-IBIS-1.7.0-
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herb
Glycyrrhiza glabra (Licorice Root)
Botanicals

definition

botanical name(s): Glycyrrhiza glabra
synonyms: licorice root, sweet licorice, sweet wood, sweetwort, liquorice, sussholz (D), bois doux (F)
part(s) used: rhizome, root
qualities: sweet, moist, bitter, cool,
affinities: lungs, stomach, liver, adrenal cortex
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 12g)
» Tincture: (1:5) 5-15 ml three times daily
» Solid Extract: (4:1) 250-500mg three times daily (Manufacturers preparations may vary)
» DGL Capsules :1-3 caps three times daily (Manufacturers preparations may vary 300-380mg is typical)
therapy:
» Internal:cough; bronchitis, asthma and allergies, peptic ulcer disease; chronic gastritis; adrenocortical insufficiency; steroid drug withdrawl, chronic fatigue, hepatitis, hypotension, hypoglycemia, rheumatism, arthritis.
» External: herpes simplex lesions, apthous stomatitis, dental caries.
constituents: Saponin Triterpenes (including Glycyrrhizin, glycyrrhetinic acid [GA], liquiritic acid): Flavonoids and isoflavonoids (including liquiritin, formononetin); coumarins, sugars, polysaccharides, asparagine, starch, bitter principle.
pharmacology
» Corticosteroid effects: The glycoside Glycyrrhizin is the major triterpenoid consituent 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 titre.(Snow, 1996). 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) for peptic ulcer therapy.
» Anti-inflammatory & Anti-allergenic effects: GA inhibits PGE2, arachadonic acid release, and has a activity similar to that of hydrocortisone in rat models of arthritis. GA suppresses dexamethasone induced histamine release, and mast cell degranulation in vivo (animal studies)
» Anti-viral effects: GA inhibits Herpes simplex type 1,Varicella zoster (VZV), decreases Hepatitis B surface antigen, inhibits HIV-1 but not via reverse transcriptase (Snow 1986)
» Hepatoprotective effects: GA reduces SGOT and SGTP and induces interferon (animal studies)
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. (Snow 1996) One study has shown that GL increases titres of prednisolone (Chen et al. 1990) A concentrated commercial preparation (SNMC) has been used to treat hepatiis, (Hikono 1988) sub acute hepatic failure (Acharya, 1993) and improved symptoms in HIV haemophilia patients (Mori, 1990)
AHPA Botanical Safety Rating: 2b, 2d
toxicity: 2
» The maximum daily therapeutic dose range should not be exceeded. Idiosyncratic hypersensitivity reactions to licorice root are rare but have been empirically noted.
» contraindicated in overweight, hypertensive or cardiac patients, especially those on cardiotonic drugs or diuretics (see drug interactions) (Brinker)
» contraindicated in severe renal insufficiency or high blood pressure due to the sodium and fluid retention (Brinker, Wichtl, De Smet)
» contraindicated in hypokalemia due to increased potassium excretion from kidneys (Wichtl)
» The effects of prolonged consumption of licorice root in excess of the safe therapeutic dose may result in Pseudoaldosteronism which mimics mineralocorticoid excess. (see footnotes). This syndrome is characterized by potassium loss,sodium retention, edema, hypertension and weight gain.
drug interactions:
» potentiates the cumulative toxicity of cardiac glycosides due to potassium loss (Brinker, Wichtl)
» increases potassium loss from thiazide diuretics, but should also not be used simultaneously with either spironolactone or amiloride (Wichtl)
» potentiates corticosteroids by prolonging steroid biological half-life
» MAOI activity 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.
» Antibiotics: hydrolysis of Glycyrrhizin into GA is performed by bowel flora. This will be adversely effected by antibiotic therapy, although this is not a potentially dangerous interaction.


Notes:
» 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 confectionary containing concentrated licorice extracts, often in combination with loop diuretics rather than the medicinal formof the herb - 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 myth see Mowrey,1986.Appendix A.

» Commission E suggests Licorice is contraindcated 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, but when severe liver disease is often accompanied by ascites licorice would be contrandicated from this point of view. Two reports of fatalities due to massive hepatic toxicity (necrosis) followed intravenous administration of SNMC - a concentrated licorice derivative.


footnotes

General reference: Snow(1996) and Mcquade-Crawford & Treasure (1998)

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

Brinker F. 1996. The Toxicology of Botanical Medicines, rev. 2nd ed., Sandy, OR: Eclectic Medical Publications.

Chen MF et al 1990. Effects of glycyrrhizin on the pharmacokinetics of prednisolone folloowing low dosage of prednisolone hemisuccinate. Endocrinol.Japon. 37:331-341.

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.

Hikono H, Kiso Y, 1988. Natural products for Liver Diseases. Economic and Medical Plant Research Vol II: 39-72

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

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

Mowrey D, 1988 The Scientific Validation of Herbal Medicine, Keats Publishing. Ct, USA.

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.

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