Glycyrrhetinic acid

Glycyrrhetinic Acid

1. Identity and Chemical Characterization

Names and Nomenclature

Glycyrrhetinic acid (also spelled glycyrrhetic acid) is the compound most rigorously identified by its systematic IUPAC name 3β-hydroxy-11-oxo-18β,20β-olean-12-en-29-oic acid. Its synonyms include 18β-glycyrrhetinic acid (18βGA), enoxolone, and glycyrrhetinic acid, with the INCI designation Glycyrrhetinic acid. Two naturally occurring stereoisomers exist: glycyrrhizic acid has two aglycone forms, 18β-glycyrrhetinic acid and 18α-glycyrrhetinic acid. The 18β form predominates in nature and is the principal subject of pharmacological research.

Glycyrrhetinic acid is a pentacyclic triterpenoid of the oleanene type, possessing a hydroxyl group at C-3, a carboxyl moiety at C-30, and a ketone functional group at C-11. Its molecular mass is 470.694 g/mol; it is insoluble in oil and only slightly soluble in water. The molecular formula is C₃₀H₄₆O₄ (PubChem CID 10114).

Botanical Source

Glycyrrhiza glabra L. (belonging to the family Leguminosae), commonly known as licorice, is a popular medicinal plant that has been used in traditional medicine worldwide for its ethnopharmacological efficacy in treating several ailments. Additional species used medicinally and as commercial sources include Glycyrrhiza uralensis Fisch. and Glycyrrhiza inflata Batalin. The primary therapeutic parts of Glycyrrhiza are the roots and rhizomes. Licorice is grown extensively throughout the Middle East, Asia, and Europe.

Occurrence and Relationship to Glycyrrhizin

Glycyrrhetinic acid is not present in appreciable free quantities in the intact root. Rather, it is the aglycone of glycyrrhizin (glycyrrhizic acid), the principal saponin of licorice root. The most significant (10 to 25 percent) active component of Glycyrrhiza glabra L. root extract is glycyrrhizin, sometimes referred to as glycyrrhizic acid. Glycyrrhizin is a glycoside occurring as a mixture of calcium, sodium, and potassium salts of glycyrrhizinic acid; following hydrolysis, it releases two molecules of d-glucuronic acid and the aglycone 18β-glycyrrhetinic acid. The licorice root extract contains from 2% to 25% glycyrrhetinic acid, mainly as the glycosidic glycyrrhizic acid.

When glycyrrhizin is ingested, intestinal bacteria and gut enzymes progressively hydrolyze it to its metabolites. Following intake, the aglycone section of glycyrrhizic acid is hydrolyzed by glucuronidase to form two isomers, 18α-glycyrrhetinic acid and 18β-glycyrrhetinic acid. Among the several reported glycyrrhizin metabolites, 18β-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid.

Common Forms and Preparations

Glycyrrhetinic acid appears in commerce and clinical research in several distinct forms:

• Free glycyrrhetinic acid — isolated by hydrolysis of purified glycyrrhizic acid; glycyrrhetinic acid as a cosmetic ingredient is described as at least 98% pure, with 0.6% 24-OH-glycyrrhetinic acid, not more than 20 µg/g of heavy metals, and not more than 2 µg/g of arsenic.
• Carbenoxolone — the hemisuccinate ester of glycyrrhetinic acid, used as an anti-inflammatory drug in the United Kingdom. Carbenoxolone is a water-soluble synthetic analog of glycyrrhetinic acid used in the treatment of peptic ulcers.
• Salts and esters of glycyrrhetinic acid — glycyrrhetinic acid and its salts and esters function as flavoring agents or skin-conditioning agents in cosmetic formulations.
• Glycyrrhizin preparations (GLPs) — formulations including diammonium glycyrrhizinate (DG), compound glycyrrhizin (CG), and magnesium isoglycyrrhizinate (MgIG) represent preparations whose primary active components are 18α- and 18β-glycyrrhetinic acid.
• Deglycyrrhizinated licorice (DGL) — a commercially prepared form in which the glycyrrhizin content has been reduced; the deglycyrrhizination process, first patented in 1962, primarily employs acid-alkali treatment causing glycyrrhizin to hydrolyze into glycyrrhetinic acid and precipitate, which is then removed via centrifugation, yielding DGL powder containing at most 1% residual glycyrrhizin.
• Topical preparations — gels, creams, and ointments containing glycyrrhetinic acid at concentrations used in dermatological research.

