InteractionsGuide Index Page

Case Analysis Toolclose

Enter Each Substance:

Analysis Search Terms:

MedicineWorks.com

TM

Health Resources Unlimited, Inc.

Licorice

Botanical Name: Glycyrrhiza glabra L.
Pharmacopoeial Names: Liquiritae radix, Radix glycyrrhizae
Synonym: Glycyrrhiza glandulifera Walst. and Kit.
Common Names: Licorice, licorice root; U.K. spelling = liquorice; literally, “sweet root.”

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Acetaminophen UGT1A substrates /	Licorice induces UGT1A and increases clearance of acetaminophen. Minor significance for acetaminophen due to multiple pathways of the drug's metabolism.	None relevant; vigilance with drugs exclusively conjugated by UGT.
Acetylsalicylic acid gastroirritant and ulcerogenic agents	Licorice helps reduce gastroirritant adverse effects of aspirin. Clinically significant; anecdotally applicable to other drugs, such as NSAIDs, mucositis-inducing chemotherapy agents, and ethanol.	Coadministration preferred. Deglycyrrhizinated licorice (DGL) is effective.
Antibiotics	Activation by hydrolysis of licorice glycoside (GL) to aglycone (GA) depends on bowel flora. Antibiotics reduce bowel flora number and function and may reduce herb bioavailability.	If coadministration necessary, use probiotics or DGL, if appropriate.
Beta-lactam antibiotics	Licorice constituents reduce or reverse drug resistance in MRSA when combined with beta-lactam antibiotics.	Coadminister licorice with drug in diagnosed MRSA.
Cimetidine Histamine (H²) receptor antagonists	Synergistic increase in ulceroprotective and ulcer-healing properties suggested by combination of drug with DGL.	Coadminister.
Cortisol Prednisolone Corticosteroids, oral /	Licorice spares steroid by inhibiting metabolic degradation, potentiates anti-inflammatory effects; reduced adverse effects because lower drug doses permitted by combination.	Combination used to minimize steroid doses; assist in tapered steroid drug withdrawal.
Digoxin Cardiac glycosides	Supratherapeutic doses of licorice may induce hypokalemia, which has been associated with potential digitalis toxicity. Clinical significance low if drug and herb correctly prescribed and monitored, with electrolyte monitoring.	Avoid excessive doses and herb administration. Monitor electrolytes, and supplement with K SUPER2 + END_SUPER2 /Mg SUPER2 ++ END_SUPER2 if coadministration indicated.
Furosemide Potassium-depleting diuretics /	Additive hypokalemic toxicity possible. In practice, reported cases all caused by unwitting or inappropriate self-administration of licorice-containing products.	Avoid. Caution patients to monitor labels of candy, laxatives, and other possible licorice-containing products.
Spironolactone Aldosterone antagonists	Complex interaction involving opposition of hypokalemia by drug at mineralocorticoid receptor, and possible reduction in licorice adverse effect of hypertension. Significance not established.	Avoid until further data available.
Nitrofurantoin Nitrofuran urinary antiseptics	Reduction of gastroirritant side effects of drug. Clinically less relevant due to replacement of nitrofurans with ciprofloxacin, etc. Arguably same interaction as with aspirin, i.e., generic gastroprotective effect of herb.	Coadminister DGL with gastroirritant drugs known to cause adverse effects.
UGT1A , Uridine diphosphate (UDP) glucuronosyltransferase; NSAIDs , nonsteroidal anti-inflammatory drugs; MRSA , methicillin-resistant Staphylococcus aureus .

herb description

Family

Fabaceae.

Related Species

Glycyrrhiza uralensis Fisch ex DC ( Gan cao ). The favored Chinese species, Gan cao is pharmacologically similar to Glycyrrhiza glabra . ¹

Habitat and Cultivation

A perennial shrub in the pea family, G. glabra is a Mediterranean native, but more than 20 related species are distributed throughout Europe, Asia, the Americas, and Australia. Glycyrrhiza uralensis and G. glabra are both widely cultivated in warmer zones throughout Eurasia.

Parts Used

Root, stolons.

Common Forms

Dried Root Whole dried root, and powdered dried root without bark.

Tincture, Fluid Extract 15% to 20% alcohol.

Standardized Extracts Up to 20% glycyrrhizin.

Deglycyrrhizinated Licorice (DGL) 0.5% to 2.0% flavonoids as liquiritigenin.

herb in clinical practice

Overview

Licorice is one of the most ubiquitous herbs in Asian medicine and has been an important remedy in Western herbalism since Greco-Roman times. Licorice is a complex and clinically valuable herb that, without substantial justification, has acquired an uneven reputation in conventional medicine. In part, confusion arises from the many different forms of the herb, its constituents, concentrates, and derivatives, such as the antiulcer drug carbenoxolone sodium, deglycyrrhizinated licorice (DGL), or parenteral products such as SNMC (no longer available) from Japan. These preparations were developed after the emergence of scientific interest in the pharmacology of the herb because of its unusually broad range of effects, including multiple actions on steroid metabolism and inflammatory pathways; hepatoprotective, chemopreventive, and antitumorigenic properties; and pronounced antiviral activities (e.g., glycyrrhizin is the most potent SARS antiviral agent currently known). ^2,3

A significant proportion of “bad press” associated with licorice root is attributable to the use of concentrated glycyrrhizin in the processed food and tobacco industries as a flavoring agent because of its characteristic intense sweetness. “Licorice” is also used to describe a range of widely available popular confectionery products; notably, in the United States, these are more often flavored with anise rather than real licorice or glycyrrhizin. Reports in the medical literature of licorice-related adverse events are invariably associated with the use/abuse of such products, rather than therapeutic doses of the crude herb or its extracts in a clinical setting.

Therapeutic monographs on licorice root are available by the European Scientific Cooperative on Phytotherapy (ESCOP), ⁴ British Herbal Medical Association (BHMA), ⁵ World Health Organization (WHO), ⁶ and German Commission E. ⁷ The herb is official in the 2003 United States Pharmacopoeia – National Formulary, the European Pharmacopoeia, and the 1997 Pharmacopoeia of the People ' s Republic of China .

Historical/Ethnomedicine Precedent

Licorice has been used for food and medicine around the world since ancient Egyptian and Assyrian records were first written on papyri and clay tablets. It was one of the riches stored in King Tutankhamen's tomb. Scythians near the Sea of Azov knew the sweet root to be a successful treatment for people with asthma and dry cough. Documented in the third centuryBCEby the Greek Theophrastus, this use is still common with many herbalists today. Medicinal uses of licorice are recorded from every dynasty of Chinese history. The herb is one of the most frequently used in Chinese formulae, often included as an adjuvant in prescriptions to harmonize other herbs, and thus esteemed as the “Great Harmonizer”; it is primarily considered to tonify spleen ( Pi ) and stomach ( Wei ) qi deficiencies, moisten the lungs ( Fei ), relieve pain, clear “Heat” and “Toxins.” ⁸ The herb is also used widely in other Asian traditions, including Kampo and Ayurvedic medicine.

In Western use, licorice attracted medical interest when the Dutch physician Revers discovered at the end of World War II that some of his patients were using licorice as a home remedy to treat their ulcers successfully. This led to the development of semisynthetic antiulcer medication called carbenoxolone, long since replaced by newer classes of drug, such as histamine (H2) blockers and proton pump inhibitors. Deglycyrrhizinated licorice was a byproduct of carbenoxolone manufacture, and DGL is currently used to deliver high levels of anti-inflammatory licorice flavonoid compounds with significantly lower levels of glycyrrhetinic acid (GA), reducing the risk of GA-induced pseudoaldosteronism. The effects of the herb on glucosteroid metabolism simultaneously led to medical interest in its use for Addison's disease. ^9,10This is reflected in the incorporation of licorice into prescriptions for (functional) “adrenal insufficiency” and chronic fatigue conditions by modern herbalists and naturopathic physicians. In botanical medicine the herb continues to be valued for its general tonic properties as well as for its more specific indications (e.g., peptic ulcers).

Known or Potential Therapeutic Uses

Addison's disease, adrenal insufficiency, asthma, bronchitis, cancer chemoprevention, chronic fatigue, constipation, cough, hepatoprotection against toxicity, herpes simplex infection (topically), human immunodeficiency virus (HIV) infection, inflammations of the gastric and urinary tracts, joint inflammation, mouth ulcers, peptic ulcers, polycystic ovarian syndrome, sudden acute respiratory syndrome (SARS), sore throat, stress, viral hepatitis.

Key Constituents

Triterpene saponins, principally glycyrrhizin 2% to 6% (aglycone = glycyrrhetin or glycyrrhetinic acid).

Polysaccharides, flavonoids (approximately 1.0%) including liquiritin, chalcones including isoliquiritin, isoflavonoids, sterols.

Note: Nomenclature for the glycyrrhizin and its aglycone varies. This monograph adopts the abbreviation “GL” for the glycoside (glycyrrhizin, glycyrrhizic acid, glycyrrhizinic acid) and “GA” for the aglycone (glycyrrhetinic acid).

Therapeutic Dosing Range

Dried Root By decoction, 3 to 10 g/day; typical maximum Chinese dose: 15 to 30 g/day.

Tincture/Fluid Extract Based on 1:1, 2 to 5 mL three times daily.

Standardized Extract Up to 20% glycyrrhizin, equivalent to 5 to 15 g/day DGL—0.5% to 2.0% flavonoids, chewable tablets approximately 380 mg three times daily.

interactions review

Strategic Considerations

The major therapeutic monographs for licorice root vary slightly in their accounts of potential interactions between licorice root preparations and prescription drugs, but the general theme is consistent. The German Commission E maintains that “potassium loss due to other drugs may be increased,” and suggests that “with potassium loss, sensitivity to digitalis glycosides may be increased.” ⁷ The same warning is repeated by ESCOP, ⁴ who include other “antiarrhythmic drugs or drugs which induce reversion to sinus rhythm such as quinidine” in their precautions about hypokalemia, as well as repeating the warnings of Commission E about combining licorice with potassium depleters, including stimulant laxatives and loop or thiazide diuretics. ESCOP also notes a possible alteration of prednisolone pharmacokinetics (i.e., glucocorticoid-sparing effect) with licorice. The WHO monograph ⁶ includes a further precaution about combining aldosterone antagonists such as spironolactone or amiloride with licorice.

