Interactions with Licorice
Angiotensin-Converting Enzyme (ACE) Inhibitors
ACE inhibitors enhance the dehydrogenase activity of 11b-hydroxysteroiddehydrogenase (11b-HSD), which is thought to contribute to their ability to cause sodium excretion by the kidneys (Kerstens and Dullaart 1999). Licorice reduces the action of 11b-HSD; in so doing, licorice may oppose some of the antihypertensive effects of ACE inhibitors.
Aspirin
Deglycyrrhizinated licorice (DGL) (100 mg, 300 mg, or 500 mg) administered with aspirin (60 mg po) reduces ulcer formation and blood loss in rats (Rees et al. 1979). The effects of licorice on aspirin-induced gastric mucosal injury also were evaluated in a double-blind cross-over study with nine healthy male volunteers. Less blood loss was associated with aspirin ingestion (325 mg tid) when administered concurrently with DGL (175 mg). It has also been shown that licorice-coated aspirin significantly reduced the number and size of ulcers in the gastric mucosa of animals compared to aspirin alone (Dehpour et al. 1994).
Cimetidine
In rats, low doses of cimetidine taken with DGL (50 mg) provided greater protection than either deglycyrrhizinated licorice or cimetidine alone (Bennett et al. 1980).
Digoxin
Licorice not only induces high blood pressure in some patients but also causes clinically significant hypokalemia, resulting in myopathy and arrhythmia (Bannister et al. 1977; Sailler et al. 1993; Shintani et al. 1992). Patients with hypokalemia may be predisposed to developing digoxin toxicity because potassium depletion sensitizes the myocardium to digoxin (PDR 1999). Licorice-induced hypokalemia and its subsequent effects on digoxin are not well documented.
Hydrocortisone; Prednisolone
A study conducted with volunteers and patients with psoriasis and eczema demonstrated that application of glycyrrhetinic acid, the active component in licorice, enhanced vasoconstriction and glucocorticoid activity in skin by local inhibition of 11 beta-hydroxysteroid dehydrogenase (11b-HSD), resulting in decreased conversion of cortisol to cortisone, the inactive steroid (Teeleucksingh et al. 1990). This report also noted that in vitro studies in nude mice confirmed the inhibition of this enzyme in skin. This investigation revealed that topical application of glycyrrhetinic acid significantly enhanced the anti-inflammatory activity of topical hydrocortisone compared to hydrocortisone alone.
Systemic administration of glycyrrhizin with prednisolone was shown to alter the pharmacokinetic parameters of prednisolone by significantly increasing the concentrations of both total and free prednisolone in plasma (Chen et al. 1990; Chen et al. 1991). These results suggest that ingestion of licorice could interact with corticosteroid treatment. In studies with rats and rabbits, glycyrrhizin exhibited an ability to enhance the immunosuppressive effects of cortisone (Kumagai et al. 1967).
Oral Contraceptives
A healthy female volunteer taking oral contraceptives developed hypertension, hypokalemia, and peripheral edema after four weeks of ingestion of dried, aqueous extract of licorice root at doses up to 814 mg (Bernardi et al. 1994). There are two other case reports cited in the literature involving women who also developed hypokalemia and hypertension when they used licorice chewing gum while on oral contraceptives (de Klerk et al. 1997). Symptoms resolved upon discontinuation of the licorice chewing gum.
Thiazide Diuretics; Loop Diuretics
When licorice-containing substances were combined with diuretics, patients were at increased risk of developing glycyrrhizin-induced hypokalemic myopathy (GIHM) (Shintani et al. 1992). In 96.6% of the cases studied, GIHM resolved completely by supplementing with potassium and discontinuing the glycyrrhizin.
Ingestion of licorice (200 gm/day) for 10 weeks concurrent with a thiazide diuretic for two weeks resulted in the development of severe hypokalemia, arterial hypertension, edema, and rhabdomyolysis in a 38-year-old man (Folkersen et al. 1996). A hypertensive 70-year-old man who ingested licorice candy (100 g/day) for 4 to 5 years became pathologically hypokalemic when treated with thiazide diuretics (Farese et al. 1990).
Drug Monographs
References
Bannister B, Ginsberg R, Scneerson J. Cardiac arrest due to liquorice-induced hypokalemia. Br Med J. 1977;17:738-739.
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;32(2):150.
Bernardi M, D'Intino PE, Trevisani F, et al. Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. Life Sci. 1994;55(11):863-872.
Chen MF, Shimada F, Kato H, Yano S, Kanaoka M. Effect of glycyrrhizin on the pharmacokinetics of prednisolone following low dosage of prednisolone hemisuccinate. Endocrinol Jpn. 1990;37(3):331-341.
Chen MF, Shimada F, Kato H, Yano S, Kanaoka M. Effect of oral glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn. 1991;38(2):167-174.
de Klerk GJ, Nieuwenhuis C, Beutler JJ. Hypokalemia and hypertension associated with use of liquorice flavoured chewing gum. BMJ. 1997;314:731-732.
Dehpour AR, Zolfaghari ME, Samadian T. The protective effect of liquorice components and their derivatives against gastric ulcer induced by aspirin in rats. J Pharm Pharmacol. 1994;46(2):148-149.
Farese RV, Biglieri EG, Shakelton CHL, et al. Licorice-induced hypermineralcorticoidism. N Engl J Med. 1990;325(17):1223-1227.
Folkersen L, Knudsen NA, Teglbjaerg PS. [Licorice. A basis for precautions one more time!]. Ugeskr Laeger. 1996;158(51):7420-7421.
Kerstens MN, Dullaart R. 11 Beta-hydroxysteroid dehydrogenase: characteristics and the clinical significance of a key enzyme in cortisol metabolism [in Dutch]. Ned Tijdschr Geneeskd. 1999;143(10):509-514.
Kumagai A, Nanaboshi M, Asanuma Y, Yagura T, Nishino K, Yamamura Y. Effects of glycyrrhizin on thymolytic and immunosuppressive action of cortisone. Endocrinol Jpn. 1967;14(1):39-42.
Rees WD, Rhodes J, Wright JE, Stamford LF, Bennett A. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol. 1979;14:605-607.
Sailler L, Juchet H, Ollier S, Nicodeme R, Arlet P. Potassium loss may increase effects, especially of digitalis and related glycosides. [Generalized edema caused by licorice: a new syndrome. Apropos of 3 cases.] Rev Med Interne. 1993;14(10):984.
Shintani S, Murase H, Tsukagoshi H, Shiigai T. Glycyrrhizin (licorice)-induced hypokalemic myopathy. Eur Neuro. 1992;32:44-51.
Teeleucksingh S, Mackie ADR, Burt D, McIntyre MA, Brett L, Edwards CR. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet. 1990;335:1060-1063.