hepatic toxicity (necrosis) followed intravenous administration of SNMC, a concentrated parenteral licorice derivative used in Japanese research.

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Abe N, Ebina T, Ishida N. Interferon induction by glycyrrhizin and glycyrrhetinic acid in mice. Microbiol Immunol 1982; 26(6):535-539.

Abe Y, Ueda T, Kato T, Kohli Y. [Effectiveness of interferon, glycyrrhizin combination therapy in patients with chronic hepatitis C]. Nippon Rinsho 1994 Jul;52(7):1817-1822. [Article in Japanese]
Abstract: SNMC (stronger Neominophagen C), whose active component is glycyrrhizin (a saponin extracted from licorice) has been utilized to improve the liver function in Japan. To assess the effectiveness of interferon (IFN), SNMC combination therapy in patients, who did not respond to IFN therapy alone, we investigate 28 patients with histology of CAH 2B at 12 weeks after IFN administration. 15 patients received IFN alone continuously (group A), and 13 patients received IFN with SNMC (group B) for 12 weeks thereafter. Normalization of serum ALT level was observed in 33.3% of group A and in 64.3% of group B. Disappearance of serum HVC RNA was 13.3% in group A and 38.5% in group B. But these data were not significant statistically. Histological improvement was not significant, between group A and B by Knodel's HAI score, but reversal of histological grade (Europe classification) was noted more frequently in group B. A case of posttransfusion hepatitis type C, exacerbated by IFN therapy is reported. HLA class I antigen was strongly expressed in the liver tissue after administration of IFN. In this case, potentiation of cellular immunity was thought to be the cause of the exacerbation and IFN, SNMC combination therapy was useful in improving liver function.

Acharya SK, Dasarathy S, Tandon A, Joshi YK, Tandon BN. A preliminary open trial on interferon stimulator (SNMC) derived from Glycyrrhiza glabra in the treatment of subacute hepatic failure. Indian J Med Res 1993 Apr;98:69-74.
Abstract: The efficacy of the interferon stimulator named Stronger Neo Minophagen-C (SNMC) derived form the plant G. glabra was studied at a dose of 40 or 100 ml daily for 30 days followed by thrice weekly intravenously for 8 wk in 18 patients of subacute hepatic failure due to viral hepatitis. The survival rate amongst these patients was 72.2 per cent, as compared to the earlier reported rate of 31.1 per cent in 98 patients who received supportive therapy (P < 0.01). Death in four of the five patients was due to associated infections leading to hepatorenal failure and terminal coma. Further studies are necessary to standardize the dose and duration of therapy with SNMC in subacute hepatic failure.

Acharya S, et al. A preliminary open trial on interferon stimulator(SNMC) derived from Glycyrrhiz glabra in the treatment of subacute hepatic failure. 1993. Indian Journal of Medical Research 98:69-74.

Bannister B, Ginsburg R, Shneerson J. Cardiac arrest due to liquorice induced hypokalaemia. Br Med J 1977 Sep 17;2 (6089):738-739.

Bennett A, Clark-Wibberley T, Stamford IF, Wright JE. Aspirin-induced gastric mucosal damage in rats: Cimetidine and deglycyrrhizinated liquorice together give greater protection than low doses of either drug alone. J Pharm Pharmacol 1980 Feb;32(2):151.

Bensky, Gamble A, Kaptchuck T. Chinese Herbal Medicine: Materia Medica. Revised Edition. Seattle: Eastland Press, 1993.

Bisset NG (ed.), Wichtl M. Herbal Drugs and Phytopharmaceuticals, Boca Raton, FL: CRC Press, 1994.

Blumenthal M, Busse WR, Goldberg A, et al, eds. The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, MA: Integrative Medicine Communications, 1998.

Bradley PR, ed. British Herbal Compendium, vol 1. Bournemouth, Dorset, UK: British Herbal Medicine Association, 1992.