2. Traditional and Historical Use

Ancient Cultures

Since the beginning of recorded history, humans have made use of licorice (mainly the species Glycyrrhiza glabra L., Leguminosae) as a remedy, with traditions from different geographical regions and different time periods documenting its extensive use; the first documented medicinal use can be traced back to ancient Assyrian, Egyptian, Chinese, and Indian cultures. Licorice root has a long history of use going back to ancient Assyrian, Egyptian, Greek, Arab, Chinese, Tibetan, and Indian cultures, where it was used in traditional medicine practices for coughing, asthma, and wound healing, as well as for diseases of the lungs, liver, and arteries.

The earliest physical evidence of licorice use comes from licorice found in Egyptian tombs of pharaohs; in 1923, archaeologists discovered a large amount of well-preserved licorice in the tomb of Tutankhamun (1343 to 1325 BCE) in ancient Egypt.

Greek sources provide the first documented use of licorice as a drug in Europe. According to Theophrastus (IV–III century BCE), the great botanist, pharmacologist, and disciple of Plato and Aristotle, the Greeks probably learned about the pharmacological uses of licorice from the Scythians, an ethnic group who lived to the north and east of Greece in the area of the Ukraine between the Black and Caspian Seas. In the IV–III century BCE, the Greeks first used licorice as a medicine in Europe to treat asthma, lung disease, and cough; by the IV–V century CE, licorice was used to relieve fever and influenza syndrome, and to nourish and restore blood circulation.

Traditional Chinese Medicine (TCM)

Glycyrrhetinic acid is one of the main components of licorice (Glycyrrhiza uralensis Fisch and Glycyrrhiza inflata Batal); having been used in China for around 2,000 years as a traditional Chinese medicine (TCM), licorice is also utilized as a resource of food according to the regulations released by the China Food and Drug Administration. Licorice is known for its high utilization rate in TCM, commonly described as "nine out of ten prescriptions must have licorice included," according to traditional Chinese drug theory which attributes to it a "coordinating effect." Traditional uses include clearing heat and removing toxin, relieving pain and cough, dispelling phlegm, and reconciling numerous medicines.

Indian Ayurvedic Tradition

Glycyrrhiza glabra L. is known in Indian medicine as mulaithi and yashtimadu; its roots are an essential ingredient in Indian traditional medicine systems, where they function as ulcer protectants, demulcents, expectorants, and antitussives.

European Traditions

In the West, Romans, Greeks, the scriptures of Ayurveda, and the ancient Egyptians mentioned the beneficial effects of licorice in traditional treatment of colds, coughs, and chills. Since the 18th century, licorice has been used in various food, industrial, pharmaceutical, and cosmetic applications. The therapeutic uses documented across all these traditions almost invariably center on the root and its preparations — decoctions, teas, pastes, and confectionery — all of which contain glycyrrhizin, the precursor to glycyrrhetinic acid. All reported uses of licorice, in the past and present, refer to the content of saponins and flavonoids found in licorice root.

3. Key Constituents and Phytochemistry of the Parent Plant

While glycyrrhetinic acid is the focus of this article, it exists within a broader phytochemical context. Over the past century, a large number of components have been isolated from licorice; water-soluble biologically active compounds account for 40% to 50% of the total weight of licorice dry matter, and the plant contains major biologically active ingredients such as flavonoids, saponins, sterols, starch, amino acids, gums, and essential oils, including glycyrrhizin, glabridin, liquiritin, and glycyrrhizic acid.

Additional triterpene constituents include liquiritic acid, glycyrretol, glabrolide, uralsaponin B, apioglycyrrhizin, araboglycyrrhizin, and licorice acid. In the flavonoid class, active components include liquirtin, rhamnoliquirilin, shinflavanone, liquiritigenin, apioside, and neoliquiritin; isoflavonoids include glabridin, glabrone, glyzarin, and galbrene; coumarins include liqcoumarin, glabrocoumarone A and B, herniarin, umbelliferone, and glycocoumarin.

