Licorice

Glycyrrhiza glabra is a herbaceous perennial legume (family Fabaceae) native to southern Europe, the Middle East, and western Asia. The plant grows to roughly 1–1.5 metres tall, producing pinnate leaves with 9–17 leaflets and pale blue to violet flowers arranged in axillary racemes. The medicinally relevant part is the root and stolon system, which develops an extensive network of woody, yellowish-brown underground runners.

Several Glycyrrhiza species are used medicinally worldwide. G. glabra (European/Mediterranean licorice) and G. uralensis (Chinese licorice, gancao) are the most commercially important. G. inflata, the source of the flavonoid licochalcone A, is also used in Chinese medicine. The glycyrrhizin content varies between species and cultivars, typically ranging from 2–12% of dry root weight.

Key phytochemical constituents beyond glycyrrhizin include liquiritigenin and isoliquiritigenin (flavonoids with oestrogenic and anti-inflammatory activity), glabridin (an isoflavane with antioxidant properties), and various coumarins and polysaccharides. The complexity of the root's chemistry means that whole-extract pharmacology cannot be reduced to glycyrrhizin alone, though glycyrrhizin dominates both the therapeutic and toxicological profile of unprocessed root.

Licorice root appears in the Ebers Papyrus (c. 1550 BCE), making it one of the earliest documented medicinal plants. Ancient Egyptian, Greek, and Roman physicians used it for coughs, throat complaints, and thirst. Theophrastus, writing around 300 BCE, described "Scythian root" — almost certainly licorice — as useful for asthma and dry cough.

In traditional Chinese medicine, gancao (G. uralensis) occupies a uniquely central role. Known as "the great harmoniser," it appears in more classical formulas than any other single herb, often serving as a moderating or synergising ingredient rather than the primary therapeutic agent. The Shennong Ben Cao Jing (c. 200 CE) classified it as a superior herb.

European use intensified in the Middle Ages. Licorice cultivation in England (notably in Pontefract, Yorkshire) dates to at least the 13th century. By the 19th century, licorice extract was a standard ingredient in pharmacopoeias for throat lozenges, cough syrups, and as a flavouring agent to mask bitter medicines.

The modern scientific understanding of licorice's risks began crystallising in the 1940s–1960s, when Dutch physician F. E. Revers observed that licorice extract could heal peptic ulcers but also caused oedema and hypertension. This led directly to the development of DGL in the 1970s as an attempt to retain the GI benefits while eliminating the mineralocorticoid side effects.

The dominant pharmacological mechanism of glycyrrhizin involves inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). This enzyme converts active cortisol to inactive cortisone in mineralocorticoid-sensitive tissues (kidneys, colon, salivary glands). When 11β-HSD2 is blocked, cortisol accumulates and activates mineralocorticoid receptors, producing aldosterone-like effects: sodium and water retention, potassium excretion, and blood pressure elevation. This is pseudoaldosteronism — the clinical picture of aldosterone excess without actual aldosterone elevation.

Glycyrrhizin and its aglycone glycyrrhetinic acid also demonstrate direct anti-inflammatory activity through inhibition of phospholipase A2, modulation of arachidonic acid metabolism, and suppression of complement activation. In vitro, glycyrrhizin shows antiviral activity against several viruses, including hepatitis C and some herpesviruses, though clinical translation of these findings remains limited.

The GI-protective effects attributed to DGL appear to involve stimulation of mucus secretion and enhancement of mucosal blood flow, likely mediated by flavonoid and saponin constituents other than glycyrrhizin. Some evidence suggests DGL may increase prostaglandin E2 production in gastric mucosa, supporting the mucosal defence barrier without the systemic mineralocorticoid effects of whole licorice.

Glabridin and other flavonoid components contribute antioxidant, mild phytoestrogenic, and antimicrobial activities. Liquiritigenin acts as a selective oestrogen receptor β (ERβ) agonist in preclinical models, which has generated interest in menopausal symptom research, though clinical evidence remains preliminary.

The best-supported use of licorice-derived products is DGL for functional dyspepsia and as an adjunct in peptic ulcer management. Several small trials suggest DGL can improve dyspeptic symptoms, and older studies indicated ulcer healing rates comparable to early-generation H2 blockers, though head-to-head comparisons with modern PPI therapy are lacking. DGL is not a substitute for evidence-based ulcer treatment (test-and-treat for H. pylori, PPI therapy) but may offer complementary mucosal support.

The EMA has approved a well-established use indication for glycyrrhizin-containing licorice root in productive cough associated with upper respiratory tract infections. This is based on long-standing traditional use and pharmacological plausibility (demulcent and mild expectorant effects) rather than robust clinical trial data. The traditional use monograph covers mild GI discomfort (heartburn, bloating).

In Japan, injectable glycyrrhizin (Stronger Neo-Minophagen C) has been used for decades as a hepatoprotective agent in chronic hepatitis, particularly hepatitis C. This is a specific pharmaceutical preparation administered under medical supervision, not comparable to oral supplementation, and is not widely used outside Japan.