These warnings are representative of most discussions on licorice's interactions with prescription drugs. Strictly speaking, these are better classified as drug “contraindications” based on the known pharmacological property of GL to induce a syndrome known as pseudoaldosteronism or “apparent mineralocorticoid excess.” The first report of licorice-induced hypokalemia was unwittingly made by London physician de Cayley in 1950, who recorded the three cases of hypokalemic arrhythmia associated with p-aminosalicylic acid (PAS) therapy for tuberculosis. ¹¹ De Cayley did not detect the connection to licorice, but the following year, Strong ¹² realized that PAS was in fact flavored with licorice root extract. In 1979, Ulick et al. ¹³ used “apparent mineralocorticoid excess” (AME) to describe the congenital pediatric syndrome of hypertension, hypokalemia, suppressed renin-angiotensin-aldosterone axis, and increased urinary ratio of 11β-hydroxy to 11-oxo metabolites of cortisol (suggesting a failure of conversion of cortisol to cortisone). ^14,15

Subsequently, the ability of licorice extracts to inhibit the enzyme 11β-hydroxysteroid dehyhydrogenase (11β-HSD) became established through in vitro, animal, and human experiments, and the resultant effects are usually termed licorice-induced “pseudoaldosteronism” to distinguish it from congenital AME. ^16-19Renal 11β-HSD-2 normally serves to “protect” local mineralocorticoid receptors from activation by cortisol by metabolizing the endogenous glucocorticoid locally to its inactive form. That is, the enzyme confers aldosterone specificity on intrinsically nonspecific renal mineralocorticoid receptors. When this enzyme is inhibited, the resulting excess cortisol stimulates both the glucocorticoid and the “unprotected” renal mineralocorticoid receptors, promoting potassium loss. If unchecked, this can lead to sodium retention and hypokalemia, with possible sequelae of hypertension, myopathy, rhabdomyolysis with potential renal failure from myoglobinemia, and cardiac rhythm disturbances. ^17-27The corollary impression that licorice is thus associated with potentially life-threatening toxicities pervades secondary accounts of the herb and reports of its interactions.

In practice, the situation is less clear-cut. First, the theoretical potential of licorice and its derivatives (except DGL) to induce pseudoaldosteronism is well known to practitioners of natural medicine who regularly use the herb and has been documented in conventional medical literature for over half a century. Coadministration of licorice with potassium-depleting drugs such as thiazide or loop diuretics, especially in patients vulnerable to electrolyte disturbance or using narrow-therapeutic-index antiarrhythmics, is a contraindication and clear departure from the standard of care. If two separate agents possessing similar toxicities are coadministered, there is risk of additive toxicity. This is not strictly speaking an interaction, unless there is evidence for unexpected “synergistic” or nonlinear increases in toxicity resulting from the combination. In botanical medicine settings, high doses of licorice are never prescribed for prolonged periods, and when used at normal therapeutic doses for 6 to 8 weeks, the adverse sequelae of pseudoaldosteronism are rarely observed. Blood pressure is usually monitored during higher-dose licorice prescription. There are no published reports of licorice-induced pseudoaldosteronism arising from practitioner-administered use of licorice; all published reports relate to either unwitting or deliberate consumption of products such as licorice candy, chewing tobacco, or flavored and sweetened beverages and laxatives. The risks of adverse events from self-administration are small but finite, given the public availability of these products, but it is appropriate to distinguish these concerns from clinical practice. ²⁸

Second, inhibition of renal 11β-HSD-2 by licorice and resulting mineralocorticoid receptor–mediated effects do not appear to account fully for the known features of the pseudoaldosteronism syndrome, particularly the varying individual expressions of both hypertension and edema. There is evidence of central nervous system (CNS) involvement unrelated to the renin-angiotensin axis, as well as local renovascular nitric oxide (NO)–mediated endothelial effects in addition to direct mineralocorticoid effects. ^29,30

The impact of licorice on steroid metabolism is complex and not fully understood. Inactivation of cortisol by 11β-HSD-2 is reversible because the enzyme is a bidirectional oxidoreductase. There are at least two isoforms of the enzyme; 11β-HSD-1 is widely distributed in peripheral tissues and the brain and acts predominantly as a reductase (i.e., reactivating glucocorticoids); 11β-HSD-2 is also bidirectional, but a higher-affinity enzyme that predominantly inactivates glucocorticoids, and it is co-localized with mineralocorticoid receptors (e.g., in the kidney). ³¹ Evidence for a third isoform, found in choriocarcinoma cells, has also been presented. ³² Glucocorticoid receptors are also subject to polymorphisms that contribute to individual variability in responses. There appears to be pronounced sexual dimorphism in humans between the relative contributions to cortisol inactivation by the A-ring reductases and 11β-HSD-1. ^33,34Licorice and GA also inhibits the A-ring reductases (5α- and 5β-reductase); both these enzymes irreversibly inactivate glucocorticoids. ^35,36The relationship between relative activities of the irreversible A-ring reductases and bidirectional oxidoreductases appears to vary widely and independently, depending on metabolic conditions. ^37,38

Data from animal studies used to explore the steroid biology must be extrapolated with caution to humans because definite species differences exist in the enzymatic determinants of steroid metabolism, which have diverged throughout mammalian evolution. ^36,39-42Pharmacokinetic variation in the bioavailability of GA has been demonstrated, and given the dependence of GL hydrolysis and release of GA on intestinal flora, this factor may be highly significant. ^43-46(See later discussion on the interaction between licorice and antibiotics.) Other compounds in food or herbal medicines may also inhibit 11β-HSD-1, notably grapefruit juice. ^47,48

In the final analysis, the inhibition of 11β-HSD isoenzymes by licorice arguably underlies only one clinically significant drug interaction, which is the consequent ability of licorice to “spare” prescription glucocorticoids (see licorice-prednisone/corticosteroid interaction). This interaction is not emphasized by secondary sources or the general literature. Licorice dosage required to effect a sustained inhibition of 11β-HSD have been estimated in a human pharmacokinetic study by Krahenbul et al. ⁴⁹ to be 1000 to 1500 mg GA per day, whereas dose levels of less than 500 mg GA/day did not appear to be able to sustain levels of inhibition. Similar results were established by Bernardi et al., ⁵⁰ who found mild adverse effects only at the highest dose (814 mg GL/day) in a trial of healthy volunteers taking different daily doses for 2 weeks, although measurable renin depression occurred at lower-dose groups of 217 and 380 mg GL daily. ⁵⁰

The modulation by licorice of multiple steroid-metabolizing enzymes has some impact on sex hormones as well as glucocorticoids. Reports have suggested mild antitestosterone effects and weak estrogen receptor (ER) binding by licorice, and pronounced biphasic phytoestrogenic activity for the flavonoid compounds isoliquiritigen and glabidrin. ^51-63Speculations about interactions between licorice and prescription steroid sex hormones have inevitably been made but are currently unsupported by clinical data. The only available trial was a small, open-label study with 15 women and 21 men that examined the effects of 4 weeks’ daily consumption of 9 g licorice (150 mg GA) on steroidal hormone levels. Negligible effects were found in the androgens, but in men a slight decrease in dehydroepiandrosterone sulfate (DHEAS) was observed ⁶⁴ (see Theoretical, Speculative, and Preliminary Interactions Research).

Effects on Drug Metabolism and Bioavailability

Effects of licorice on the major drug-metabolizing and xenobiotic-metabolizing enzymes and effects of its compounds have not been fully characterized. Kent et al. ⁶⁵ tested recombinant human cytochrome P450 (CYP450) enzymes in vitro for inhibition by whole-licorice-root extract and the licorice flavonoid glabidrin and found significant inhibition of 3A4 and 2B6 by both licorice extract and glabidrin. The effects were mechanism based and dose dependent but were demonstrated at plausible concentrations of licorice extract, with 6.9 micromolar (µM) achieving more than 50% inhibition of 3A4. CYP 2C9 was competitively inhibited by the licorice flavonoid glabidrin, whereas 2D6 and 2E1 did not appear to be affected by either licorice extract or isolated glabidrin. ⁶⁵ Using a live rodent model, however, Jeong et al. ⁶⁶ demonstrated that CYP450 2E1 inhibition was a component part of the mechanism underlying carbon tetrachloride hepatotoxicity prevention by oral pretreatment with GA. ⁶⁶

Paolini et al. ^67,68found that single doses of licorice extract or GL had no effect on mixed oxidases in a murine model. However, prolonged administration of 240 or 480 mg/kg GA resulted in significant increases of CYP450 3A4 activity, also shown to result from changes in messenger ribonucleic acid (mRNA), denoting increased induction of the enzyme. Smaller increases in 2A1, 2B1, 1A2, and 2B9 were also noted. A much-quoted in vitro fluorometric screening assay by Budzinski et al. ⁶⁹ of several commercial herbal extracts and compounds on human 3A4 suggests that licorice extract was a moderate inhibitor of 3A4. However, the concentrations used were effectively in the 5-millimolar range, far in excess of attainable in vivo levels. Also, the relationship between in vitro fluorometric data and in vivo activity has not been demonstrated to have any consistent correlation.

The current picture of licorice effects on phase I drug metabolism remains incomplete. Clinical studies are required to establish how the preliminary and inconclusive experimental data may translate into significant drug-herb interactions. One rodent study suggests a possible enhancement effect of licorice on the phase II conjugase enzyme uridine diphosphate (UDP) glucuronosyltransferase (UGT1A), which did not appear to be an induction (mRNA) effect. ⁷⁰ Additional evidence suggests possible effects of licorice on drug transporters of the organic anion peptide subfamily. ⁷¹ Finally, some animal data suggest that steroid drug distribution may be affected by licorice modulating steroid-binding globulins; however, the clinical significance of these data is not known. ^72,73

In conclusion, preliminary evidence exists that licorice may exert pharmacokinetic interaction effects on phases I, II, and III of drug metabolism, as well as some aspects of drug distribution. A preliminary report based on Chinese licorice (Gan cao) suggests the possibility that Glycyrrhiza uralensis compounds may bind to the pregnane X receptor (PXR). ⁷⁴ If corroborated for licorice root, such effects might indicate a more significant potential for pharmacokinetic interactions than has been established to date. At present, however, clinical reports suggestive of pronounced pharmacokinetic interactions between licorice and pharmaceutical drugs are absent, and the complex effects on steroid-metabolizing enzymes dominate the considerations of the herb from an interactions perspective.

herb-drug interactions

Acetaminophen

Evidence Acetaminophen (APAP, paracetamol; Tylenol); combination drugs: acetaminophen and codeine (Capital with Codeine; Phenaphen with Codeine; Tylenol with Codeine); acetaminophen and hydrocodone (Anexsia, Anodynos-DHC, Co-Gesic, Dolacet, DuoCet, Hydrocet, Hydrogesic, Hy-Phen, Lorcet 10/650, Lorcet-HD, Lorcet Plus, Lortab, Margesic H, Medipain 5, Norco, Stagesic, T-Gesic, Vicodin, Vicodin ES, Vicodin HP, Zydone); acetaminophen and oxycodone (Endocet, Percocet 2.5/325, Percocet 5/325, Percocet 7.5/500, Percocet 10/650, Roxicet 5/500, Roxilox, Tylox); acetaminophen and pentazocine (Talacen); acetaminophen and propoxyphene (Darvocet-N, Darvocet-N 100, Pronap-100, Propacet 100, Propoxacet-N, Wygesic).

