Gan Cao (Glycyrrhiza uralensis / Licorice Root) Pharmacology

In the materia medica of every East Asian medical tradition — Han Chinese, Korean, Japanese Kampō, Vietnamese, and the various pharmacopoeial offshoots that grew out of them — one root shows up in roughly six out of every ten formulas. The Han literature gave it the nickname 国老 (Guó Lǎo, “the Venerable Elder of the State”): the senior statesman whose role at court is not to fight wars but to reconcile factions. That root is Gan Cao (甘草 / Radix Glycyrrhizae), the stolons and rhizomes of Glycyrrhiza uralensis Fisch., G. inflata Bat., and G. glabra L. (Fabaceae). All three are accepted in the Chinese Pharmacopoeia, with G. uralensis dominating Northeast Asian supply (Inner Mongolia, Xinjiang, Heilongjiang), G. inflata characteristic of Xinjiang, and G. glabra — the same species as Mediterranean and European licorice — used interchangeably in many modern compound products.

For a medicated-oil formulator the question is not whether Gan Cao is in the formula (it almost always is) but what it is actually doing chemically when applied to inflamed skin, bruised tissue, eczematous patches, or a burn. The answer turns out to be far more interesting than the textbook line of “it harmonizes the other herbs.” Gan Cao is one of the very few classical Chinese herbs whose topical mechanism is so well-mapped that a synthetic single-molecule derivative of its principal saponin — disodium glycyrrhizinate / dipotassium glycyrrhizinate / stearyl glycyrrhetinate — is in the active pharmaceutical ingredient list of cosmeceutical regulations across Japan, Korea, the EU, and ASEAN as a standalone anti-inflammatory. The TCM lineage and the modern dermatology lineage have, quietly, fused.

This article walks through the chemistry, the topical mechanism, the formulation rules, and the safety boundaries — then traces how Gan Cao actually sits inside the dit da jow, eczema wash, burn salve, and pediatric oil categories you find on every Hong Kong, Taipei, and Bangkok dispensary shelf.

1. Botany, Sourcing, and Why “Sheng” vs “Zhi” Gan Cao Matters Externally

Glycyrrhiza species are perennial leguminous shrubs producing extensive horizontal stolons up to 1.5 m long, which are the medicinal part. Wild collection from Inner Mongolia and Xinjiang was the dominant supply chain until the 1990s, when desertification concerns triggered cultivation programs; the modern Chinese Pharmacopoeia (2020) authenticates the herb against glycyrrhizic acid (glycyrrhizin) ≥ 2.0 % and liquiritin ≥ 0.50 % as paired markers.

Two processing forms dominate the trade and they are not interchangeable in external formulations:

生甘草 (Shēng Gān Cǎo, “raw licorice”) — sliced and air-dried only. Higher in glycyrrhizin and the flavonoid liquiritin; the form chosen for external washes, antitoxic decoctions, throat formulas, and the heat-clearing / fire-purging side of the herb’s profile. This is what almost every external medicated-oil formula uses.
炙甘草 (Zhì Gān Cǎo, “honey-fried licorice”) — stir-baked with honey to a dark amber. Some of the glycyrrhizin is hydrolysed to glycyrrhetinic acid during roasting, the flavonoid profile shifts toward the lipophilic flavones, and the herb takes on a warmer, qi-tonifying clinical character. Used in oral tonics (e.g. 炙甘草汤, Zhi Gan Cao Tang for arrhythmia) but rarely in medicated oils, because the honey caramelisation produces compounds that brown the carrier oil and shorten its shelf life.

For alcohol-based liniments (e.g. dit da jow, 跌打酒, 风湿药酒) the rule of thumb is that raw sliced Gan Cao should be added at 3–6 % of total herb weight — high enough to assert its harmonizing role, low enough not to dominate the formula taste or sweeten the alcohol uncomfortably. In oil-based salves the loading is lower (1–3 %) because oil extracts the lipophilic flavonoids efficiently but barely touches glycyrrhizin (which is a hydrophilic triterpenoid saponin); formulators who want full Gan Cao activity in an oil base will often use a hydrolyzed glycyrrhizin (i.e. glycyrrhetinic acid or its esters) as a co-additive.

2. The Phytochemistry: Triterpenoid Saponins on One Wing, Retrochalcone Flavonoids on the Other

Over 400 compounds have been isolated from Glycyrrhiza species. For external pharmacology, you do not need the full list — you need to hold two scaffolds in mind, because they explain almost everything Gan Cao does on skin.

2.1 The triterpenoid saponin wing (glycyrrhizin → glycyrrhetinic acid)

The flagship compound is glycyrrhizin (glycyrrhizic acid), the diglucuronide of an oleanane-type pentacyclic triterpenoid. Glycyrrhizin itself is large, polar, and poorly skin-permeating; intestinal and skin β-glucuronidases hydrolyse it to its aglycone, 18β-glycyrrhetinic acid (GA), which is the molecule that actually does most of the topical work. A minor 18α-epimer (enoxolone) is the form used in many European pharmaceutical ointments.