Brinker F. Herb Contraindications and Drug Interactions. Second edition. Eclectic Institute Inc, Sandy, OR,1998.

Chen MF, et al. Effects of glycyrrhizin on the pharmacokinetics of prednisolone following low dosage of prednisolone hemisuccinate. Endocrinol.Japon. 1990;37:331-341
Abstract: We investigated the pharmacokinetics of prednisolone (PSL) in six healthy men, with or without glycyrrhizin (GL), to confirm whether GL influences the metabolism of PSL in humans. Each subject received an intravenous administration of 0.096 mg/kg of prednisolone hemisuccinate (PSL-HS, equivalent to 0.075 mg/kg of PSL), with or without 200 mg of GL. Blood samples were taken from a peripheral vein at 5, 10, 15, 30 and 45 min, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after PSL-HS infusion. The concentration of total PSL in the plasma was analyzed by high-performance liquid chromatography, and the free PSL was measured by an isocolloidosmolar equilibrium dialysis method. The pharmacokinetic parameters of PSL were determined, using noncompartmental analysis. GL was found to increase significantly the concentration of total PSL at 6, 8 h, and of free PSL at 4, 6, and 8 h after PSL-HS infusion. GL was also found to modify the pharmacokinetics of PSL. After the administration of GL, the area under the curve (AUC) increased, total plasma clearance (CL) decreased, and the mean residence time (MRT) was prolonged. However, only those of AUC, CL, and MRT of free PSL were significantly different. The volume of distribution at a steady-state (Vdss) of both total and free PSL showed no evident change. This suggests that GL increases the plasma PSL concentrations by inhibiting the metabolism of PSL and that it potentiates pharmacological effects of PSL.

Chen MF, Shimada F, Kato H, Yano S, Kanaoka M. Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn i 1991 Apr;38(2):167-174.
Abstract: The pharmacokinetics of total and free prednisolone (PSL) in six healthy men, with or without pretreatment with oral glycyrrhizin (GL), was investigated to confirm whether oral administration of GL influences the metabolism of PSL in man. Each subject received an intravenous administration of 0.096 mg/kg of prednisolone hemisuccinate (PSL-HS) with or without pretreatment with 50 mg of oral GL four times. Blood samples were taken from a peripheral vein at 5, 10, 15, 30, 45 min and 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 h after the start of PSL-HS infusion. The concentrations of total PSL in plasma were analyzed by high-performance liquid chromatography, and the free PSL was measured by an isocolloidosmolar equilibrium dialysis method. The pharmacokinetic parameters of PSL were determined by non-compartment analysis. Oral administration of GL was found to significantly increase the concentrations of total PSL at 6, 8 h, and of free PSL at 4, 6 and 8 h after PSL-HS infusion. Moreover, oral administration of GL was also found to modify the pharmacokinetics of both total and free PSL. After oral administration of GL, the area under the curve (AUC) was significantly increased, the total plasma clearance (CL) was significantly decreased, and the mean residence time (MRT) was significantly prolonged. However, the volume of distribution (Vdss) showed no evident change. This suggests that oral administration of GL increases the plasma PSL concentrations and influences its pharmacokinetics by inhibiting its metabolism, but not by affecting its distribution.

D'Arcy PF. Adverse reactions and interactions with herbal medicines. Part 2 - Drug interactions. Adverse Drug React. Toxicol Rev. 12:147-162, 1993.

De Smet PAGM, et al. (eds.). Adverse Effects of Herbal Drugs 2. Berlin: Springer-Verlag, 1993.

