From ancient herbal remedy to cutting-edge pharmaceutical candidate
For thousands of years, traditional healers across Asia and Europe have reached for a special root to treat ailments from coughs and stomach ulcers to skin inflammations. The ancient Egyptians, including King Tut, were buried with supplies of licorice root, considering it essential for the afterlife. Chinese medicine has celebrated its harmonizing properties in approximately 50% of all herbal formulations, while Greek physicians named it "sweet root" (glycyrrhiza) for its distinctive taste. Today, science is uncovering the remarkable secret behind this plant's power: a compound called glycyrrhetic acid (GA).
Used for millennia in traditional medicine across cultures
Contemporary research reveals potent therapeutic properties
Acts on multiple biological pathways for diverse effects
Did you know? What makes this natural molecule so fascinating to modern researchers? Beyond its sweet origins lies a complex substance with impressive therapeutic potential. Contemporary laboratories are revealing that GA can fight viruses, calm inflammation, and even combat cancer cells. As we explore the science behind this ancient remedy, we discover how a traditional herbal medicine is finding new relevance in addressing some of today's most challenging health conditions.
Glycyrrhetic acid doesn't actually exist in the licorice plant in significant amounts. Its story begins with a fascinating chemical transformation. The licorice root contains glycyrrhizin (also called glycyrrhizic acid), a compound 50 times sweeter than sugar that makes licorice a popular natural sweetener in foods and confectionery 5 7 . When we consume licorice, our digestive systems—specifically bacteria in our intestines—perform a remarkable alchemy: they strip away the sugar molecules from glycyrrhizin, revealing the biologically active core known as glycyrrhetic acid 7 .
This transformation is crucial because while glycyrrhizin itself isn't well absorbed by our bodies, glycyrrhetic acid is rapidly taken into our bloodstream, where it exerts its powerful pharmacological effects 7 . This metabolic activation turns a simple sweet compound into a multifaceted therapeutic agent.
Glycyrrhizin → Glycyrrhetic Acid
(via bacterial metabolism in the gut)
Licorice root containing glycyrrhizin is consumed
Gut bacteria remove sugar molecules from glycyrrhizin
Glycyrrhetic acid is formed and absorbed into bloodstream
GA exerts its pharmacological effects throughout the body
Chemically, glycyrrhetic acid is classified as a pentacyclic triterpenoid, meaning it has a five-ring structure with thirty carbon atoms 7 . This complex architecture enables it to interact with numerous biological targets in our bodies. The most studied form is 18β-glycyrrhetinic acid (18β-GA), though a minor variant called 18α-glycyrrhetinic acid also exists 7 . This seemingly small structural difference significantly influences the compound's biological activity, with the 18β form generally demonstrating greater therapeutic potential.
Modern research has uncovered an astonishing range of biological activities for glycyrrhetic acid, transforming it from a traditional remedy into a multi-target therapeutic agent with applications across numerous medical specialties.
| Pharmacological Activity | Potential Applications | Mechanistic Insights |
|---|---|---|
| Anti-inflammatory | Sepsis, arthritis, skin inflammation | Inhibits HMGB1 protein; reduces pro-inflammatory cytokines (TNF-α, IL-1β) 4 |
| Anticancer | Gastric, liver, lung, breast cancers | Suppresses proliferation, induces apoptosis, inhibits metastasis via multiple pathways including TCTP/AKT/P53 1 8 |
| Antiviral | Hepatitis, potential broad-spectrum applications | Interferes with viral replication; enhances interferon response 1 7 |
| Hepatoprotective | Liver fibrosis, toxin-induced damage | Suppresses NF-κB and MAPK signaling pathways 6 7 |
| Neuroprotective | Alzheimer's, Parkinson's, multiple sclerosis | Blocks connexin hemichannels; reduces microglial activation; promotes myelin repair 4 |
The anti-cancer properties of GA are particularly compelling. A 2025 study revealed that 18β-GA specifically inhibits the proliferation and metastasis of gastric cancer by targeting the TCTP/AKT/P53 signaling pathway 8 . The experiments demonstrated that GA treatment increases proteins that promote cell death (Bax) while decreasing those that prevent it (Bcl-2). It also regulates proteins involved in the cell cycle (increasing P21 and P27) and inhibits epithelial-mesenchymal transition—a crucial step in cancer metastasis—by increasing E-cadherin while decreasing N-cadherin and vimentin 8 .
In the realm of neurological disorders, GA shows significant promise. Research has identified it as a potent non-selective blocker of gap junction channels and hemichannels in the nervous system 4 . This property is particularly valuable in conditions like multiple sclerosis, where 18β-GA has been shown to enhance the proliferation of oligodendrocyte precursor cells, suppress proinflammatory factors released by microglia, and facilitate myelin repair—essentially helping to regenerate the protective coating around nerves that is damaged in this disease 4 .