Topical licorice extracts (particularly those standardised to glabridin) are used in dermatology and cosmetics for skin-lightening and anti-inflammatory effects. There is modest evidence supporting efficacy for melasma and atopic dermatitis, though most studies are small.

DGL (deglycyrrhizinated licorice) is available as chewable tablets, capsules, and powders. The traditional recommendation is to chew DGL tablets 15–20 minutes before meals. Typical doses range from 380–760 mg of DGL extract per dose, taken two to three times daily. DGL should contain less than 3% glycyrrhizin to meaningfully reduce mineralocorticoid risk.

Glycyrrhizin-containing licorice root is available as dried root (for decoction), powdered root in capsules, fluid extracts, and solid extracts. The EMA monograph for cough specifies 1.5–5 g of dried root as a decoction, or equivalent preparations, taken up to three times daily. Crucially, the EMA advises a maximum treatment duration of four weeks for glycyrrhizin-containing preparations.

Licorice root tea is widely available and popular, but consumers rarely consider glycyrrhizin content. A strong cup of licorice tea can deliver a pharmacologically relevant dose of glycyrrhizin. Habitual daily consumption has caused documented cases of pseudoaldosteronism.

Standardised extracts vary enormously in glycyrrhizin content. Products may be standardised to glycyrrhizin (typically 10–25% in concentrated extracts) or to other marker compounds. Always check the label for glycyrrhizin content, and if it is not declared, assume the product contains a full glycyrrhizin load.

The signature adverse effect of glycyrrhizin-containing licorice is pseudoaldosteronism. Symptoms develop with sustained intake (typically >50 mg glycyrrhizin per day for more than two weeks, though susceptibility varies) and include hypertension, hypokalaemia, peripheral oedema, headache, lethargy, and in severe cases, cardiac arrhythmias, rhabdomyolysis, and respiratory failure. Hypokalaemia can become severe enough to cause paralysis. The syndrome is dose-dependent and reversible upon discontinuation, but recovery may take days to weeks.

The EU Scientific Committee on Food set an upper limit of 100 mg glycyrrhizin per day for occasional consumption, noting that some individuals develop symptoms at lower intakes. People with pre-existing hypertension, heart failure, renal disease, or electrolyte disturbances are at heightened risk and should avoid glycyrrhizin-containing licorice entirely.

Other reported adverse effects include menstrual irregularities (related to phytoestrogenic and cortisol-modulating activity), decreased testosterone levels in men at high doses, and potential exacerbation of oestrogen-sensitive conditions.

DGL preparations are generally well tolerated. Because most glycyrrhizin has been removed, the mineralocorticoid side effects are largely absent at recommended doses. Mild GI symptoms (nausea, loose stools) are occasionally reported.

Glycyrrhizin-containing licorice is contraindicated in hypertension, heart failure, liver cirrhosis with portal hypertension, hypokalaemia, and renal insufficiency. The mineralocorticoid effects can worsen all of these conditions, potentially catastrophically.

Pregnancy is a firm contraindication for glycyrrhizin-containing products. Epidemiological data from Finland (the GLAKU cohort) found associations between high maternal licorice intake during pregnancy and adverse developmental outcomes in offspring, including earlier puberty and poorer cognitive performance. Glycyrrhizin crosses the placenta and may impair the foetal cortisol barrier normally maintained by placental 11β-HSD2.

Patients with cholestatic liver disease, severe hepatic impairment, or conditions requiring strict electrolyte control (e.g., those on dialysis) should avoid glycyrrhizin-containing preparations.

DGL has far fewer absolute contraindications. However, patients with known allergies to Fabaceae (legume) plants should exercise caution. Individuals on medications affected by even trace glycyrrhizin exposure should verify the glycyrrhizin content of any DGL product they use.

The most clinically important drug interactions involve the hypokalaemia caused by glycyrrhizin. Co-administration with potassium-depleting diuretics (thiazides, loop diuretics) creates additive risk for dangerous hypokalaemia. Cardiac glycosides (digoxin) become more toxic in the setting of low potassium, making concurrent licorice use potentially lethal.

Corticosteroids: glycyrrhizin potentiates the effects of endogenous and exogenous corticosteroids by inhibiting their metabolic inactivation. This can result in amplified steroid side effects, including fluid retention, glucose dysregulation, and immunosuppression.

Antihypertensive medications may be rendered less effective by the sodium-retaining and blood-pressure-raising effects of glycyrrhizin. Patients on ACE inhibitors, ARBs, or other antihypertensives who use glycyrrhizin-containing licorice may experience unexplained loss of blood pressure control.

Warfarin and other anticoagulants: licorice may alter coumarin metabolism and has theoretical additive antiplatelet effects from some flavonoid constituents. Monitoring INR more closely is prudent if licorice use cannot be avoided.

CYP enzyme interactions: glycyrrhizin and glycyrrhetinic acid inhibit CYP3A4 and CYP2D6 in vitro. Clinical significance is uncertain at typical doses, but caution is warranted with narrow-therapeutic-index drugs metabolised by these pathways (e.g., cyclosporine, certain statins).