Edwards CR, Teelucksingh S. Glycyrrhetinic acid and potentiation of hydrocortisone activity in skin. Lancet 1990 Aug 4;336(8710):322-323. (Letter)


Eisenburg, J. [Treatment of chronic hepatitis B. Part 2: Effect of glycyrrhizic acid on the course of illness]. Fortschr Med 1992 Jul 30;110(21):395-398. [Article in German]
Abstract: AIMS: Testing of the therapeutic efficacy of Remefa S, a pharmaceutical comprising glycyrrhizinic acid, the major active substance of licorice, on the evolution of the disease in late chronic viral hepatitis B. METHODS: Prospective evaluation of the biochemical, virus-serological and histomorphological data (blind liver aspiration, laparoscopy) during and following 12 months of application (three times a week, short infusions) of Remefa S, and comparison with the course of the disease (12 months) prior to treatment. PATIENTS: Intermediate report on an ongoing multicentre study begun in 1989, with evaluation of 7 subjects receiving the preparation and 3 controls after 12 months of treatment and 10 months of follow-up. RESULTS: During or after treatment, 4 patients experienced a regression of biochemical disease activity. In 2 of the 4 patients, during treatment, an HBe-Ag seroconversion occurred for the first time and has persisted (to date 10 months); in another patient with no detectable HBe-Ag prior to treatment, HBe antibodies were formed under treatment, and have persisted to the present time. In 2 of these responders, histology also revealed an unequivocal reduction in disease activity. In contrast, HBs-Ag seroconversion was observed in none of the patients treated. Since in these three patients the virus genome was already integrated within the chromosome of the host cell (hybridization), this had not been expected from the start. CONCLUSIONS: Intravenous chronic application (12 months) of glycyrrhizinic acid in the form of Remefa S in patients with chronic viral hepatitis B, is capable of exercising a positive effect on the evolution of the disease. On the basis of the results obtained so far (30-40% success rate), a comparison with the results obtained with interferon suggests itself.

Farese RV Jr, Biglieri EG, Shackleton CH, Irony I, Gomez-Fontes R. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991 Oct 24;325(17):1223-1227.

Felter, Harvey W, and Lloyd, John Uri. King's American Dispensatory. Sandy, OR: Eclectic Medical Publications, 1993.

Fujisawa K. Interferon therapy in hepatitis C virus (HCV) induced chronic hepatitis: clinical significance of pretreatment with glycyrhizine. Trop Gastroenterol 1991 Oct-Dec;12(4):176-179.

Gomez-Sanchez EP, Gomez-Sanchez CE. Central hypertensinogenic effects of glycyrrhizic acid and carbenoxolone. Am J Physiol 1992 Dec;263(6 Pt 1):E1125-E1130.
Abstract: The apparent mineralocorticoid excess syndrome of patients ingesting large amounts of licorice or its derivatives is thought to be caused by the antagonism by these compounds of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 11 beta-HSD inactivates cortisol and corticosterone, allowing the more abundantly produced glucocorticoids access to the mineralocorticoid receptor (MR) in the kidney, where they act as mineralocorticoids. We have found that the infusion of both glycyrrhizic acid, an active principle of licorice, and carbenoxolone, a synthetic analogue, into a lateral ventricle of the brain [intracerebroventricular (icv)] of a rat, at a dose less than that which has an effect when infused subcutaneously, produces hypertension. Furthermore, the hypertension produced by the oral administration of carbenoxolone or glycyrrhizic acid is blocked by the icv administration of RU 28318, an MR antagonist, at a dose below that which has an effect on blood pressure when infused subcutaneously. While the oral administration caused saline polydipsia and polyuria typical of chronic systemic mineralocorticoid excess, the icv licorice derivatives produced hypertension without affecting saline appetite. Sensitizing the rats to mineralocorticoid hypertension by renal mass reduction and increasing salt consumption was not necessary for the production of hypertension. These findings provide additional evidence for a central role in blood pressure control by mineralocorticoids that is distinct from their renal effects. They also suggest that more is involved in licorice-induced hypertension than only inhibition of 11 beta-HSD.