Extrapolated, based on similar properties Substrates of glucuronosyltransferase (UGT1A).

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

In this pharmacokinetic interaction, acetaminophen clearance is increased by the induction of glucuronosyltransferase activity by licorice.

Research

Moon and Kim ⁷⁰ used a rodent model to investigate the effects of licorice root on acetaminophen pharmacokinetics. Pretreatment with glycyrrhizin (1 g/kg) for 6 days increased biliary and urinary excretion of glucuronic conjugates, but not of sulfate or thioether conjugates. Acetaminophen is also conjugated by sulfurotransferases and oxidized by CYP450 3A4.

Clinical Implications and Adaptations

Because acetaminophen is metabolized by multiple pathways, the significance of this interaction is low. Notably, the critical factors in acetaminophen toxicity are the extent of the hepatotoxic metabolite NAPQI formation by CYP 2E1 and the availability of glutathione for its conjugation.

Acetylsalicylic Acid and Other Gastroirritant and Ulcerogenic Agents

Evidence Acetylsalicylic acid (acetosal, acetyl salicylic acid, ASA, salicylsalicylic acid; Arthritis Foundation Pain Reliever, Ascriptin, Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin, Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength, Empirin, Extra Strength Adprin-B, Extra Strength Bayer Enteric 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, Heartline, Regular Strength Bayer Enteric 500 Aspirin, St. Joseph Adult Chewable Aspirin, ZORprin); combination drugs: ASA and caffeine (Anacin); ASA, caffeine, and propoxyphene (Darvon Compound); ASA and carisoprodol (Soma Compound); ASA, codeine, and carisoprodol (Soma Compound with Codeine); ASA and codeine (Empirin with Codeine); ASA, codeine, butalbital, and caffeine (Fiorinal); ASA and extended-release dipyridamole (Aggrenox, Asasantin).

Extrapolated, based on similar properties Ulcerogenic/gastropathic drugs of several unrelated classes, including NSAIDs, ethanol, and antineoplastic chemotherapy agents.

Beneficial or Supportive Interaction, with Professional Management

Probability: 1. Certain
Evidence Base:

Emerging

Effect and Mechanism of Action

The antiulcer and gastroprotective effects of licorice and DGL reduce the incidence of aspirin-induced gastric irritation and bleeding. The mechanism is multifactorial, including increase of mucin secretion to restore the gastric mucosal barrier, together with probable inhibition of gastric acid secretion; anti-inflammatory and cell proliferation effects may also be involved.

Research

A rodent study demonstrated that ulcer lesion scores and bleeding severity after gastric tube administration of ASA at 64 mg/kg were reduced significantly by coadministration of DGL at 2000 mg/kg. However, pretreatment with DGL did not have the same protective effect. ⁷⁵ Other rodent studies found a protective reduction in bile acid and aspirin-induced ulceration in rats with DGL coadministration and a reduction in ulcer index using oral aspirin with a licorice coating. ^76,77 The mechanism appears to be primarily related to increased mucin production. ⁷⁸ Only one human study has examined the effects of coadministering aspirin with DGL. Rees et al. ⁷⁹ performed a placebo-controlled, double-blind crossover study with patients who received either aspirin alone (325 mg three times daily) or aspirin (325 mg) plus DGL (175 mg three times daily). Fecal blood loss was significantly lower in the combination group, and the authors believed the result would have been more marked with higher doses of DGL.

Clinical Implications and Integrative Therapeutics

Aspirin-induced (and NSAID-induced) gastropathy is a well-documented and widespread problem and the cause of a significant number of serious drug-related adverse events, even at cardioprotective doses of 80 mg ASA/day. ^80,81 Coadministration with proton pump inhibitors (PPIs) is considered a pharmaceutical management approach. An alternative is cotreatment with DGL, which appears to provide substantial protection while avoiding the adverse effects of long-term PPI use. Anecdotal clinical uses of the gastroprotective effects of licorice and DGL include prophylaxis and treatment of antineoplastic chemotherapy–induced mucositis.

Antibiotics and Antimicrobial Agents (Systemic)

Aminoglycoside AntibioticsAmikacin (Amikin), gentamicin (G-mycin, Garamycin, Jenamicin), kanamycin (Kantrex), neomycin (Mycifradin, Myciguent, Neo-Fradin, NeoTab, Nivemycin), netilmicin (Netromycin), paromomycin (monomycin; Humatin), streptomycin, tobramycin (AKTob, Nebcin, TOBI, TOBI Solution, TobraDex, Tobrex).

Beta-Lactam AntibioticsMethicillin (Staphcillin); aztreonam (Azactam injection); carbapenem antibiotics: meropenem (Merrem I.V.); combination drug: imipenem and cilastatin (Primaxin I.M., Primaxin I.V.); penicillin antibiotics: amoxicillin (Amoxicot, Amoxil, Moxilin, Trimox, Wymox); combination drug: amoxicillin and clavulanic acid (Augmentin, Augmentin XR, Clavulin); ampicillin (Amficot, Omnipen, Principen, Totacillin); combination drug: ampicillin and sulbactam (Unisyn); bacampicillin (Spectrobid), carbenicillin (Geocillin), cloxacillin (Cloxapen), dicloxacillin (Dynapen, Dycill), mezlocillin (Mezlin), nafcillin (Unipen), oxacillin (Bactocill), penicillin G (Bicillin C-R, Bicillin L-A, Pfizerpen, Truxcillin), penicillin V (Beepen-VK, Betapen-VK, Ledercillin VK, Pen-Vee K, Robicillin VK, Suspen, Truxcillin VK, V-Cillin K, Veetids), piperacillin (Pipracil); combination drug: piperacillin and tazobactam (Zosyn); ticarcillin (Ticar); combination drug: ticarcillin and clavulanate (Timentin).

Cephalosporin AntibioticsCefaclor (Ceclor), cefadroxil (Duricef), cefamandole (Mandol), cefazolin (Ancef, Kefzol), cefdinir (Omnicef), cefepime (Maxipime), cefixime (Suprax), cefoperazone (Cefobid), cefotaxime (Claforan), cefotetan (Cefotan), cefoxitin (Mefoxin), cefpodoxime (Vantin), cefprozil (Cefzil), ceftazidime (Ceptaz, Fortaz, Tazicef, Tazidime), ceftibuten (Cedax), ceftizoxime (Cefizox), ceftriaxone (Rocephin), cefuroxime (Ceftin, Kefurox, Zinacef), cephalexin (Keflex, Keftab), cephapirin (Cefadyl), cephradine (Anspor, Velocef), imipenem combination drug: imipenem and cilastatin (Primaxin I.M., Primaxin I.V.); loracarbef (Lorabid), meropenem (Merrem I.V.).

Fluoroquinolone (4-Quinolone) AntibioticsCinoxacin (Cinobac, Pulvules), ciprofloxacin (Ciloxan, Cipro), enoxacin (Penetrex), gatifloxacin (Tequin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox), nalidixic acid (Neggram), norfloxacin (Noroxin), ofloxacin (Floxin, Ocuflox), sparfloxacin (Zagam), trovafloxacin (alatrofloxacin; Trovan).

Macrolide AntibioticsAzithromycin (Zithromax), clarithromycin (Biaxin), dirithromycin (Dynabac), erythromycin oral (EES, EryPed, Ery-Tab, PCE Dispertab, Pediazole), troleandomycin (Tao).

Sulfonamide AntibioticsSodium sulfacetamide (AK-Sulf, Bleph-10, Sodium Sulamyd), sulfamethoxazole (Gantanol), sulfanilamide (AVC), sulfasalazine (salazosulfapyridine, salicylazosulfapyridine, suphasalazine; Apo-Sulfasalazine, Azulfidine, Azulfidine EN-Tabs, PMS-Sulfasalazine, Salazopyrin, Salazopyrin EN-Tabs, SAS), sulfisoxazole (Gantrisin); combination drug: sulfamethoxazole and trimethoprim (cotrimoxazole, co-trimoxazole, SXT, TMP-SMX, TMP-sulfa; Bactrim, Bactrim DS, Cotrim, Septra, Septra DS, Sulfatrim, Uroplus); triple sulfa (Sultrin Triple Sulfa).

Chemotherapy, Cytotoxic AntibioticsBleomycin (Blenoxane), dactinomycin (Actinomycin D, Cosmegen, Cosmegen Lyovac), mitomycin (Mutamycin), plicamycin (Mithracin).

Miscellaneous AntibioticsBacitracin (Caci-IM), chloramphenicol (Chloromycetin), chlorhexidine (Peridex), colistimethate (Coly-Mycin M), dapsone (DDS, diaminodiphenylsulphone; Aczone Gel, Avlosulfon), furazolidone (Furoxone), lincomycin (Lincocin), linezolid (Zyvox), nitrofurantoin (Macrobid, Macrodantin), oral clindamycin (Cleocin), trimethoprim (Proloprim, Trimpex), vancomycin (Vancocin).

Effect and Mechanism of Action

Bioavailability of licorice root metabolites is partially dependent on bacterial flora which hydrolyze glycyrrhizic acid (GL) to its aglycone form. Oral antibiotic therapy suppresses normal bowel commensal flora and may reduce bioavailability of glycyrrhetinic acid (GA).

Research

The involvement of bowel flora in hydrolysis of GL to GA was first demonstrated in humans by Hattori et al. ^44,45 Animal studies suggest significant species differences in stomach and bowel formation of licorice metabolites. ⁴⁶ A rodent study showed that coadministration of a licorice-containing Chinese formula to rats with triple anti– Helicobacter pyloridrug combination (omeprazole, amoxicillin, and metronidazole) significantly reduced the AUC of GA compared with administration of the formula alone. The authors attribute the effect to loss of GL-hydrolysis activity through reduction of bowel flora caused by the antimicrobials. ⁸²

Human data are equivocal. Cantelli-Forti et al. ⁴³ showed little difference between the bioavailability of GL and GA up to 36 hours after single dosing. ⁴³ A human pharmacokinetic study by Krahenbuhl et al. ⁸³ demonstrated that GL and GA both undergo biliary elimination; GL is recycled enterohepatically, whereas GA is conjugated as a glucuronide before removal in the bile. Almost all orally administered GL reaches systemic circulation as GA after bowel flora hydrolysis.