Glycyrrhetinic acid is formed when the parent saponin glycoside is hydrolyzed: one molecule of 18-glycyrrhetinic acid and two molecules of glucuronic acid make up the full glycyrrhizic acid structure (18-glycyrrhetinic acid-3-O-β-D-glucuronopyranosyl-(1→2)-β-D-glucuronide). The two isomers differ in the spatial orientation of the hydrogen atom at C-18; the α-form has higher lipophilicity than the β-form, making it more likely to bind to receptor proteins within the body.

4. Established Mechanisms of Action

4.1 Inhibition of 11β-Hydroxysteroid Dehydrogenase (11β-HSD)

The best-characterized and most clinically significant mechanism of glycyrrhetinic acid is its potent inhibition of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD). Glycyrrhetinic acid primarily exerts its effects through its role as an inhibitor of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the enzyme responsible for converting active cortisol into its inactive form, cortisone; by inhibiting 11β-HSD2, glycyrrhetinic acid increases the levels of active cortisol, which in turn affects various metabolic and immune pathways.

Glycyrrhetinic acid is known for its anti-inflammatory activity, acting as an 11β-hydroxysteroid dehydrogenase inhibitor responsible for the conversion of cortisol to cortisone, and as a result, it functions as an indirect glucocorticoid anti-inflammatory agent by extending cortisol half-life. In quantitative terms, 18β-glycyrrhetinic acid potently inhibited 11β-HSD activity of hepatic (IC₅₀ for inhibition of cortisone production = 0.09 µM) and renal (IC₅₀ = 0.36 µM) homogenate in laboratory assays.

The two isomers show selective activity at the two enzyme subtypes: 18α-glycyrrhetinic acid preferentially inhibits the activity of 11β-HSD-1, while 18β-glycyrrhetinic acid selectively inhibits the activity of 11β-HSD-2. The oral administration of 18β-glycyrrhetinic acid has been confirmed to induce this glucocorticoid response in vivo.

4.2 Mineralocorticoid Receptor Activation and Electrolyte Effects

A direct consequence of 11β-HSD2 inhibition at the kidney is a pseudo-mineralocorticoid state. Glycyrrhizin metabolites inhibit type 2 11β-hydroxysteroid dehydrogenase (11β-HSD2), which normally decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. The mineralocorticoid receptor stabilizes epithelial sodium channels on the apical side of the cortical collecting duct principal cell, which increases sodium reabsorption, corresponding to peripheral edema, hypertension, and lower plasma renin activity, whereas potassium is excreted via the renal outer medullary potassium channel, resulting in hypokalemia.

Glycyrrhetinic acid is also an inhibitor of the 11β-hydroxysteroid dehydrogenase (EC₅₀ = 300 nM) and has been found to inhibit voltage-sensitive Ca²⁺ currents with a significant effect at 10 µM (18β-GA). Moderate chronic or high acute exposure to glycyrrhetinic acid has been demonstrated to cause increased potassium excretion, sodium and water retention, body weight gain, alkalosis, suppression of the renin–angiotensin–aldosterone system, hypertension, and muscular paralysis.

4.3 Inhibition of the NF-κB Signaling Pathway

Glycyrrhetinic acid has been found to interfere with the NF-κB pathway, a crucial regulator of inflammation; by inhibiting NF-κB activation, glycyrrhetinic acid reduces the production of pro-inflammatory cytokines and mediators, thereby exhibiting anti-inflammatory properties. The anti-inflammatory mechanism of glycyrrhetinic acid and glycyrrhizin is realized via cytokines including interferon-γ, tumor necrosis factor-α, interleukin-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IL-17.

4.4 HMGB1 Inhibition

Glycyrrhizin, its metabolite glycyrrhetinic acid, and other licorice-derived compounds exert potent anti-inflammatory effects via a wide range of mechanisms including high mobility group box 1 protein (HMGB1) inhibition, gap junction blockade, and α₂A-adrenoceptor antagonism. HMGB1 is a pro-inflammatory cytokine mediator released during cellular stress and viral infection. In murine hepatitis virus (MHV) infection models, glycyrrhetinic acid treatment inhibited activation of hepatic inflammatory responses by blocking high-mobility group box 1 (HMGB1) cytokine activity.