Key pharmacology of glycyrrhetinic acid in skin:

Inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). This is the single most important — and most under-explained — mechanism of Gan Cao’s topical activity. 11β-HSD2 is the enzyme that converts active cortisol into inactive cortisone inside keratinocytes and immune cells. By inhibiting it, GA causes local cortisol to accumulate at the application site, potentiating the body’s own endogenous anti-inflammatory glucocorticoid signal without administering an exogenous steroid. This is the molecular basis for the well-documented “steroid-sparing” effect of compound glycyrrhizin ointments in eczema and atopic dermatitis: a clinically relevant anti-inflammatory effect that does not produce skin atrophy, telangiectasia, or steroid rebound.
Direct inhibition of phospholipase A2 and downstream arachidonic acid release, blunting prostaglandin and leukotriene generation.
Glycyrrhetinic acid binds and antagonises HMGB1, a danger-associated molecular pattern released by injured cells. This is the mechanism that links Gan Cao to the empirical TCM observation that it “resolves toxin” — it is literally pulling a major sterile-inflammation alarm signal out of circulation in the dermis.
Hyaluronidase inhibition, contributing to the herb’s traditional reputation for slowing the spread of swelling and bruising.

2.2 The flavonoid wing (liquiritin, liquiritigenin, isoliquiritigenin, glabridin, licochalcone A)

The second scaffold is a rich, structurally diverse set of flavonoids, prenylated chalcones, and isoflavanoids that the Glycyrrhiza genus produces almost uniquely.

Liquiritin and its aglycone liquiritigenin — flavanones that inhibit COX-2 expression, scavenge reactive oxygen species, and protect keratinocytes from UV-induced apoptosis.
Isoliquiritigenin — a retrochalcone with strong NF-κB inhibition, tyrosinase inhibition (skin lightening), and an anti-allergic profile that includes stabilisation of mast cells and inhibition of histamine release. This compound carries much of Gan Cao’s empirical “anti-itch” activity.
Glabridin (mainly in G. glabra) — one of the most potent natural tyrosinase inhibitors known, the molecule behind the entire commercial category of “licorice-extract” skin-lightening serums.
Licochalcone A (concentrated in G. inflata) — broad-spectrum anti-inflammatory, antimicrobial against Cutibacterium acnes and Staphylococcus aureus, and the active in several major European pharmaceutical anti-rosacea and anti-redness OTC lines.

The flavonoid wing is why Gan Cao behaves clinically as more than a steroid-potentiator: it brings COX-2 inhibition, mast-cell stabilisation, antimicrobial coverage, and pigment modulation, all at once, from molecules that are small enough and lipophilic enough to penetrate the stratum corneum efficiently from an oil or alcohol vehicle.

3. The Mechanistic Story: Why a Formula Containing Gan Cao Just Behaves Better on Skin

Bring these two wings together and you can re-explain almost every classical claim made for Gan Cao in external medicine:

“Resolves the toxicity of the other herbs” (解百毒). Glycyrrhetinic acid inhibits CYP3A4 and CYP2C9 in skin, slowing the local oxidative activation of aconite alkaloids (aconitine → less cardiotoxic form), strychnine-family alkaloids from Ma Qian Zi, and several other narrow-margin externals. It also chelates and sequesters reactive aldehydes and quinones generated by oxidation of phenolic herbs in alcohol. The classical clinical observation — that aconite, nux vomica, and croton-containing liniments are noticeably safer when Gan Cao is co-formulated — has a mechanistic basis that the Tang-dynasty formulators could not have known but were empirically tracking.
“Harmonises the formula” (调和诸药). Glycyrrhizin is a natural surfactant — its molecule has a hydrophobic triterpenoid body and a hydrophilic diglucuronide head, giving it a real critical micelle concentration in solution. In alcohol-water-oil mixed liniments this is exactly what holds the lipophilic essential-oil components (camphor, menthol, eugenol, eucalyptol) in stable suspension with the hydrophilic flavonoid and alkaloid extracts. The “harmonizing” is not metaphor; it is colloid chemistry.
“Relieves urgency, slows spasm” (缓急止痛). Glycyrrhetinic acid weakly inhibits voltage-gated calcium channels in vascular and visceral smooth muscle, and the flavonoid liquiritigenin has direct GABA-A modulation at high tissue concentrations. Topically, this manifests as smoothing of the sharp, “biting” feel of strong rubefacients — a formula with Gan Cao is subjectively warmer-but-rounder than the same formula without.
“Clears heat-toxin and treats sores” (清热解毒, 治痈疮). Licochalcone A and isoliquiritigenin’s antimicrobial coverage — including against S. aureus, C. acnes, and several streptococci — plus the broad anti-inflammatory action of GA, are the modern read of this classical indication.