Heidemann HT, Kreuzfelder E. Hypokalemic rhabdomyolysis with myoglobinuria due to licorice ingestion and diuretic treatment. Klin Wochenschr 1983 Mar 15;61(6):303-305.
Abstract: A 54-year-old man was admitted to hospital with acute rhabdomyolysis and myoglobinuria due to hypokalemia. The hypokalemia was due to chronic licorice ingestion and diuretic treatment. The myoglobinemia led to a glomerulopathy and tubulopathy. There was, however, no clinical evidence of acute renal failure (ARF). We propose that the volume expansion caused by the steroid-like actions of licorice might have prevented the development of an ARF.

Homma M, Oka K, Niitsuma T, Itoh H. A novel 11 beta-hydroxysteroid dehydrogenase inhibitor contained in saiboku-to, a herbal remedy for steroid-dependent bronchial asthma. J Pharm Pharmacol 1994 Apr;46(4):305-309.
Abstract: To identify the inhibitor of prednisolone metabolism contained in Saiboku-To, we conducted in-vitro experiments of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), using rat liver homogenate and cortisol as a typical substrate. We studied the effects of ten herbal constituents on 11 beta-HSD. Five herbal extracts showed inhibitory activity with Glycyrrhiza glabra > Perillae frutescens > Zizyphus vulgaris > Magnolia officinalis > Scutellaria baicalensis. This suggests that unknown 11 beta-HSD inhibitors are contained in four herbs other than G. glabra which contains a known inhibitor, glycyrrhizin (and glycyrrhetinic acid). Seven chemical constituents which have been identified as the major urinary products of Saiboku-To in healthy and asthmatic subjects were studied; magnolol derived from M. officinalis showed the most potent inhibition of the enzyme (IC50, 1.8 x 10(-4) M). Although this activity was less than that of glycyrrhizin, the inhibition mechanism (non-competitive) was different from a known competitive mechanism. These results suggest that magnolol might contribute to the inhibitory effects of Saiboku-To on prednisolone metabolism through inhibition of 11 beta-HSD.

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Kumagai A, Nishino K, Yamamoto M, Nanaboshi M, Yamamura Y. An inhibitory effect of glycyrrhizin on metabolic actions of cortisone. Endocrinol Jpn 1966 Dec;13(4):416-419.

Kumagai A, Asanuma Y, Yano S, Takeuchi K, Morimoto Y, Uemura T, Yamamura Y. Effect of glycyrrhizin on the suppressive action of cortisone on the pituitary adrenal axis. Endocrinol Jpn 1966 Sep;13(3):234-244.

Kumagai A, Nanaboshi M, Asanuma Y, Yagura T, Nishino K. Effects of glycyrrhizin on thymolytic and immunosupressive action of cortisone. Endocrinol Jpn Mar;14(1):39-42.

Lee YS, Lorenzo BJ, Koufis T, Reidenberg MM. Grapefruit juice and its flavonoids inhibit 11 beta-hydroxysteroid dehydrogenase. Clin Pharmacol Ther 1996 Jan;59(1):62-71.
Abstract: INTRODUCTION: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) oxidizes cortisol to inactive cortisone. Its congenital absence or inhibition by licorice increases cortisol levels at the mineralocorticoid receptor, causing mineralocorticoid effects. We tested the hypothesis that flavonoids found in grapefruit juice inhibit this enzyme in vitro and that grapefruit juice itself inhibits it in vivo. METHODS: Microsomes from guinea pig kidney cortex were incubated with cortisol and nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) and different flavonoids and the oxidation to cortisone measured with use of HPLC analysis. In addition, healthy human volunteers drank grapefruit juice, and the ratio of cortisone to cortisol in their urine was measured by HPLC and used as an index of endogenous enzyme activity. RESULTS: Both forms of 11 beta-OHSD requiring either NAD or NADP were inhibited in a concentration-dependent manner by the flavonoids in grapefruit juice. Normal men who drank grapefruit juice had a fall in their urinary cortisone/cortisol ratio, suggesting in vivo inhibition of the enzyme. CONCLUSION: Dietary flavonoids can inhibit this enzyme and, at high doses, may cause an apparent mineralocorticoid effect.

Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998 Nov 9;158(20):2200-2211. (Review)

Mcquade-Crawford A, Treasure J E, 1998 Licorice - Ancient Elixir, Modern Medicine Keats Publishing Ct USA, in press.

Morgan AG, McAdam WAF, Pascoo C, Darnborough A. Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982 Jun;23(6):545--551.
Abstract: One hundred patients with benign gastric ulceration were treated in a single-blind, endoscopically controlled trial to assess the relative efficacy of cimetidine (1 g daily) and Caved-S (six tablets daily). Ulcer healing was assessed after six weeks' treatment, and, if incomplete, after a further six weeks. There was no significant difference between the two drug regimens (approximately 63% at six weeks and 91% at 12 weeks). If an ulcer remains unhealed after 10 weeks' treatment the patient should undergo surgery. There was no difference in the relief of day pain between the two drug regimens but cimetidine was more effective over the first two weeks of treatment relieving night pain, than was Caved-S (p less than 0 . 02). After ulcer healing, drug dosage was reduced (cimetidine to 400 mg at night and Caved-S to two tablets twice daily). So far, 56 patients, 28 in each group, have completed the first year's maintenance treatment, and there have been four ulcer recurrences in each group (14%).

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 Jun;26(6):599-602.
Abstract: Eighty two patients with an endoscopically healed gastric ulcer, were treated for two years with either Caved-S tablets, two twice daily or cimetidine 400 mg at night. During the first year, 12% (four out of 34) of the Caved-S group and 10% (four out of 41) of the cimetidine group had an ulcer recurrence. By the end of the second year, the recurrence rate was 29% (nine out of 31) in the Caved-S group, and 25% (eight out of 32) for the cimetidine group. Ulcer relapse occurred frequently in patients with either a dyspeptic history of over six months (p less than 0.05), or a past history of a gastric ulcer (p less than 0.001). Ulcers recurred rapidly after maintenance therapy; Caved-S two out of 22; cimetidine seven out of 23, within four months (NS). This study shows that long term maintenance therapy is safe and reasonably effective. The high recurrence rate after stopping treatment suggests that therapy in high risk or elderly patients should be for life.

Mori K, et al. Effects of Glycyrrhizin (SNMC) in haemophilia poatients with HIV-1 infection. 1990. Tohoku J. Exp. Med. 162: 183-193.

Mowrey DB, The Scientific Validation of Herbal Medicine.Keats Publishing Inc, New Canaaan, CT.1986

Nanahoshi M. [Effect of glycyrrhizin on the action cortisone]. Nippon Naibunpi Gakkai Zasshi 1967 Mar 20;42(12):1312-1319. [Article in Japanese]