4.5 Gap Junction Channel Blockade

Glycyrrhetinic acid is a potent non-selective blocker of gap junction channels (18α-GA — EC₅₀ = 1.5 µM; 18β-GA — EC₅₀ = 2 µM). Gap junction channels mediate intercellular communication, and their blockade by glycyrrhetinic acid has been explored in neurological and cardiovascular contexts. Research has investigated blood-brain barrier (BBB)-permeable gap junction hemichannel blockers based on glycyrrhetinic acid; notably, glycyrrhetinic acid itself and its derivative carbenoxolone hardly penetrate the intact BBB in conditions such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease.

4.6 Antioxidant Activity

18β-glycyrrhetinic acid, with a structure similar to cortisol, can mimic the activity of cortisol by inhibiting 11β-hydroxysteroid dehydrogenase activity; it also inhibits the activation of the classical complement pathway and reduces reactive oxygen species (ROS) levels, exerting anti-inflammatory and glucocorticoid hormone-like effects. Glycyrrhizin and glycyrrhetinic acid have been demonstrated to possess antioxidant properties as well as robust anti-inflammatory, antiviral, antitumor, and immune-regulatory properties.

4.7 Steroid Hormone Interactions

The conformation of the D and E rings of glycyrrhetinic acid closely resembles that of prednisolone, allowing it to easily bind to target cells of steroid hormones, which confers its antitoxic effects. Glycyrrhetinic acid can also inhibit the activity of cytosolic 5β-reductase and microsomal 3β-HSD enzyme in vivo.

4.8 Cytochrome P450 Enzyme Inhibition

Glycyrrhetinic acid has been used clinically in the treatment of patients with chronic hepatitis; in laboratory evaluations, it greatly decreased CYP3A4 activity with IC₅₀ values of 8.195 µM in human liver microsomes (HLMs) and 7.498 µM in recombinant cDNA-expressed CYP3A4 enzyme systems using a midazolam probe substrate. Results showed that glycyrrhetinic acid could inhibit CYP3A4 activity competitively, with a Ki value of 1.57 µM in HLMs; additionally, CYP2C9 and CYP2C19 could also be inhibited significantly by glycyrrhetinic acid with IC₅₀ values of 42.89 and 40.26 µM in HLMs, respectively.

5. Scientific Evidence by Area of Use

5.1 Hepatoprotection and Liver Disease

The hepatoprotective use of glycyrrhizin-derived compounds (from which glycyrrhetinic acid is the active metabolite) is one of the most clinically developed areas. Glycyrrhizic acid/glycyrrhetinic acid has been used clinically for more than 20 years in patients with chronic hepatitis in China and Japan and shows a satisfactory therapeutic effect in many other diseases. The pharmacological actions include inhibition of hepatic apoptosis and necrosis; anti-inflammatory and immune-regulatory actions; antiviral effects; and antitumor effects.

A 2026 narrative review critically evaluated clinical evidence across major liver diseases, including viral hepatitis, drug-induced liver injury, alcoholic liver disease, non-alcoholic fatty liver disease, and autoimmune hepatitis; it highlighted heterogeneity in study designs and geographical concentration of evidence; formulations studied include diammonium glycyrrhizinate (DG), compound glycyrrhizin (CG), and magnesium isoglycyrrhizinate (MgIG). Clinical studies have shown that glycyrrhizin injection therapy can successfully reduce the incidence of hepatocellular carcinoma and ALT levels in patients with chronic liver disease related to hepatitis C; when combined with conventional Western medicine in the treatment of acute icteric hepatitis, compound glycyrrhizin injection effectively improved patients' liver function parameters, markedly reducing total bilirubin, ALT, and AST levels.

Glycyrrhetinic acid has been regarded as an anti-inflammatory agent for the treatment of a variety of inflammatory diseases, including hepatitis, though the mechanism by which it inhibits viral hepatic inflammatory injury is not completely understood. Evidence in this domain is predominantly from Asian (Chinese and Japanese) clinical settings, often using injected glycyrrhizin preparations rather than isolated oral glycyrrhetinic acid. Most published trials are moderate-quality, with significant variability in formulation, dose, and disease stage. Evidence strength: moderate for glycyrrhizin preparations; preliminary for isolated glycyrrhetinic acid in human studies.