Integrative Therapeutics, Clinical Concerns, and Adaptations

No studies are available demonstrating decreased bioavailability of GA in patients with reduced bowel flora after antibiotic therapy. Based on current information, however, antibiotics may reduce GA plasma levels if coadministered. This would not affect DGL preparations.

Beta-Lactam Antibiotics

Evidence Oxacillin (Bactocill).

Extrapolated, based on similar properties Methicillin (Staphcillin); beta-lactamase–resistant penicillins: cloxacillin (Cloxapen), dicloxacillin (Dynapen, Dycill); carbapenem antibiotics: meropenem (Merrem I.V.); combination drug: imipenem and cilastatin (Primaxin I.M., Primaxin I.V.); cephalosporin antibiotics, ciprofloxacin and other fluoroquinolone antibiotics, ketaconazoles, macrolide antibiotics, other penicillin antibiotics; combination drugs: amoxicillin and clavulanic acid (Augmentin, Augmentin XR, Clavulin, Nuclav); clavulanic acid and ticarcillin (Timentin).

Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Licorice constituents may reduce or reverse drug resistance of methicillin-resistant Staphylococcus aureus(MRSA) to beta-lactam antibiotics.

Research

Experimental data are accumulating that a variety of natural compounds can effectively reverse drug resistance in various phenotypes of resistant S. aureus.

Licorice compounds have shown this potential with oxacillin against MRSA in vitro. ⁸⁴ Mechanisms are not fully understood, but direct binding to bacterial wall peptidoglycans by the flavonoids is considered likely, and the effect is synergistic, not additive. ⁸⁵

Clinical Implications and Integrative Therapeutics

Clinical implementation of this potential interaction by combining licorice extracts with antibiotic therapy in MRSA has not been institutionally implemented. Substantial in vitro evidence also exists for green tea polyphenols and other natural compounds that exhibit similar resistance-reversing potential (see Green Tea monograph). Despite current lack of clinical support in the literature, integrative practitioners encountering MRSA infection, whether hospital or community acquired, should consider empirical trials of potentially synergistic herb-drug combinations given the serious nature of these infections.

Cimetidine and Related Histamine (H ² ) Receptor Antagonists

Effect and Mechanism of Action

Cimetidine and DGL combined are reported experimentally to exert synergistic antiulcer effects greater than either agent used alone.

Research

The efficacy of licorice derivatives in the form of DGL (Caved-S) has been compared to cimetidine in several clinical trials. ^86-88 On balance, the evidence suggests that the botanical and the pharmaceutical are comparable in their ulcer-healing effects, possibly with slightly more rapid results achieved by cimetidine. Relapse rates are also no different between the two agents. A single study by Bennet et al. ⁸⁹ suggested that in a rat model of aspirin-induced mucosal damage, coadministration of DGL and cimetidine resulted in greater gastroprotection than either agent given alone.

Clinical Implications and Integrative Therapeutics

The clinical significance of this possible synergy is not established, although it presents an “integrative” treatment choice that may be superior to the use of either herb or drug alternative alone.

Cortisol, Prednisolone, and Related Corticosteroids (Oral and Topical)

Evidence Hydrocortisone oral (Cortef), methylprednisolone oral (Medrol), prednisolone oral (Delta-Cortef, Orapred, Pediapred, Prelone); topical hydrocortisone 17-butyrate/acetate/probutate/valerate (Acticort100, Aeroseb-HC, Ala-Cort, Ala-Scalp HP, Allercort, Alphaderm, Bactine, Beta-HC, Caldecort Anti-Itch, Cetacort, Cort-Dome, Cortaid, Cortef, Cortifair, Cortizone, Cortone, Cortril, Delacort, Dermacort, Dermarest, DriCort, DermiCort, Dermtex HC, Epifoam, Gly-Cort, Hi-Cor, Hydro-Tex, Hytone, LactiCare-HC, Lanacort, Lemoderm, Locoid, MyCort, Nutracort, Pandel, Penecort, Pentacort, Proctocort, Rederm, S-T Cort, Synacort, Texacort, Westcort).

Similar properties but evidence indicating no or reduced interaction effects Cortisone and prednisone (semisynthetic steroids with an 11-keto substitution), including prednisone oral (Deltasone, Liquid Pred, Meticorten, Orasone); triamcinolone oral (Aristocort).

Extrapolated, based on similar properties Topical corticosteroids: Alclometasone (Aclovate, Modrasone), amcinonide (Cyclocort), beclomethasone, betamethasone dipropionate/valerate (betamethasone topical; Alphatrex, Beta-Val, Betaderm, Betanate, Betatrex, Diprolene AF, Diprolene, Diprosone, Luxiq, Maxivate, Teladar, Uticort, Valisone), clobetasol (clobetasol topical; Cormax, Dermoval, Dermotyl, Dermovate, Dermoxin, Eumosone, Lobate, Olux, Temovate, Temovate E, Topifort), clobetasone (Eumovate), clocortolone (clocortolone pivalate topical; Cloderm), desonide (DesOwen, Tridesilon), desoximetasone (Topicort, Topicort LP), desoxymethasone, dexamethasone (Aeroseb-Dex, Decaderm, Decadron, Decaspray), diflorasone (Apexicon, Florone, Maxiflor, Psorcon), diflucortolone (Nerisona, Nerisone), fluocinolone (Derma-Smoothe/FS, Fluonid, Synelar, Synemol), fluocinonide (Fluonex, Lidex, Lidex-E, Lonide, Vanos), fludroxycortide (flurandrenolone), fluocortolone (Ultralan), flurandrenolide (Cordran, Drenison), fluticasone (Cutivate), halcinonide (Halog), halobetasol (Ultravate), mometasone (Elocon, mometasone topical), triamcinolone (Aristocort, Triderm, Kenalog, Flutex, Kenonel, triamcinolone topical); combination drug: triamcinolone and nystatin (Mycolog II).

	Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 1. Certain
Evidence Base:

Emerging

Effect and Mechanism of Action

Licorice pharmacokinetically potentiates prednisone and cortisol and spares endogenous cortisol through inhibition of the enzymatic degradation by A-ring reductase and oxidoreductase enzymes. Steroid side effects may be reduced indirectly through sparing of the drug, allowing lower doses, and directly through pharmacodynamic mechanisms, including increased anti-inflammatory effects.

Research

The inhibitory effects of GL and GA on 11β-SDH isoforms, A-ring reductases, and other steroid-metabolizing enzymes are well documented (see Strategic Considerations). An interesting rodent study by Whorwood et al. ⁹⁰ found that the inhibition of 11β-HSD by licorice derivatives combined with exogenous cortisol resulted in large changes in mRNA of the enzyme, indicating pretranslational inhibition significantly greater than that observed with either cortisol or GA alone. Inhibition of endogenous cortisol breakdown by GA in humans has been confirmed by Mackenzie et al. ²³ in a small ( n= 10) open-label study. Another small ( n= 6) crossover human study examined the effect of oral pretreatment with GL (50 mg four times daily) on the pharmacokinetics of a single-dose infusion of prednisolone. The AUC of free plasma prednisolone was significantly increased and clearance significantly decreased by the GL pretretament. ⁹¹ In a skin vasoconstrictor assay, topical GA potentiated the action of hydrocortisone on human skin. ⁹² An unrelated study examined the effects of GA on the antiproliferative activity of glucocorticoids against breast cancer cell lines MCF-7 and ZR-75-1; GA significantly increased the degree of antiproliferative activity by the steroids. ⁹³

Clinical Implications and Integrative Therapeutics

The sparing effect of GL and GA on glucocorticoids is well established and follows from the same enzyme inhibition mechanisms that underlie licorice-induced pseudoaldosteronism. Unlike the latter, this potentially beneficial interaction is not generally recognized in the conventional literature. A primary area of application of the sparing effect of licorice on corticosteroids has been in the context of tapered steroid drug withdrawal. ⁹⁴ Anecdotally, this is an important clinical use of the herb in botanical medicine, along with the related ability to minimize steroid daily-dose levels required for maintenance of chronic inflammatory conditions such as temporal arteritis. The inhibitory effects of GA and GL persist after cessation of administration, at least 2 to 4 weeks. ⁹⁵ This partly results from a transcriptional component in the lowering of the enzyme activity, evidenced in rodent studies by reduced mRNA levels for the enzyme after GA administration. ⁹⁰ A possibly relevant point in consideration of this interaction is that the semisynthetic steroids with an 11-keto substitution (e.g., cortisone, prednisone) require initial activation by reduction, which is effected through hepatic 11β-HSD (i.e., the enzyme inhibited by GL). Therefore, if coadministration is proposed, it would be preferable to use steroids that do not require enzymatic activation, such as cortisol and prednisolone.

Digoxin and Related Cardiac Glycosides

Evidence Digoxin (Digitek, Lanoxin, Lanoxicaps, purgoxin).

Extrapolated, based on similar properties Cardiac glycosides and antiarrhythmics including deslanoside (cedilanin-D), digitoxin (Cystodigin), ouabain (g-strophanthin)

Minimal to Mild Adverse Interaction—Vigilance Necessary

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Licorice extracts in supratherapeutic doses may induce hypokalemia, which theoretically may increase toxicity of antiarrhythmic drugs such as digitalis. Arguably, this is more an avoidable toxicity than an interaction. A single case report is available, but this fails to establish the interaction because of confounding factors.

Research

Potential hypokalemic effects consequent to licorice inhibition of renal 11β-HSD-2 are described in Strategic Considerations. A recent experimental study may have bearing on the kinetics of the licorice and digoxin combination. Ismair et al. ⁷¹ demonstrated that GL is both a substrate and inhibitor of several organic anion-transporting polypeptides (OATPs) localized in human hepatocytes, including OATP-8. Digoxin is known to be transported by OATP-8. ⁹⁶ Whether and how this may affect the bioavailability of digoxin coadministered with licorice remains to be clarified.

Report

A single, well-documented report is available. ⁹⁷ An 84-year-old man with a history of mitral regurgitation and atrial fibrillation was prescribed furosemide (80 mg/day) and digoxin (0.125 mg/day; plasma digoxin level of 1.0 ng/mL). The patient took a Chinese herbal laxative formula containing licorice root (400 mg) and rhubarb root (1600 mg) three times daily for 7 days. By day 7 he complained of fatigue, appetite loss, and dependent edema. On examination he had a heart rate of 30 beats per minute, blood pressure of 120/60, enlarged heart and lung congestion on radiograph, digoxin level of 2.9 ng/mL, and potassium of 2.9 mEq/L. Renin activity and aldosterone were low normal. Both the digoxin and the laxative were discontinued; 18 days later his pulse was 60 beats per minute, potassium 4.3 mEq/L, and renin and aldosterone levels midrange. Digoxin was restarted, and the plasma level was 0.6 ng/mL.