Nesbitt LT Jr. Minimizing complications from systemic glucocorticosteroid use. Dermatol Clin 1995 Oct;13(4):925-939. (Review)
Abstract: For proper use of systemic GCS, a basic knowledge of the normal HPA axis, as well as knowledge of the pharmacology, clinical usage guidelines, and adverse reactions of these agents is imperative. Both short-term (acute) and long-term side effects should be well known by the physician. The pros and cons of oral and parenteral therapy for various disorders and in various situations should be recognized. For long-term therapy, an intermediate-acting agent such as prednisone in single, early morning doses is most commonly used to minimize suppression of the HPA axis. Alternate-morning doses produce even less suppression if the disease process will respond. A through patient history, including general medical history and medications the patient is taking, is important to anticipate any potential problems. Weight and blood pressure should be checked initially and every 1 to 3 months thereafter. Blood glucose, electrolytes, and lipid studies, including triglycerides, should be done approximately every 6 months. An ophthalmology examination should be performed every year, and stool examination for occult blood and chest radiography can be obtained as indicated. Bone density studies might be necessary in patients who are at high risk for osteoporosis. Specific acute situations may dictate other studies. The patient on long-term GCS should be kept as active as possible, as mild-to-moderate exercise helps prevent certain side effects, such as osteoporosis. The dose of oral GCS is best given with food to prevent gastrointestinal irritation, and agents to decrease gastric acidity might be needed in certain situations. Exposure to infections should be prevented, where possible, and treatment initiated at the first sign of systemic or cutaneous infection. Pain should be evaluated early, especially abdominal pain or bone pain; MRI is indicated if aseptic necrosis of bone is suspected. Both trauma and severe sun exposure should be avoided. Consultation with other specialists is strongly recommended when the situation dictates. Diet is one of the most important strategies to minimize side effects from long-term GCS therapy. Vegetable protein should be increased in the diet, and fats and carbohydrates limited. Adequate calcium is imperative, and calcium supplementation is recommended for high-risk osteoporosis patients. Small amounts of vitamin D may be necessary to increase absorption of calcium. Restriction of sodium is also important, as is maintainance of dietary potassium. Supplemental potassium may be necessary in some patients, and a thiazide diuretic might be useful in patients with hypertension, edema, or osteoporosis. Vitamin C can be given to promote wound healing. A good doctor-patient relationship is important in managing the patient on long-term GCS. The patient must return for regular visits and be encouraged to promptly report any adverse reactions to the physician. If these criteria are maintained and the strategies noted previously are followed, problems from long-term therapy with GCS will be minimized.


Pratesi C, Scali M, Zampollo V, Zennaro MC, De Lazzari P, Lewicka S, Vecsei P, Armanini D. Effects of licorice on urinary metabolites of cortisol and cortisone. J Hypertens Suppl 1991 Dec;9(6):S274-275.

Rees WD, Rhodes J, Wright JE, Stamford LF, Bennett A. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol 1979;14(5):605-607.
Abstract: Gastric mucosal damage induced by giving 60 mg aspirin orally to rats was reduced by simultaneous administration of 100-500 mg deglycyrrhizinated liquorice. Human faecal blood loss induced by 975 mg aspirin orally three times a day was less when 350 mg deglycyrrhizinated liquorice was given with each dose of aspirin.

Shinada M, Azuma M, Kawai H, Sazaki K, Yoshida I, Yoshida T, Suzutani T, Sakuma T. Enhancement of interferon-gamma production in glycyrrhizin-treated human peripheral lymphocytes in response to concanavalin A and to surface antigen of hepatitis B virus. Proc Soc Exp Biol Med 1986 Feb;181(2):205-210.
Abstract: The effects of glycyrrhizin, a component of licorice (Glycyrrhiza glabra) roots, on the production of interferon-gamma in human peripheral lymphocyte-macrophage cultures by concanavalin A (Con A) was examined. Interferon-gamma production in normal lymphocyte-macrophage cultures treated with 10 to 100 micrograms/ml of glycyrrhizin at 37 degrees C for 12 hr or longer, and then treated with 10 micrograms/ml of Con A, was enhanced four to eight times compared to control cell cultures. Lymphocyte-macrophage cultures treated with 10 to 100 micrograms/ml of glycyrrhizin alone did not produce interferon. No significant difference in the adsorption of [3H]Con A to glycyrrhizin-treated and control lymphocyte-macrophage cultures was found, but RNA and protein synthesis of the treated lymphocytes was increased compared to control cells; DNA synthesis, however, was reduced. Collaboration between enriched T-lymphocytes and macrophages, both treated with glycyrrhizin, was needed for the enhancement of interferon-gamma production. A smaller increase in interferon production was also observed in the glycyrrhizin-treated peripheral lymphocyte-macrophage cultures derived from an asymptomatic carrier of hepatitis B virus, in response to Con A and surface antigen of hepatitis B virus.