5.2 Anti-inflammatory and Immune Modulation

Glycyrrhizin and glycyrrhetinic acid have been demonstrated to possess antioxidant properties as well as robust anti-inflammatory, antiviral, antitumor, and immune-regulatory properties. The anti-inflammatory mechanisms are multi-targeted and well established at the mechanistic level in cell and animal studies.

18β-glycyrrhetinic acid can inhibit complement component C2 expression; among inflammatory diseases, especially in pulmonary inflammatory diseases, 18β-glycyrrhetinic acid plus hydrocortisone can exhibit a synergistic effect. Glycyrrhetinic acid has also been shown to reduce TNF-α production and NF-κB activation and suppressed mouse ear inflammation stimulated by tissue plasminogen activator.

Human clinical evidence for glycyrrhetinic acid as a standalone oral anti-inflammatory agent is very limited. The bulk of available mechanistic data derives from in vitro cell studies and in vivo animal models. Evidence strength: strong at mechanistic/preclinical level; weak at the level of isolated human clinical studies.

5.3 Antiviral Activity

Glycyrrhizin and its metabolites (including glycyrrhetinic acid) have a wide range of antiviral activities against viruses such as the hepatitis virus, herpes virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both glycyrrhizinic acid and glycyrrhetinic acid have shown similar antiviral and anticancer physiological properties.

18-β glycyrrhetinic acid, an active constituent of glycyrrhizic acid, shows antiviral activity against a number of DNA and RNA viruses possibly due to activation of NF-κB and induction of IL-8 secretion. Glycyrrhizin has been used in Japan for more than 20 years orally and as the intravenous drug Stronger Neo-Minophagen C (SNMC).

Glycyrrhizic acid and its primary metabolite glycyrrhetinic acid are the main active ingredients in licorice roots, which are widely used in East Asian countries (China, Japan), and these ingredients and their derivatives play an important role in treating many diseases, especially infectious diseases such as COVID-19 and hepatic infections. Most antiviral evidence for glycyrrhetinic acid specifically (as opposed to glycyrrhizin) comes from in vitro and animal studies. Human clinical data specifically on isolated glycyrrhetinic acid as an antiviral are scarce. Evidence strength: preliminary to moderate; predominantly preclinical with some clinical data for glycyrrhizin preparations in hepatitis C and herpes.

5.4 Dermatological Applications

As far as being applied topically, glycyrrhizin and its metabolite 18β-glycyrrhetinic acid have been shown to have antimicrobial, anti-inflammatory, and antioxidative properties, being particularly useful in skin conditions like atopic dermatitis, hyperpigmentation, and androgenic alopecia; attention has been focused on their role in preventing and controlling various skin conditions, including inflammation-related diseases such as atopic dermatitis and UV-induced skin photoaging.

Glycyrrhetinic acid and licochalcone A from licorice have been shown to be effective in the treatment of atopic dermatitis. The steroid saponin β-glycyrrhetinic acid is the best studied anti-inflammatory compound of licorice; in a randomized, placebo-controlled, double-blind intra-individual comparison study, the effect of an ointment with 2.5% β-glycyrrhetinic acid on the subcutaneous fat tissue of the thigh was investigated in 18 female volunteers; when applied twice daily over 4 weeks, the ointment with β-glycyrrhetinic acid significantly reduced the circumference of the thigh compared to the non-treated or placebo-treated contralateral thigh.

Glycyrrhetinic acid also has a beneficial influence on peptic ulcers, associated with its strong in vitro activity against 29 different H. pylori strains; its effectiveness against clarithromycin-resistant strains provides hope that it can serve as an alternative therapeutic agent against H. pylori. However, these observations are primarily from laboratory-based studies. Evidence strength for dermatological applications: preliminary to moderate in human studies (small trials and observational data); mechanistic rationale is well established.