This report cannot be used to infer any direct causal support for a licorice-digoxin interaction. Furosemide, a potassium depleter, was already coadministered with digoxin in this patient. However, the case illustrates the possible risks of drug toxicity in at-risk patient populations when narrow-therapeutic-index drugs are combined with inappropriate herbal formulae added to polypharmacy. Rhubarb root ( Rheum palmatum) is an anthraquinone-containing stimulant laxative, typically regarded as having the potential to induce electrolyte imbalance and volume depletion (both demonstrated in this case report). In this case, threepotassium-depleting agents are involved: the furosemide, the rhubarb root, and the licorice. Finally, regarding the digoxin-licorice interaction, this patient, although bradycardic, was only mildly hypokalemic and did not display signs of more extreme digitalis intoxication, such as bigeminy, or require treatment with digoxin Fab.

Clinical Implications and Adaptations

The effects of potassium depletion on digitalis toxicity are not established. Stockley ⁹⁸ reviewed data from several retrospective studies for evidence of a connection between potassium-depleting diuretics and digitalis toxicity and concluded that a link is not established beyond reasonable doubt, with several studies failing to demonstrate any connection. Nonetheless, the apparent consensus is that concurrent use of potassium-depleting diuretics with cardiac glycosides may result in digitalis intoxication. One management solution is the use of potassium-sparing diuretics, such as spironolactone or triamterene. ⁹⁹ However, spironolactone interacts with licorice, as discussed later.

Complications of drug therapy in elderly patients with heart failure are common, particularly with the cardiac glycosides. ^100,101 Digoxin itself causes increased renal magnesium excretion, and magnesium depletion also increases digitalis toxicity. ¹⁰² Elderly cardiac patients, especially those on polypharmacy regimens, should have their drugs regularly reviewed. Use of cardiac glycosides with potassium-depleting agents should ideally be accompanied by monitoring of drug and electrolyte levels, and where appropriate, patients should be supplemented with both potassium and magnesium.

Cases of licorice root–induced hypokalemia have been described only after self-administration of licorice-containing products by consumers. No reports support an interaction between licorice and digitalis. Hypokalemia resulting from therapeutic-dose levels of licorice is unlikely in clinical practice. The licorice–cardiac glycoside combination is better regarded as a contraindication because of additive adverse effects, and unless compelling reasons exist for coadministration, it should be avoided. Notably, this warning would not apply to the use of DGL.

Potassium-Depleting Diuretics: Loop and Thiazide Diuretics

Evidence Furosemide (Lasix).

Extrapolated, based on similar properties:

Loop diuretics:Bumetanide (Bumex), ethacrynic acid (Edecrin), torsemide (Demadex).

Thiazide diuretics:Bendroflumethiazide (bendrofluazide; Naturetin), benzthiazide (Exna), chlorothiazide (Diuril), chlorthalidone (Hygroton), cyclopenthiazide (Navidrex), hydrochlorothiazide (Aquazide, Esidrix, Ezide, Hydrocot, HydroDiuril, Microzide, Oretic); hydroflumethiazide (Diucardin), methyclothiazide (Enduron), metolazone (Zaroxolyn, Mykrox), polythiazide (Renese), quinethazone (Hydromox), trichlormethiazide (Naqua).

Related but evidence lacking for extrapolation:Combination drugs bendrofluazide and propranolol (Inderex); cyclopenthiazide and oxprenolol (Trasidrex); hydrochlorothiazide and amiloride (Moduretic); hydrochlorothiazide and captopril (Acezide, Capto-Co, Captozide, Co-Zidocapt); hydrochlorothiazide and enalapril (Vaseretic); hydrochlorothiazide and lisinopril (Prinzide, Zestoretic); hydrochlorothiazide and losartan (Hyzaar); hydrochlorothiazide and metoprolol (Lopressor HCT); hydrochlorothiazide and amiloride (Moduretic); hydrochlorothiazide and enalapril (Vaseretic); hydrochlorothiazide and lisinopril (Prinzide, Zestoretic); hydrochlorothiazide and spironolactone (Aldactazide); hydrochlorothiazide and triamterene (Dyazide, Maxzide).

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Adverse Drug Effect on Herbal Therapeutics, Strategic Concern

Probability: 2. Probable
Evidence Base:

0 Consensus

Effect and Mechanism of Action

Inhibition of renal 11β-HSD-2 by licorice may induce hypokalemia, especially at excessive doses administered for chronic periods. In combination with potassium-depleting diuretics such as furosemide, additive hypokalemic toxicity results. Myopathy and acute renal failure resulting from rhabdomyolysis and myoglobinuria have been recorded in settings of consumer self-administration of licorice.

Research

The pseudoaldosterone effects of licorice have been documented for more than 50 years in the medical literature (see Strategic Considerations). Potential adverse renal and muscular sequelae have been reviewed. ⁹⁵ Importantly, furosemide, as with GL and GA, inhibits renal 11β-HSD-2 directly, thus sharing (at least in part) the same mechanism of potassium depletion. ⁴⁷

Reports

Shintani et al. ¹⁰³ reviewed 57 published case reports of glycyrrhizin-induced hypokalemic myopathy in the literature from the 1960s to 1980s. Two salient features emerged from their review.

First, the reports appeared linked to different historical “fashions” of licorice consumption by the public. Initially, cases in the 1950s were from England and Australia related to PAS in the treatment of tuberculosis. In the 1960s, case reports predominantly originated from France and were associated with excessive consumption of a licorice-flavored alcoholic beverage, “Boisson de Coco.” From the 1970s on, the emphasis shifted to Chinese herbal medicines and various commercial products for gastrointestinal complaints, including antiulcer medications and laxatives; more recently, a variety of licorice-flavored products (e.g., chewing tobacco) as well as licorice confectionary (e.g., “pontefract cakes”) have been implicated. Notably, the cases reviewed were associated with self-administration of licorice compounds, often at supratherapeutic doses, and often for extended periods.

Second, the overwhelming associated factor in the reports of licorice-induced hypokalemia was the concurrent use of potassium-depleting diuretics. Also, the majority of patients belonged to the older-age demographic of 60 to 89 years. ¹⁰³

Another effect of prolonged hypokalemia is rhabdomyolysis. Chandler ⁹⁵ analyzed three available case reports linking glomerulopathy, tubulopathy, and acute renal failure to myoglobinemia resulting from rhabdomyolysis induced by licorice consumption. In all three cases, furosemide was in concurrent use and regarded as a contributing factor in the renal reactions. Recent reports of hypokalemic myopathy or renal complications are extremely rare. Chubachi et al. ¹⁰⁴ reported a case of renal failure associated with both furosemide and licorice ingestion. Elinav and Chajek-Shaul ¹⁰⁵ reported an unusual case of licorice-induced myopathy related to use of licorice as a sweetener and not associated with furosemide.

Clinical Implications and Adaptations

No therapeutic rationale exists for coadministration of licorice root extracts with potassium-depleting diuretics. The potential additive hypokalemic effects amount to a contraindication for the combination, particularly in vulnerable demographics such as older cardiac patients. The availability of the potassium-sparing diuretics, together with the licorice derivative DGL, which lacks the mineralocorticoid effects of the parent herb for use in peptic ulcer treatment, provides alternative management strategies. Patients prescribed potassium-depleting agents should be warned of the possible risks of unwitting consumption of licorice as an ingredient of commercial products.

Spironolactone

Evidence Spironolactone (Aldactone).
Extrapolated, based on similar properties combination drug: spironolactone and hydrochlorothiazide (Aldactazide).

Interaction Likely but Uncertain Occurrence and Unclear Implications

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

Spironolactone is classified as a potassium-sparing diuretic but is a competitive inhibitor of aldosterone at the mineralocorticoid receptor, used clinically to oppose hypokalemia. Experimental evidence suggests spironolactone appears to normalize licorice-induced hypertension by restoring endothelial-dependent vascular relaxation function. The clinical significance of this is not established.

Research

Quaschning et al. ^106,107 investigated renovascular hemodynamics in a rodent model of hypertension. Rats were fed GA for 21 days to induce hypertension through 11β-HSD-2 inhibition by the licorice derivative. The resulting hypertension was causally related to the renovascular nitric oxide (NO) system as well as mineralocorticoid receptor–mediated effects. The GA administration reduced endothelial NO synthase (eNOS) and endothelin-1 levels, which were restored by spironolactone. There is emerging evidence that 11β-HSD activity may be depressed in essential hypertension. ¹⁰⁸

Clinical Implications and Adaptations

The reversal of GA-induced hypertension by spironolactone suggests a therapeutic potential for treatment of 11β-HSD deficiency–related cardiac disease. However, the implications of the interaction are unclear, given that coadministration of licorice and spironolactone would generally be avoided because of their opposing effects on kaliuresis.

Nitrofurantoin and Related Nitrofuran Antibiotics

Evidence Nitrofurantoin (Furadantin, Macrobid, Macrodantin).

Extrapolated, based on similar properties Nitrofuran antibiotics: Furazolidone (Furasian, Furoxone), furaltadone, nitrofurazone (Actin-N, Furacin).

Prevention or Reduction of Drug Adverse Effect

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

The urinary antibiotic nitrofurantoin is associated with pronounced adverse effects. It has been suggested that coadministration with DGL reduces nausea and vomiting. The mechanism is not established but is probably related to the established gastroprotective effects of DGL.

Research

The nitrofurans were important urinary antiseptics, particularly for treatment of infection by Escherichia coliand other enterococci in the 1970s and 1980s. Despite concentration by the renal tubules and localization in the bladder, nitrofurantoin is associated with pronounced systemic adverse effects, including nausea and vomiting, and possible serious pulmonary fibrosis. Two studies performed more than 25 years ago suggested that coadministration with DGL led to increased clearance and a reduction in nausea and vomiting, together with improved effects on pyelonephritis. ^109,110

Clinical Implications and Adaptations

Nitrofuran treatment of urinary tract infection is less common now, partly because of the resistance of many strains of bacteria to the drug and its poor adverse effects profile. Fluoroquinolones (e.g., ciprofloxacin) have a superior oral bioavailability and fewer adverse effects and are now the preferred agents. The apparently beneficial DGL-nitrofurantoin interaction was established at the time of widespread prescription of the drug and is likely to receive minimal further investigation. However, a number of drugs with pronounced gastroirritant properties may be better tolerated with coadministration by DGL.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Cyclophosphamide

Cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox).