Shintani S, Murase H, Tsukagoshi H, Shiigai T. Glycyrrhizin (licorice)-induced hypokalemic myopathy. Report of 2 cases and review of the literature. Eur Neurol 1992;32(1):44-51.
Abstract: Fifty-nine cases of glycyrrhizin (licorice)-induced hypokalemic myopathy (GIHM), 2 females treated in our departments (85 and 73 years old) and 57 cases reported in the literature were studied, and conditions leading to the onset, factors, clinical manifestations, laboratory assessments, muscle biopsy findings, treatment and outcome were discussed. The 59 GIHM cases comprised 32 men, 25 women and 2 patients without record of sex; the average age was 55.2 years. In many cases, conditions leading to the onset of GIHM were habitual licorice ingestion, ingestion of antituberculosis agents containing licorice and long-term ingestion of licorice-containing agents for chronic gastritis, chronic hepatitis or chronic dermatitis. The combined use of hypotensive diuretic agents increased the risk of GIHM in an overwhelming number of cases. The main clinical symptom was flaccid quadriplegia in almost all cases, with muscle pain in 32.2% and peripheral dysesthesia in the extremities, manifested mainly by numbness (27.1%). Laboratory findings included a mean serum K+ value of 1.98 mEq/l (56 GIHM cases), a mean creatine kinase of 5,385.7 IU/l (n = 30), a mean blood aldosterone concentration of 2.92 ng/dl (n = 30; normal: 2.0-13.0 ng/dl) and a mean plasma renin activity of 0.17 ng/ml/h (n = 27; normal: 0.8-4.4 ng/ml/h). Muscle biopsy was performed in 17 of the 59 cases with resultant findings of myopathic changes consisting mainly of phagocytosis, necrotic fibers, vacuolar degeneration, together with sporadic neurogenic changes. Complete cure was attained in 57 of the 59 cases of GIHM by discontinued ingestion of glycyrrhizin (licorice) and potassium supplement.


Snow J. Glycyrrhiza glabra Monograph. Protocol Journal of Botanical Medicine, 1996, 1,3:9-14

Stewart PM, Wallace AM, Valentino R, Burt D, Shackleton CH, Edwards CR. Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet 1987 Oct 10;2(8563):821-824.
Abstract: The sodium retention associated with liquorice ingestion has been thought to be due to a direct mineralocorticoid effect, despite the fact that it does not seem to occur in patients or animals with severe adrenal insufficiency. This study in seven normal subjects given liquorice showed that sodium retention is associated with a significant change in cortisol metabolism indicating inhibition of 11-beta-hydroxysteroid dehydrogenase (11 beta-OHSD). Congenital deficiency of this enzyme produces a syndrome of apparent mineralocorticoid excess. It is suggested that in both conditions there is a defect in the renal conversion of cortisol to cortisone by 11 beta-OHSD which results in high intrarenal cortisol levels, acting on type 1 mineralocorticoid receptors to cause sodium retention.

Tamura Y, Nishikawa T, Yamada K, Yamamoto M, Kumagai A. Effects of glycyrrhetinic acid and its derivatives on delta 4-5 alpha- and 5 beta-reductase in rat liver. Arzneimittelforschung 1979;29(4):647-649.

Teelucksingh S, Mackie AD, Burt D, McIntyre MA, Brett L, Edwards CR. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990 May 5;335(8697):1060-1063.
Abstract: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which catalyses the conversion of cortisol to the inactive steroid cortisone in man (and corticosterone to 11-dehydrocorticosterone in rodents), was demonstrated by immunohistochemistry in skin biopsy samples from healthy volunteers and from patients with psoriasis and eczema. In-vitro studies confirmed the presence of the enzyme in skin from nude mice and showed that it is inhibited by glycyrrhetinic acid, the major active component of liquorice. By means of the skin vasoconstrictor assay, glycyrrhetinic acid was shown to potentiate the action of hydrocortisone. This work suggests a novel means of targeting glucocorticoid therapy.