5.5 Carbenoxolone in Peptic Ulcer Disease and Cognitive Function

Carbenoxolone, the synthetic hemisuccinate ester of glycyrrhetinic acid, has an established clinical history in peptic ulcer disease. It was historically used as an antiulcer drug before the advent of proton pump inhibitors. More recently, its 11β-HSD inhibitory action has been explored in the context of cognitive function. Both carbenoxolone and glycyrrhetinic acid are non-specific inhibitors of 11β-hydroxysteroid dehydrogenases (11β-HSD), which are involved in the interconversion between active cortisol and inactive cortisone; 11β-HSD type 1 converts cortisone to cortisol, while 11β-HSD type 2 catalyzes the inverse reaction. Based on post-mortem human tissue analysis, 11β-HSD1 is the major type found in the brain, including in the hippocampus and frontal cortex; therefore, 11β-HSD inhibitors may be expected to reduce brain levels of active cortisol and dampen stress-associated damage; in a small, double-blind, placebo-controlled, crossover randomized controlled trial, treatment with carbenoxolone (100 mg three times per day plus 10 mg/day amiloride) for 4 weeks improved verbal memory outcomes. This human trial is small and the results require replication. Evidence strength for cognitive effects of carbenoxolone: preliminary.

5.6 Anticancer Activity

Glycyrrhetinic acid is one of many interesting pentacyclic triterpenoids showing significant anticancer activity by triggering apoptosis in tumor cell lines. Through inhibition of the PI3K/Akt/mTOR pathway, glycyrrhizin/glycyrrhetinic acid modulates cell survival and apoptosis, downregulates the expression of cell cycle-related proteins such as cyclin D1 and survivin, and promotes tumor cell apoptosis.

Both glycyrrhizic acid and glycyrrhetinic acid have pharmacological effects against tumors, inflammation, viral infection, liver diseases, neurological diseases, and metabolic diseases. However, essentially all anticancer evidence for glycyrrhetinic acid specifically resides in cell culture (in vitro) and animal model studies. No high-quality randomized clinical trials in humans have evaluated isolated glycyrrhetinic acid as a cancer treatment. Evidence strength: preclinical only; not yet established in human clinical trials.

5.7 Gastrointestinal Effects and Intestinal Homeostasis

Glycyrrhetinic acid is one of the main components of the traditional Chinese medicine licorice, which coordinates and promotes the effects of other medicines in traditional prescriptions; research has found that glycyrrhetinic acid can promote proliferation, decrease the apoptotic rate, and attenuate growth arrest and delay in restitution after wounding in intestinal epithelial cells. In in vivo assays, glycyrrhetinic acid was shown to maintain the integrity of the intestinal epithelium under 48 hours of fasting in rats via raising HuR and its downstream genes such as EGF, EGFR, and MEK, suggesting via HuR modulation that it could promote intestinal epithelium homeostasis.

Clinical evidence in humans for these gastrointestinal mechanisms is limited. Evidence strength: preclinical; human evidence largely indirect (through glycyrrhizin preparations and carbenoxolone's ulcer history).

5.8 Antimicrobial Activity

A review in the International Journal of Cosmetic Science examined the valuable biological properties of glycyrrhetinic acid, highlighting its key anti-inflammatory, antioxidant, and antimicrobial properties. Laboratory studies have demonstrated activity against a range of bacteria and fungi. 18β-glycyrrhetinic acid inhibits methicillin-resistant Staphylococcus aureus (MRSA) survival and attenuates virulence gene expression. To enhance the antibacterial activity of glycyrrhetinic acid and minimize its side effects, PLGA (poly lactide-co-glycolide)-based nanocarrier systems have been developed; glycyrrhetinic acid-loaded PLGA nanoparticles have demonstrated greater activity against S. aureus, S. epidermidis, and P. aeruginosa than glycyrrhetinic acid alone. Evidence strength: primarily in vitro; no established human clinical data for antimicrobial indications.

5.9 Neuroprotection

Neuroprotective effects of glycyrrhizic acid and 18β-glycyrrhetinic acid have been demonstrated in PC12 cells via modulation of the PI3K/Akt pathway. Some reports show that 18β-glycyrrhetinic acid is likely responsible for amelioration of dysfunction of glutamate transport in astrocytes, and the inhibition of protein kinase C activity might be related to its pharmacological efficacy. These observations are derived from cell and animal models. Evidence strength: preclinical only.