A single animal study examined the effects of several herbal preparations, including licorice, coadministered with cyclophosphamide on mice inoculated with Lewis lung carcinoma and found reduction in tumorigenesis and metastasis compared with cyclophosphamide alone, although quantitative and statistical details were not available. ¹¹¹ Suggestions of a synergistic interaction with cyclophosphamide or related antineoplastic chemotherapy have not been made to date and would be premature.

Insulin

Animal-source insulin (Iletin); human analog insulin (Humanlog); human insulin (Humulin, Novolin, Novo-Rapid, Oralin).

A human study suggested that carbenoxolone may improve insulin sensitivity in healthy individuals. ¹¹² Another study, however, indicated coadministration of parenteral (SNMC) licorice with insulin in diabetic patients led to hypokalemia, sodium retention, and suppression of the renin-angiotensin axis, which the authors claimed was not caused by the pseudoaldosterone effects of SNMC because of normal urinary potassium levels. ¹¹³ The implications of these two studies are unclear but insufficient to support the claim of an insulin-licorice interaction.

Interferon and Related Antiviral Immunotherapy

Interferon alpha (Alferon N, Intron A, Roferon-A); combination drug: interferon alpha-2b and ribavirin (Rebetron).

Licorice is an established component of botanical medical treatment of viral hepatitis B and C, and GA has demonstrated potent antiviral activity against SARS. ^2,3 In vitro evidence suggests that GL and GA can increase endogenous interferon production by lymphocytes and macrophages in response to concanavalin A. ¹¹⁴ A human study with hepatitis patients using SNMC (parenteral GA) in combination with interferon demonstrated a significant effect on normalization of alanine transaminase (ALT) compared with interferon alone. ¹¹⁵ Related experimental data support a possible role for licorice in stimulation of interferon production and efficacy against viral hepatitis. ^116-118 Although the data suggest a possible interaction between licorice and recombinant interferon immunotherapies, this remains speculative pending further studies, particularly with oral rather than parenteral preparations.

Laxatives

Two reports indicated hypokalemia after use of licorice-containing laxatives. ^97,119 Both preparations included anthraquinone-containing laxative herbs, which are also associated with potential electrolyte disturbances, especially when abused. Harada et al. ⁹⁷ reported concurrent administration with a potassium-depleting diuretic (see licorice-furosemide interaction under Digoxin). Generic cautions about laxative use interactions with licorice are overstated.

Monoamine Oxidase (MAO) Inhibitors

MAO-A inhibitors
Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), procarbazine (Matulane), tranylcypromine (Parnate).

MAO-B inhibitors
Selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak); pargyline (Eutonyl), rasagiline (Azilect).

An in vitro study demonstrated that the licorice isoflavone isoliquiritigenin from G. uralensisexhibited MAO-inhibition activity (IC ⁵⁰ =17.3 millimolar). ¹²⁰ Hatano recorded moderate in vitro MAO-inhibiting activity by a number of licorice compounds, including coumarins such as licocoumarone. The in vivo significance of these studies is unclear, and suggestions of potential interactions between licorice root and MAO inhibitors or biogenic amines is unsupported by clinical reports or pharmacological data. Recently, however, licorice isoflavonoids were shown to inhibit serotonin reuptake in vitro. ¹²¹

Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)

Ethinyl estradiol and desogestrel (Desogen, Ortho-TriCyclen).

Ethinyl estradiol and ethynodiol (Demulen 1/35, Demulen 1/50, Nelulen 1/25, Nelulen 1/50, Zovia).

Ethinyl estradiol and levonorgestrel (Alesse, Levlen, Levlite, Levora 0.15/30, Nordette, Tri-Levlen, Triphasil, Trivora).

Ethinyl estradiol and norethindrone/norethisterone (Brevicon, Estrostep, Genora 1/35, GenCep 1/35, Jenest-28, Loestrin 1.5/30, Loestrin1/20, Modicon, Necon 1/25, Necon 10/11, Necon 0.5/30, Necon 1/50, Nelova 1/35, Nelova 10/11, Norinyl 1/35, Norlestin 1/50, Ortho Novum 1/35, Ortho Novum 10/11, Ortho Novum 7/7/7, Ovcon-35, Ovcon-50, Tri-Norinyl, Trinovum).

Ethinyl estradiol and norgestrel (Lo/Ovral, Ovral).

Mestranol and norethindrone (Genora 1/50, Nelova 1/50, Norethin 1/50, Ortho-Novum 1/50).

Related, internal application
Etonogestrel/ethinyl estradiol vaginal ring (Nuvaring).

Suggestions of potential interactions between licorice and oral contraceptives (OCs) have been made speculatively. Pharmaceutical drug induction of UGT1A and CYP3A4 (e.g., by griseofulvin, rifampin) has been documented to lead to increased clearance of ethinyl estriol and progestins, with potential breakthrough bleeding and loss of clinical efficacy. Evidence for UGT and CYP3A4 induction by licorice is confined to murine and in vitro models at this time. Healthy volunteers consuming 9 g licorice/day for 4 weeks exhibited no changes in androgens or DHEAS. ⁶⁴ Additionally, biphasic dose-related phytoestrogenic effects have been observed with licorice isoflavones, and GL inhibition of 17β-hydroxylase and modulation of sex steroid–binding globulin contribute to the difficulty of extrapolating from the complex pharmacological data to an in vivo interaction. Until clinical reports are available, the potential interaction with OCs should be classified as speculative.

Oral Vitamin K Antagonist Anticoagulants

Anisindione (Miradon), dicumarol, ethyl biscoumacetate (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar), warfarin (Coumadin, Marevan, Warfilone).

A licorice coumarin derivative was demonstrated in vitro to have antiplatelet activity, mediated through cyclic adenosine monophosphate, and GL has been shown to have in vitro antithrombin properties. ^122,123 Currently, no support exists for interactions between licorice and anticoagulant drugs, and clinical reports are unavailable.