4. Where Gan Cao Sits Inside Real Medicated-Oil Categories

4.1 Dit Da Jow and rheumatism liniments (跌打酒 / 风湿药酒)

In old Cantonese dit da jow formulas, raw sliced Gan Cao appears at 3–5 % of dry herb weight, almost always alongside Chuan Wu / Cao Wu (aconite tubers), Ma Qian Zi (nux vomica), Sheng Nan Xing (Arisaema), and similar narrow-margin externals. Its presence is a safety device first — it raises the LD50 of co-formulated aconitine in animal models by roughly 2–4 fold via the CYP modulation and surfactant solubilisation effects discussed above — and a delivery-vehicle device second.

4.2 Eczema washes, atopic-dermatitis lotions, and the modern “compound glycyrrhizin” category (湿疹外洗方)

Both the Japanese Kampō (e.g. 消風散 Shōfū-san derivatives applied topically) and the modern Chinese dermatology hospital pharmacopoeia rely heavily on Gan Cao for chronic-eczema washes. The marketed extension of this lineage is 复方甘草酸单铵 / 复方甘草酸苷 (compound glycyrrhizin) topical preparations now standard in mainland China and Japan, sometimes paired with a low-potency synthetic steroid, sometimes used as a steroid-sparing maintenance monotherapy.

4.3 Burn salves and “Mei Bao” lineage (烫伤膏)

The famous Moist Exposed Burn Ointment (MEBO / 美宝湿润烧伤膏) developed in 1980s China lists Gan Cao alongside sesame oil, beta-sitosterol, and berberine sources as a foundational anti-inflammatory and re-epithelialising component. Glycyrrhetinic acid’s HMGB1 antagonism is especially valuable in second-degree burns where sterile inflammation drives much of the late tissue loss.

4.4 Hemorrhoid ointments and mucosal-adjacent salves (痔疮膏)

Almost every classical and modern Chinese hemorrhoid ointment contains Gan Cao or its glycyrrhetinic acid extract: the combination of 11β-HSD2 inhibition (local steroid potentiation), hyaluronidase inhibition (anti-swelling), and surfactant-mediated drug delivery makes it uniquely well-suited to mucosal anorectal use.

4.5 Pediatric and elderly-skin formulas

Because Gan Cao’s anti-inflammatory action runs through endogenous cortisol rather than an exogenous steroid, it does not produce the skin-thinning and HPA-axis suppression risks of even mild topical hydrocortisone. This is why pediatric brands like the Indonesian Minyak Telon family, the Japanese Kampō baby-skin preparations, and several Hong Kong infant oils include licorice or licorice extract as the principal soothing component.

5. Safety, Sensitisation, and the Pseudoaldosteronism Question

Topical Gan Cao is exceptionally well-tolerated; the contact-sensitisation rate in patch testing is below 0.5 %, lower than most botanical anti-inflammatories.

The pharmacological caveat is systemic mineralocorticoid effect. Oral high-dose licorice (more than ~100 mg glycyrrhizin/day chronically) inhibits renal 11β-HSD2, allowing cortisol to occupy the mineralocorticoid receptor in the kidney and producing hypokalemia, sodium retention, and hypertension — the well-described “licorice pseudoaldosteronism.” Topical exposure delivers a tiny fraction of this dose, and absorbed glycyrrhizin is largely deconjugated to glycyrrhetinic acid before reaching renal tissue, but large-surface-area application of high-concentration compound glycyrrhizin ointments in patients with hypertension, congestive heart failure, or chronic kidney disease should still be monitored, and patients on potassium-wasting diuretics (loop or thiazide) should not be on chronic high-area topical glycyrrhetinic acid without electrolyte surveillance.

There is no clinically meaningful pregnancy or lactation contraindication for the herb-loaded medicated oils in which Gan Cao appears at 1–5 % loading; the cautions above are for purified single-compound topical pharmaceuticals at much higher concentrations.

6. Closing: Why the “Venerable Elder” Is the Single Most Underrated Ingredient on Your Yaoyou Shelf

If you pick up a Hong Kong Po Sum On bottle, a Singapore Eagle Brand bottle, a Taiwan 新萬仁綠油精 bottle, a Japanese Mentholatum jar, or a Bangkok Siang Pure inhaler, the aromatic top notes — camphor, menthol, eucalyptol, methyl salicylate — are what your nose registers. Gan Cao is not aromatic. It does not contribute scent or warmth. It does not appear on the front-label marketing copy. It is, in most cases, not even listed in English on the ingredient panel.

But it is almost always in there, and once you understand the 11β-HSD2 mechanism, the flavonoid mast-cell stabilisation, the surfactant micellisation of the lipophilic actives, and the CYP-mediated detoxification of co-formulated alkaloids, you stop seeing it as a polite addition and start seeing it as the silent infrastructure on which the entire medicated-oil tradition stands. The Han pharmacologists who nicknamed it 国老 in the second century already knew this empirically. The modern dermatological literature is now, finally, catching up to what they meant.