6. Body Systems and Health Areas of Association

Based on available peer-reviewed literature, glycyrrhetinic acid has been studied in association with the following body systems:

• Liver and Hepatobiliary System: Hepatoprotection, anti-inflammatory and antiviral effects in hepatitis, reduction of liver enzyme elevation (ALT, AST), inhibition of hepatic apoptosis, anti-fibrotic effects.
• Endocrine and Adrenal System: Inhibition of cortisol/cortisone interconversion via 11β-HSD, mineralocorticoid-mimicking effects, effects on the renin–angiotensin–aldosterone axis.
• Cardiovascular and Renal Systems: Sodium retention, potassium excretion, blood pressure elevation (as an adverse effect at high doses), and studied protectively in renal tubular oxidative injury models.
• Immune System: Modulation of cytokine production, inhibition of NF-κB signaling, complement pathway modulation, HMGB1 inhibition.
• Skin (Integumentary System): Anti-inflammatory, antimicrobial, and antioxidant activity for atopic dermatitis, hyperpigmentation, contact dermatitis, acne, UV-induced skin damage.
• Gastrointestinal System: Support of intestinal epithelial integrity, anti-H. pylori activity, historical use in peptic ulcer disease (via carbenoxolone).
• Nervous System: Gap junction hemichannel blockade; neuroprotection studied in cell and animal models; cognitive effects via 11β-HSD1 inhibition (carbenoxolone, small human study).
• Oncological (preclinical): Apoptosis induction, cell cycle arrest, PI3K/Akt/mTOR pathway modulation in tumor cell lines.
• Antiviral: Broad antiviral activity studied against DNA and RNA viruses including hepatitis viruses and herpes simplex virus.

7. Dosage Forms and Reported Dosages

The following dosages and forms appear in the cited scientific literature. These are reported values from specific studies and are not recommendations.

• Topical cosmetic/dermatological preparations: In cosmetic products, glycyrrhetinic acid is unregulated in dose; the recommended dosage to induce benefits is between 0.5% and 2% in the finished product.
• Topical ointment (clinical research): In a clinical study, an ointment with 2.5% β-glycyrrhetinic acid was applied twice daily over 4 weeks to 18 female volunteers.
• Oral glycyrrhetinic acid (animal research): Glycyrrhetinic acid at 200 mg/kg orally significantly inhibited 11β-HSD activity in rat liver and kidney at 3 hours after administration in rodent experiments.
• Carbenoxolone (human clinical trial): In a small, double-blind, placebo-controlled, crossover RCT, treatment with carbenoxolone at 100 mg three times per day plus 10 mg/day amiloride was administered for 4 weeks.
• Glycyrrhetinic acid, intraperitoneal (animal hepatitis model): In a murine hepatitis virus model, mice were injected with glycyrrhetinic acid at 20 mg/kg intraperitoneally every other day (total three times).
• Animal cholestasis model (intraperitoneal): In a lithocholic acid-induced cholestatic liver injury model, glycyrrhetinic acid (50 mg/kg) was injected intraperitoneally in C57BL/6 mice.
• Deglycyrrhizinated licorice (DGL): Oral licorice products that do not contain glycyrrhizin (deglycyrrhizinated licorice) might be safe for up to 4 months.

8. Safety Considerations and Drug Interactions

8.1 Pseudoaldosteronism (Pseudo-hyperaldosteronism)

The most well-documented and clinically significant adverse effect of glycyrrhetinic acid exposure (through licorice consumption or supplements) is drug-induced pseudoaldosteronism. Pseudohyperaldosteronism (PHA) is characterized by hypertension, hypokalemia, and a decrease in plasma renin and aldosterone levels; the most frequent dietary cause is excess intake of licorice, and the effect is mediated by the active metabolite glycyrrhetinic acid, which acts by blocking 11-hydroxysteroid dehydrogenase type 2 and binding to the mineralocorticoid receptor as an agonist.

Continuous intake of large amounts of licorice is a widely known cause of pseudo-hyperaldosteronism leading to hypertension and hypokalemia; these manifestations are usually mild, although in some cases they may generate life-threatening complications including arrhythmias, muscle paralysis, rhabdomyolysis, and coma.