Citations

1.Chen J, Chen T. Gan cao (Radix glycyrrhizae). Chinese Medical Herbology and Pharmacology. City of Industry, Calif: Art of Medicine Press Inc; 2004:867-872.
2.Cinatl J, Morgenstern B, Bauer G et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003;361:2045-2046.View Abstract
3.Hoever G, Baltina L, Michaelis M et al. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J Med Chem 2005;48:1256-1259.View Abstract
4.ESCOP. Liquiritiae radix. ESCOP Monographs: the Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK: European Scientific Cooperative on Phytotherapy and Thieme; 2003:297-305.
5.BHMA. Liquorice root. In: Bradley P, ed. British Herbal Compendium. Bournemouth, UK: British Herbal Medical Association; 1992:145-148.
6.WHO. Radix glycyrrhizae. WHO Monographs on Selected Medicinal Plants. 1 vol. Geneva: World Health Organization; 1999:183-194.
7.Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, Texas: American Botanical Council: Integrative Medicine Communications; 1998.
8.Bensky D, Clavey S, Stogër E, Gamble A. Gan cao. Chinese Herbal Medicine: Materia Medica. 3rd ed. Seattle: Eastland Press; 2004:732-735.
9.Pelser HE, Willebrands AF, Frenkel M et al. Comparative study of the use of glycyrrhizinic and glycyrrhetinic acids in Addison’s disease. Metabolism 1953;2:322-334.
10.Borst JG, Ten Holt SP, De Vries LA, Molhuysen JA. Synergistic action of liquorice and cortisone in Addison’s and Simmonds’s disease. Lancet 1953;1:657-663.
11. De W Cayley FE. Potassium deficiency in p-aminosalicylic acid therapy: cardiac and paralytic effects. Lancet 1950;255:447-448.
12.Strong JA. Serum potassium deficiency during treatment with sodium P.A.S. and liquorice extract. Br Med J 1951;4738:998-1002.
13.Ulick S, Levine LS, Gunczler P et al. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab 1979;49:757-764.View Abstract
14.White PC, Mune T, Agarwal AK. 11β-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr Rev 1997;18:135-156.
15.Benediktsson R, Edwards CR. Apparent mineralocorticoid excess. J Hum Hypertens 1994;8:371-375.View Abstract
16.Monder C, Shackleton CH, Bradlow HL et al. The syndrome of apparent mineralocorticoid excess: its association with 11β-dehydrogenase and 5β-reductase deficiency and some consequences for corticosteroid metabolism. J Clin Endocrinol Metab 1986;63:550-557.
17.Stewart PM, Wallace AM, Valentino R et al. Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid dehydrogenase deficiency comes of age. Lancet 1987;2:821-824.View Abstract
18.Stewart PM, Whorwood CB, Walker BR. Steroid hormones and hypertension: the cortisol-cortisone shuttle. Steroids 1993;58:614-620.View Abstract
19.Walker BR, Edwards CR. Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am 1994;23:359-377.View Abstract
20.Monder C, Stewart PM, Lakshmi V et al. Licorice inhibits corticosteroid 11β-dehydrogenase of rat kidney and liver: in vivo and in vitro studies. Endocrinology 1989;125:1046-1053.
21.MacKenzie MA, Hoefnagels WH, Jansen RW et al. The influence of glycyrrhetinic acid on plasma cortisol and cortisone in healthy young volunteers. J Clin Endocrinol Metab 1990;70:1637-1643.View Abstract
22.Ojima M, Satoh K, Gomibuchi T et al. [The inhibitory effects of glycyrrhizin and glycyrrhetinic acid on the metabolism of cortisol and prednisolone: in vivo and in vitro studies]. Nippon Naibunpi Gakkai Zasshi 1990;66:584-596.View Abstract
23.Kato H, Kanaoka M, Yano S, Kobayashi M. 3-Monoglucuronyl-glycyrrhetinic acid is a major metabolite that causes licorice-induced pseudoaldosteronism. J Clin Endocrinol Metab 1995;80:1929-1933.View Abstract
24.Palermo M, Shackleton CH, Mantero F, Stewart PM. Urinary free cortisone and the assessment of 11β-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol (Oxf) 1996;45:605-611.
25.Sardi A, Geda C, Nerici L, Bertello P. [Rhabdomyolysis and arterial hypertension caused by apparent excess of mineralocorticoids: a case report]. Ann Ital Med Int 2002;17:126-129.View Abstract
26.Serra A, Uehlinger DE, Ferrari P et al. Glycyrrhetinic acid decreases plasma potassium concentrations in patients with anuria. J Am Soc Nephrol 2002;13:191-196.View Abstract
27. Van Uum SH, Lenders JW, Hermus AR. Cortisol, 11β-hydroxysteroid dehydrogenases, and hypertension. Semin Vasc Med 2004;4:121-128.
28.Mowrey D. Licorice root (Appendix A). The Scientific Validation of Herbal Medicine. New Canaan, Conn: Keats; 1986:294-295.
29.Ruschitzka F, Quaschning T, Noll G et al. Endothelin 1 type A receptor antagonism prevents vascular dysfunction and hypertension induced by 11β-hydroxysteroid dehydrogenase inhibition: role of nitric oxide. Circulation 2001;103:3129-3135.
30.Negro A, Rossi E, Regolisti G, Perazzoli F. Liquorice-induced sodium retention: merely an acquired condition of apparent mineralocorticoid excess? A case report. Ann Ital Med Int 2000;15:296-300.View Abstract
31.Seckl JR. 11β-Hydroxysteroid dehydrogenase in the brain: a novel regulator of glucocorticoid action? Front Neuroendocrinol 1997;18:49-99.
32.Gomez-Sanchez EP, Cox D, Foecking M et al. 11β-Hydroxysteroid dehydrogenases of the choriocarcinoma cell line JEG-3 and their inhibition by glycyrrhetinic acid and other natural substances. Steroids 1996;61:110-115.
33.Panarelli M, Holloway CD, Fraser R et al. Glucocorticoid receptor polymorphism, skin vasoconstriction, and other metabolic intermediate phenotypes in normal human subjects. J Clin Endocrinol Metab 1998;83:1846-1852.View Abstract
34.Finken MJ, Andrews RC, Andrew R, Walker BR. Cortisol metabolism in healthy young adults: sexual dimorphism in activities of A-ring reductases, but not 11β-hydroxysteroid dehydrogenases. J Clin Endocrinol Metab 1999;84:3316-3321.
35.Tamura Y, Nishikawa T, Yamada K et al. Effects of glycyrrhetinic acid and its derivatives on δ4-5α- and 5β-reductase in rat liver. Arzneimittelforschung 1979;29:647-649.
36.Iyer RB, Binstock JM, Schwartz IS et al. Human hepatic cortisol reductase activities: enzymatic properties and substrate specificities of cytosolic cortisol delta 4-5β-reductase and dihydrocortisol-3α-oxidoreductase(s). Steroids 1990;55:495-500.
37.Raven PW, Taylor NF. Evidence for independent modulation of human 11-HSD and 5α/5β reductase activities. Endocr Res 1996;22:811-815.
38.Iki K, Miyamori I, Hatakeyama H et al. The activities of 5β-reductase and 11β-hydroxysteroid dehydrogenase in essential hypertension. Steroids 1994;59:656-660.
39.Abel SM, Back DJ, Maggs JL, Park BK. Cortisol metabolism in vitro. II. Species difference. J Steroid Biochem Mol Biol 1993;45:445-453.View Abstract
40.Latif SA, Conca TJ, Morris DJ. The effects of the licorice derivative, glycyrrhetinic acid, on hepatic 3α- and 3β-hydroxysteroid dehydrogenases and 5α- and 5β-reductase pathways of metabolism of aldosterone in male rats. Steroids 1990;55:52-58.
41.Baker ME. Licorice and enzymes other than 11β-hydroxysteroid dehydrogenase: an evolutionary perspective. Steroids 1994;59:136-141.
42.Baker ME. Evolution of enzymatic regulation of prostaglandin action: novel connections to regulation of human sex and adrenal function, antibiotic synthesis and nitrogen fixation. Prostaglandins 1991;42:391-410.View Abstract
43.Cantelli-Forti G, Maffei F, Hrelia P et al. Interaction of licorice on glycyrrhizin pharmacokinetics. Environ Health Perspect 1994;102 Suppl 9:65-68.View Abstract
44.Hattori M, Sakamoto T, Kobashi K, Namba T. Metabolism of glycyrrhizin by human intestinal flora. Planta Med 1983;48:38-42.View Abstract
45.Hattori M, Sakamoto T, Yamagishi T et al. Metabolism of glycyrrhizin by human intestinal flora. II. Isolation and characterization of human intestinal bacteria capable of metabolizing glycyrrhizin and related compounds. Chem Pharm Bull (Tokyo) 1985;33:210-217.View Abstract
46.Akao T, Hayashi T, Kobashi K et al. Intestinal bacterial hydrolysis is indispensable to absorption of 18β-glycyrrhetic acid after oral administration of glycyrrhizin in rats. J Pharm Pharmacol 1994;46:135-137.
47.Zhang YD, Lorenzo B, Reidenberg MM. Inhibition of 11β-hydroxysteroid dehydrogenase obtained from guinea pig kidney by furosemide, naringenin and some other compounds. J Steroid Biochem Mol Biol 1994;49:81-85.
48.Song D, Lorenzo B, Reidenberg MM. Inhibition of 11β-hydroxysteroid dehydrogenase by gossypol and bioflavonoids. J Lab Clin Med 1992;120:792-797.
49.Krahenbuhl S, Hasler F, Frey BM et al. Kinetics and dynamics of orally administered 18β-glycyrrhetinic acid in humans. J Clin Endocrinol Metab 1994;78:581-585.
50.Bernardi M, D’Intino PE, Trevisani F et al. Effects of prolonged ingestion of graded doses of licorice by healthy volunteers. Life Sci 1994;55:863-872.
51.Armanini D, Bonanni G, Palermo M. Reduction of serum testosterone in men by licorice [letter]. N Engl J Med 1999;341:1158.
52.Armanini D, Bonanni G, Mattarello MJ et al. Licorice consumption and serum testosterone in healthy man. Exp Clin Endocrinol Diabetes 2003;111:341-343.View Abstract
53.Josephs RA, Guinn JS, Harper ML, Askari F. Liquorice consumption and salivary testosterone concentrations. Lancet 2001;358:1613-1614.View Abstract
54.Sakamoto K, Wakabayashi K. Inhibitory effect of glycyrrhetinic acid on testosterone production in rat gonads. Endocrinol Jpn 1988;35:333-342.View Abstract
55.Armanini D, Fiore C, Mattarello MJ et al. History of the endocrine effects of licorice. Exp Clin Endocrinol Diabetes 2002;110:257-261.View Abstract
56.Fu Y, Hsieh TC, Guo J et al. Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells. Biochem Biophys Res Commun 2004;322:263-270.View Abstract
57.Maggiolini M, Statti G, Vivacqua A et al. Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. J Steroid Biochem Mol Biol 2002;82:315-322.View Abstract
58.Mori H, Niwa K, Zheng Q et al. Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cells. Mutat Res 2001;480/481:201-207.View Abstract
59.Rafi MM, Rosen RT, Vassil A et al. Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res 2000;20:2653-2658.View Abstract
60.Somjen D, Katzburg S, Vaya J et al. Estrogenic activity of glabridin and glabrene from licorice roots on human osteoblasts and prepubertal rat skeletal tissues. J Steroid Biochem Mol Biol 2004;91:241-246.View Abstract
61.Somjen D, Knoll E, Vaya J et al. Estrogen-like activity of licorice root constituents: glabridin and glabrene, in vascular tissues in vitro and in vivo. J Steroid Biochem Mol Biol 2004;91:147-155.View Abstract
62.Tamir S, Eizenberg M, Somjen D et al. Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells. Cancer Res 2000;60:5704-5709.View Abstract
63.Tamir S, Eizenberg M, Somjen D et al. Estrogen-like activity of glabrene and other constituents isolated from licorice root. J Steroid Biochem Mol Biol 2001;78:291-298.View Abstract
64.Sigurjonsdottir HA, Axelson M, Johannsson G et al. Liquorice in moderate doses does not affect sex steroid hormones of biological importance although the effect differs between the genders. Horm Res 2006;65:106-110.
65.Kent UM, Aviram M, Rosenblat M, Hollenberg PF. The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6, and 2C9. Drug Metab Dispos 2002;30:709-715.View Abstract
66.Jeong HG, You HJ, Park SJ et al. Hepatoprotective effects of 18β-glycyrrhetinic acid on carbon tetrachloride–induced liver injury: inhibition of cytochrome P450 2E1 expression. Pharmacol Res 2002;46:221-227.
67.Paolini M, Pozzetti L, Sapone A, Cantelli-Forti G. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases. Life Sci 1998;62:571-582.View Abstract
68.Paolini M, Barillari J, Broccoli M et al. Effect of liquorice and glycyrrhizin on rat liver carcinogen metabolizing enzymes. Cancer Lett 1999;145:35-42.View Abstract
69.Budzinski JW, Foster BC, Vandenhoek S, Arnason JT. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine 2000;7:273-282.View Abstract
70.Moon A, Kim SH. Effect of Glycyrrhiza glabra roots and glycyrrhizin on the glucuronidation in rats. Planta Med 1997;63:115-119.View Abstract
71.Ismair MG, Stanca C, Ha HR et al. Interactions of glycyrrhizin with organic anion transporting polypeptides of rat and human liver. Hepatol Res 2003;26:343-347.View Abstract
72.Tamaya T, Sato S, Okada HH. Possible mechanism of steroid action of the plant herb extracts glycyrrhizin, glycyrrhetinic acid, and paeoniflorin: inhibition by plant herb extracts of steroid protein binding in the rabbit. Am J Obstet Gynecol 1986;155:1134-1139.View Abstract
73.Tamaya T, Sato S, Okada H. Inhibition by plant herb extracts of steroid bindings in uterus, liver and serum of the rabbit. Acta Obstet Gynecol Scand 1986;65:839-842.View Abstract
74.Mu Y, Zhang J, Zhang 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;316:1369-1377.View Abstract
75.Russell RI, Morgan RJ, Nelson LM. Studies on the protective effect of deglycyrrhinised liquorice against aspirin (ASA) and ASA plus bile acid–induced gastric mucosal damage, and ASA absorption in rats. Scand J Gastroenterol Suppl 1984;92:97-100.View Abstract
76.Dehpour AR, Zolfaghari ME, Samadian T, Vahedi Y. The protective effect of liquorice components and their derivatives against gastric ulcer induced by aspirin in rats. J Pharm Pharmacol 1994;46:148-149.View Abstract
77.Morgan RJ, Nelson LM, Russell RI, Docherty C. The protective effect of deglycyrrhinized liquorice against aspirin and aspirin plus bile acid–induced gastric mucosal damage, and its influence on aspirin absorption in rats. J Pharm Pharmacol 1983;35:605-607.View Abstract
78.Goso Y, Ogata Y, Ishihara K, Hotta K. Effects of traditional herbal medicine on gastric mucin against ethanol-induced gastric injury in rats. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1996;113:17-21.View Abstract
79.Rees WD, Rhodes J, Wright JE et al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol 1979;14:605-607.View Abstract
80.Prichard PJ, Hawkey CJ. Aspirin and gastroduodenal injury. Dig Dis 1989;7:28-38.View Abstract
81.Kimmey MB. Cardioprotective effects and gastrointestinal risks of aspirin: maintaining the delicate balance. Am J Med 2004;117 Suppl 5A:72S-78S.View Abstract
82.He JX, Akao T, Nishino T, Tani T. The influence of commonly prescribed synthetic drugs for peptic ulcer on the pharmacokinetic fate of glycyrrhizin from Shaoyao-Gancao-tang. Biol Pharm Bull 2001;24:1395-1399.View Abstract
83.Krahenbuhl S, Hasler F, Krapf R. Analysis and pharmacokinetics of glycyrrhizic acid and glycyrrhetinic acid in humans and experimental animals. Steroids 1994;59:121-126.View Abstract
84.Hatano T, Kusuda M, Inada K et al. Effects of tannins and related polyphenols on methicillin-resistant Staphylococcus aureus. Phytochemistry 2005;66:2047-2055.View Abstract
85.Zhao WH, Hu ZQ, Okubo S et al. Mechanism of synergy between epigallocatechin gallate and beta-lactams against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2001;45:1737-1742.
86.Morgan AG, McAdam WA, Pacsoo C, Darnborough A. Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982;23:545-551.
87.D’Imperio N, Giuliani Piccari G, Sarti F et al. Double-blind trial in duodenal and gastric ulcers: cimetidine and deglycyrrhizinized liquorice. Acta Gastroenterol Belg 1978;41:427-434.
88.Cook PJ, Vincent-Brown A, Lewis SI et al. Carbenoxolone (duogastrone) and cimetidine in the treatment of duodenal ulcer—a therapeutic trial. Scand J Gastroenterol Suppl 1980;65:93-101.View Abstract
89.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;32:151.
90.Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11β-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology 1993;132:2287-2292.
91.Chen MF, Shimada F, Kato H et al. Effect of oral administration of glycyrrhizin on the pharmacokinetics of prednisolone. Endocrinol Jpn 1991;38:167-174.View Abstract
92.Teelucksingh S, Mackie AD, Burt D et al. Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid. Lancet 1990;335:1060-1063.View Abstract
93.Hundertmark S, Buhler H, Rudolf M et al. Inhibition of 11β-hydroxysteroid dehydrogenase activity enhances the antiproliferative effect of glucocorticosteroids on MCF-7 and ZR-75-1 breast cancer cells. J Endocrinol 1997;155:171-180.
94.Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.
95.Chandler RF. Glycyrrhiza glabra. In: DeSmet PA, Keller K, Hansel R, Chandler RF, eds. Adverse Effects of Herbal Drugs. 3 vol. Berlin: Springer Verlag; 1997:67-87.
96.Kullak-Ublick GA, Ismair MG, Stieger B et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 2001;120:525-533.View Abstract
97.Harada T, Ohtaki E, Misu K et al. Congestive heart failure caused by digitalis toxicity in an elderly man taking a licorice-containing Chinese herbal laxative. Cardiology 2002;98:218.View Abstract
98.Stockley I. Stockley’s Drug Interactions. 6th ed. London: Pharmaceutical Press; 2002.
99.Finnegan TP, Spence JD, Cape RD. Potassium-sparing diuretics: interaction with digoxin in elderly men. J Am Geriatr Soc 1984;32:129-131.View Abstract
100.Wofford JL, Ettinger WH. Risk factors and manifestations of digoxin toxicity in the elderly. Am J Emerg Med 1991;9:11-15; discussion 33-14.View Abstract
101.Misiaszek B, Heckman GA, Merali F et al. Digoxin prescribing for heart failure in elderly residents of long-term care facilities. Can J Cardiol 2005;21:281-286.View Abstract
102.Schwinger RH, Erdmann E. Heart failure and electrolyte disturbances. Methods Find Exp Clin Pharmacol 1992;14:315-325.View Abstract
103.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;32:44-51.View Abstract
104.Chubachi A, Wakui H, Asakura K et al. Acute renal failure following hypokalemic rhabdomyolysis due to chronic glycyrrhizic acid administration. Intern Med 1992;31:708-711.View Abstract
105.Elinav E, Chajek-Shaul T. Licorice consumption causing severe hypokalemic paralysis. Mayo Clin Proc 2003;78:767-768.View Abstract
106.Quaschning T, Ruschitzka F, Niggli B et al. Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension. Nephrol Dial Transplant 2001;16:2146-2151.View Abstract
107.Quaschning T, Ruschitzka F, Shaw S, Luscher TF. Aldosterone receptor antagonism normalizes vascular function in liquorice-induced hypertension. Hypertension 2001;37:801-805.View Abstract
108.Soro A, Ingram MC, Tonolo G et al. Evidence of coexisting changes in 11β-hydroxysteroid dehydrogenase and 5β-reductase activity in subjects with untreated essential hypertension. Hypertension 1995;25:67-70.
109.Gromotka R, Bruhl W, Jr., Schmid E. Improved treatment of chronic pyelonephritis with nitrofurantoin in combination with deglycyrrhizinated liquorice. Arzneimittelforschung 1972;22:627-629.
110.Datla R, Rao SR, Murthy KJ. Excretion studies of nitrofurantoin and nitrofurantoin with deglycyrrhizinated liquorice. Indian J Physiol Pharmacol 1981;25:59-63.View Abstract
111.Razina TG, Zueva EP, Amosova EN, Krylova SG. [Medicinal plant preparations used as adjuvant therapeutics in experimental oncology]. Eksp Klin Farmakol 2000;63:59-61.View Abstract
112.Walker BR, Connacher AA, Lindsay RM et al. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. J Clin Endocrinol Metab 1995;80:3155-3159.View Abstract
113.Fujiwara Y, Kikkawa R, Nakata K et al. Hypokalemia and sodium retention in patients with diabetes and chronic hepatitis receiving insulin and glycyrrhizin. Endocrinol Jpn 1983;30:243-249.View Abstract
114.Shinada M, Azuma M, Kawai H et al. 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;181:205-210.View Abstract
115.Abe Y, Ueda T, Kato T, Kohli Y. [Effectiveness of interferon, glycyrrhizin combination therapy in patients with chronic hepatitis C]. Nippon Rinsho 1994;52:1817-1822.View Abstract
116.Fujisawa K. Interferon therapy in hepatitis C virus (HCV) induced chronic hepatitis: clinical significance of pretreatment with glycyrrhizine. Trop Gastroenterol 1991;12:176-179.
117.Dai JH, Iwatani Y, Ishida T et al. Glycyrrhizin enhances interleukin-12 production in peritoneal macrophages. Immunology 2001;103:235-243.View Abstract
118.Eisenburg J. [Treatment of chronic hepatitis B. Part 2. Effect of glycyrrhizic acid on the course of illness]. Fortschr Med 1992;110:395-398.View Abstract
119.Cumming AM, Boddy K, Brown JJ et al. Severe hypokalaemia with paralysis induced by small doses of liquorice. Postgrad Med J 1980;56:526-529.View Abstract
120.Tanaka S, Kuwai Y, Tabata M. Isolation of monoamine oxidase inhibitors from Glycyrrhiza uralensis roots and the structure-activity relationship. Planta Med 1987;53:5-8.View Abstract
121.Ofir R, Tamir S, Khatib S, Vaya J. Inhibition of serotonin re-uptake by licorice constituents. J Mol Neurosci 2003;20:135-140.View Abstract
122.Francischetti IM, Monteiro RQ, Guimaraes JA. Identification of glycyrrhizin as a thrombin inhibitor. Biochem Biophys Res Commun 1997;235:259-263.View Abstract
123.Tawata M, Yoda Y, Aida K et al. Anti-platelet action of GU-7, a 3-arylcoumarin derivative, purified from glycyrrhizae radix. Planta Med 1990;56:259-263.View Abstract