One of the biggest challenges in developing GA as a therapeutic agent is its poor water solubility, which limits its absorption and bioavailability in the body 3 . To overcome this hurdle, researchers have devised ingenious pharmaceutical strategies, with one of the most effective approaches being the development of ternary solid dispersions (TSDs).
In a groundbreaking 2020 study, scientists set out to dramatically improve GA's dissolution properties by creating advanced delivery systems using hot melt extrusion technology 3 . The research team developed a systematic approach:
They tested various alkalizers (L-arginine, meglumine, Na₂CO₃, Mg(OH)₂) and polymer carriers (Kollidon® VA64, Soluplus, poloxamers) to identify the most effective combinations for enhancing GA solubility.
Selected components were mixed with GA and processed using a twin-screw hot melt extruder at 160°C, creating a homogeneous dispersion where GA molecules were molecularly dispersed within the polymer-alkalizer matrix.
The researchers employed an impressive array of analytical techniques including scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS) to understand the structural changes and molecular interactions.
The TSD systems achieved what previous formulations couldn't—they transformed crystalline GA into an amorphous state and created high-binding-energy ion-pair complexes between GA and the alkalizers 3 . These complexes successfully destroyed the strong hydrogen bonds between GA molecules that normally prevent dissolution.
| Parameter | Pure GA | Binary Solid Dispersion | Ternary Solid Dispersion |
|---|---|---|---|
| Dissolution Rate | Low | Moderate | Significantly increased |
| Physical State | Crystalline | Partially amorphous | Fully amorphous |
| Molecular Interaction | GA-GA H-bonds | GA-polymer H-bonds | GA-alkalizer ion pairs + polymer H-bonds |
| Wettability | Poor | Improved | Greatly enhanced |
The study revealed that the alkalizers played a dual role: they formed strong ion-pair complexes with GA while also establishing intermolecular hydrogen bonds with the polymer carrier (Kollidon® VA64) 3 . This dual interaction mechanism not only prevented GA crystallization but also significantly improved the drug's wettability—both critical factors in enhancing dissolution.
Most notably, the researchers observed that the TSD approach resulted in a lower apparent pKa value for GA, indicating higher ionization that further contributed to improved dissolution in physiological environments 3 . This comprehensive strategy successfully addressed multiple barriers to GA delivery simultaneously.
Studying a complex natural product like glycyrrhetinic acid requires specialized reagents and methodologies. The table below highlights key tools and substances essential for experimental work with GA:
| Research Reagent | Function/Application | Experimental Context |
|---|---|---|
| Kollidon® VA64 | Polymer carrier for solid dispersions | Improves solubility and prevents crystallization in formulations 3 |
| L-arginine/Meglumine | Alkalizers for pH modification | Enhance dissolution of weakly acidic GA via ion-pair formation 3 |
| C18 Chromatography Columns | HPLC/HPLC-MS/MS analysis | Separation and quantification of GA and metabolites in biological samples 6 9 |
| Hot Melt Extruder | Pharmaceutical processing | Continuous, solvent-free production of solid dispersions 3 |
| 0.1% Formic Acid in Methanol | Mass spectrometry mobile phase | Enhances ionization for sensitive detection in LC-MS/MS 6 |
| Ammonium Acetate Buffer | HPLC mobile phase component | Improves chromatographic separation of glycyrrhizic acid 2 |
Analytical techniques are particularly crucial in GA research. High-performance liquid chromatography (HPLC) methods have been developed for precise quantification of GA, using mobile phases like methanol-0.4% phosphoric acid (85:15) and detection at 251 nm wavelength 9 . More advanced HPLC-MS/MS systems provide even greater sensitivity for pharmacokinetic studies, enabling researchers to track GA and its metabolites in biological samples with impressive precision 6 .
For tissue distribution studies—essential for understanding where GA travels in the body—researchers employ specialized sample preparation techniques including protein precipitation with acetonitrile, followed by centrifugation and analysis of the supernatant 9 . These methodological advances have been instrumental in revealing that modified GA formulations can achieve wider and higher tissue distribution in organs including the kidney, spleen, liver, lung, and even the brain 6 .
Glycyrrhetic acid stands as a compelling example of how traditional knowledge and modern science can converge to create novel therapeutic opportunities. From its origins as a sweet component in licorice root, GA has emerged as a multifaceted pharmacological agent with demonstrated effects against inflammation, cancer, viral infections, and neurological disorders. The creative approaches to overcoming its bioavailability challenges—such as ternary solid dispersions—exemplify the innovation driving natural product research forward.
As nanotechnology, targeted delivery systems, and synthetic biology continue to advance, the potential for developing GA-based therapeutics will expand dramatically. The remarkable journey of glycyrrhetic acid—from ancient herbal remedy to modern pharmaceutical candidate—serves as a powerful reminder that sometimes, the most advanced medical solutions can be found by looking back at traditional wisdom through the lens of contemporary science.