The management of licorice-induced PHA depends on several individual factors such as age, gender, comorbidities, duration and amount of licorice intake, and metabolism; the clinical picture usually reverts upon licorice withdrawal, but sometimes mineralocorticoid-like effects can be critical and persist for several weeks, requiring treatment with mineralocorticoid receptor blockers and potassium supplements.

8.2 Cardiovascular Risk

Licorice contains glycyrrhizin that can cause serious adverse effects such as irregular heartbeat and cardiac arrest, especially when consumed in large amounts or in the long term; even small amounts of glycyrrhizin from licorice root products have been linked to severe adverse effects in people who consume a lot of salt, in people with hypertension, and in people with heart or kidney conditions.

8.3 Risk Factors for Toxicity

High dosage and long-term use of licorice are constitutional risk factors for pseudoaldosteronism; orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites; under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11β-HSD2 at the distal nephron. Older age is associated with reduced 11β-HSD2 function, and several concomitant medications such as diuretics have been reported to affect the phenotype; risk factors include daily dosage, long-term use, constipation, hypoalbuminemia, elevated direct bilirubin, older age, and concomitant medications.

Hepatic dysfunction, alcohol use disorder, and interindividual metabolic variability can markedly delay glycyrrhetinic acid elimination, increasing the risk of persistent toxicity even with moderate exposure.

The inhibitory effect on 11β-HSD2 occurs even at low glycyrrhetinic acid concentrations; the direct effect on mineralocorticoid receptors is usually negligible and is therefore only observed in cases of chronic overconsumption.

8.4 Pregnancy

Birth weight and maternal blood pressure were unrelated to the level of consumption of glycyrrhizic acid in 1,049 Finnish women with infants, but babies whose mother consumed more than 500 mg per week were more likely to be born before 38 weeks. This suggests a potential risk for preterm birth at higher glycyrrhizin intake levels during pregnancy.

8.5 Drug Interactions — Cytochrome P450 Inhibition

Glycyrrhetinic acid, the active metabolite of licorice, may increase the toxicity of bakuchiol (the main chemical ingredient in Psoralea corylifolia), by inhibiting its detoxification enzymes CYP450s. More broadly, glycyrrhetinic acid greatly decreased CYP3A4 activity with IC₅₀ values of 8.195 µM in HLMs and inhibited this activity in a dose- but not time-dependent manner. CYP3A4 is responsible for the metabolism of a large proportion of pharmaceutical drugs; inhibition of this enzyme by glycyrrhetinic acid raises the potential for elevated plasma levels of co-administered CYP3A4-substrate drugs.

8.6 Interactions with Corticosteroids

Interactions between licorice and corticosteroids have been reported. Because glycyrrhetinic acid potentiates endogenous cortisol activity via 11β-HSD inhibition, concurrent use with exogenous corticosteroids may amplify glucocorticoid effects. Among inflammatory diseases, especially in pulmonary inflammatory diseases, 18β-glycyrrhetinic acid plus hydrocortisone can exhibit a synergistic effect.

8.7 Topical Safety

Topical licorice root may be safe to use in the short term, but it may cause skin irritation in some people.

8.8 Metabolite Kinetics and Biliary Excretion

Glycyrrhetinic acid metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). This has implications for patients with hepatic impairment, as biliary excretion dysfunction can lead to metabolite accumulation.

9. Overall Evidence Summary

Glycyrrhetinic acid is a pharmacologically multi-targeted pentacyclic triterpenoid with a rich body of mechanistic and preclinical data. Its most robustly established pharmacological action — inhibition of 11β-HSD — is supported both biochemically and by direct clinical consequence (pseudoaldosteronism). Clinical evidence for specific therapeutic applications (particularly hepatoprotection via glycyrrhizin preparations) is strongest in Asian clinical settings and predominantly involves injected or combination preparations rather than isolated oral glycyrrhetinic acid. Some studies of licorice in people have been completed, but there isn't enough high-quality evidence to clearly support its use for any health condition. Areas including anticancer activity, antimicrobial use, and neuroprotection remain at the preclinical stage as of the current literature. The dermatological and hepatological applications are the most clinically developed, though even these require larger, well-controlled independent trials.

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