The information presented in InteractionsGuide™ is provided for healthcare professionals and members of the general public seeking information on healthcare options for educational and reference purposes only. The data is based on published scientific studies, clinical experience, and established usage, with selected sources cited as available for each topic. In considering the information provided healthcare professionals are advised to apply their educational training, clinical experience, and a reasonable standard of care.

InteractionsGuide™ is not intended to provide users with information on the treatment of specific medical conditions outside of the context of the relationship with their healthcare provider. The therapeutic options contained in InteractionsGuide™ will not be appropriate for all individuals nor will the therapeutic outcomes suggested necessarily occur in all individuals. Further, different individuals with the same symptoms or diagnosis often require differing treatments.

Users of InteractionsGuide™ who are not health care professionals are advised to consult their physician, appropriately-trained healthcare practitioner, and/or pharmacist before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using any supplements, herbs, remedies, dietary changes or other forms of self-care. Complete information about the effects of specific nutrients, herbs, dietary supplements and possible interactions between such substances and a prescription or over-the-counter medication should be confirmed with the prescribing physician, a pharmacist, or both. Health Resources Unlimited, Inc. does not recommend specific substances, therapies or practitioners.

Please review the Terms and Conditions and Licensing Agreement for further information and the terms and conditions governing your use of InteractionsGuide.com.

© 2008-2010 MedicineWorks.com, a division of Health Resources Unlimited, Inc., and its licensors. All rights reserved.
The Interactions logo and InteractionsGuide are trademarks of Health Resources Unlimited, Inc.
All other products and brands mentioned are trademarks or registered trademarks of their respective trademark owners.

User login

InteractionsGuide Index Page

MedicineWorks.com

TM

Health Resources Unlimited, Inc.

Family

Related Species

Habitat and Cultivation

Parts Used

Common Forms

Overview

Historical/Ethnomedicine Precedent

Known or Potential Therapeutic Uses

Key Constituents

Therapeutic Dosing Range

Strategic Considerations

Effects on Drug Metabolism and Bioavailability

Effect and Mechanism of Action

Research

Clinical Implications and Adaptations

Effect and Mechanism of Action

Research

Clinical Implications and Integrative Therapeutics

Effect and Mechanism of Action

Research

Integrative Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Clinical Implications and Integrative Therapeutics

Effect and Mechanism of Action

Research

Clinical Implications and Integrative Therapeutics

Effect and Mechanism of Action

Research

Clinical Implications and Integrative Therapeutics

Effect and Mechanism of Action

Research

Report

Clinical Implications and Adaptations

Effect and Mechanism of Action

Research

Reports

Clinical Implications and Adaptations

Effect and Mechanism of Action

Research

Clinical Implications and Adaptations

Effect and Mechanism of Action

Research

Clinical Implications and Adaptations