Licochalcone

• Anti-inflammatory
• Antimicrobial
• Antioxidant
• Anticancer properties

• Skin health
• Hepatoprotection
• Neuroprotection
• Metabolic regulation
• Cardiovascular support

Licochalcones are a group of prenylated chalcones found primarily in the roots and rhizomes of licorice (Glycyrrhiza species), particularly Glycyrrhiza inflata and Glycyrrhiza glabra. The most extensively studied licochalcones include Licochalcone A (Lico A), Licochalcone B (Lico B), Licochalcone C (Lico C), Licochalcone D (Lico D), and Licochalcone E (Lico E), each with distinct but overlapping biological activities. Their chemical structure features a chalcone backbone (1,3-diphenyl-2-propen-1-one) with various substitution patterns, including hydroxyl, methoxy, and prenyl groups, which contribute to their diverse biological activities. Among these, Licochalcone A is the most abundant and well-studied.

One of the most significant mechanisms of licochalcones is their potent anti-inflammatory activity, primarily mediated through inhibition of the nuclear factor-kappa B (NF-κB) signaling pathway. In the canonical NF-κB pathway, inflammatory stimuli activate the IκB kinase (IKK) complex, which phosphorylates inhibitor of κB (IκB) proteins, leading to their ubiquitination and degradation. This releases NF-κB dimers, allowing them to translocate to the nucleus and induce the expression of pro-inflammatory genes. Licochalcones, particularly Licochalcone A, can inhibit this pathway at multiple points: they prevent the activation of the IKK complex, inhibit the phosphorylation and degradation of IκB, and directly interfere with the DNA-binding activity of NF-κB.

Through these mechanisms, licochalcones suppress the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines (MCP-1, IL-8), adhesion molecules (ICAM-1, VCAM-1), and enzymes involved in inflammation (COX-2, iNOS). Additionally, licochalcones modulate other inflammatory signaling pathways, including the mitogen-activated protein kinase (MAPK) cascades (p38 MAPK, ERK, JNK) and the JAK-STAT pathway. Licochalcone A has been shown to inhibit the phosphorylation and activation of p38 MAPK, ERK, and JNK, thereby reducing the expression of pro-inflammatory genes regulated by these pathways. Licochalcones also demonstrate significant antioxidant properties through multiple mechanisms.

They can directly scavenge reactive oxygen species (ROS) and free radicals through their phenolic hydroxyl groups, which can donate hydrogen atoms to neutralize free radicals. However, their antioxidant effects extend beyond direct radical scavenging. Licochalcones, particularly Licochalcone A, are potent activators of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a master regulator of cellular antioxidant defenses. Under normal conditions, Nrf2 is bound to Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm, which targets it for ubiquitination and degradation.

Licochalcones can modify the cysteine residues of Keap1, disrupting the Keap1-Nrf2 interaction and allowing Nrf2 to translocate to the nucleus. In the nucleus, Nrf2 binds to antioxidant response elements (AREs) in the promoter regions of target genes, inducing the expression of antioxidant and detoxifying enzymes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GSTs), and γ-glutamylcysteine synthetase (γ-GCS). This indirect antioxidant mechanism allows licochalcones to provide long-lasting protection against oxidative stress by enhancing the cell’s own antioxidant capacity. In cancer biology, licochalcones exhibit anticancer properties through multiple mechanisms.

They induce cell cycle arrest, primarily at the G0/G1 and G2/M phases, by modulating the expression and activity of cell cycle regulators including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors (p21, p27). Licochalcones trigger apoptosis (programmed cell death) in cancer cells through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways. In the intrinsic pathway, licochalcones increase the expression of pro-apoptotic proteins (Bax, Bad) and decrease the expression of anti-apoptotic proteins (Bcl-2, Bcl-xL), leading to mitochondrial membrane permeabilization, cytochrome c release, and caspase activation. In the extrinsic pathway, licochalcones can upregulate death receptors (Fas, TRAIL receptors) and their ligands, initiating the caspase cascade.

Licochalcones also inhibit angiogenesis (formation of new blood vessels) by downregulating vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α), thereby limiting tumor growth and metastasis. Additionally, they suppress cancer cell migration and invasion by inhibiting matrix metalloproteinases (MMPs) and modulating epithelial-mesenchymal transition (EMT) markers. Licochalcones demonstrate epigenetic effects, including inhibition of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), potentially reversing aberrant epigenetic modifications in cancer cells. Licochalcones possess potent antimicrobial activities against a wide range of pathogens, including bacteria, fungi, viruses, and parasites.

Their antimicrobial mechanisms include disruption of cell membranes, inhibition of cell wall synthesis, interference with nucleic acid synthesis, and inhibition of energy metabolism. The prenyl groups in licochalcones enhance their ability to interact with and disrupt microbial membranes. Licochalcone A has been shown to inhibit bacterial growth by disrupting the bacterial membrane potential and increasing membrane permeability. It also inhibits bacterial DNA and RNA synthesis, as well as protein synthesis.

Against fungi, licochalcones inhibit ergosterol biosynthesis, a critical component of fungal cell membranes, and disrupt fungal cell wall integrity. Licochalcones exhibit antiviral activities by interfering with viral attachment, entry, replication, and assembly. They have been shown to inhibit the replication of various viruses, including influenza virus, herpes simplex virus, and human immunodeficiency virus (HIV). Against parasites, particularly Leishmania and Plasmodium species, licochalcones inhibit mitochondrial functions and disrupt energy metabolism.

In metabolic regulation, licochalcones demonstrate significant effects through multiple mechanisms. They activate adenosine monophosphate-activated protein kinase (AMPK), a master regulator of energy metabolism, in skeletal muscle, liver, and adipose tissue. AMPK activation leads to increased glucose uptake, enhanced fatty acid oxidation, and reduced lipogenesis. Licochalcones inhibit adipogenesis (formation of new fat cells) by downregulating key adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα).

They also enhance thermogenesis in brown adipose tissue and promote the browning of white adipose tissue, increasing energy expenditure. Additionally, licochalcones improve insulin sensitivity by enhancing insulin signaling pathways and reducing inflammation and oxidative stress in insulin-responsive tissues. In liver metabolism, licochalcones demonstrate hepatoprotective effects through multiple mechanisms. They reduce hepatic steatosis (fatty liver) by inhibiting lipogenesis and enhancing fatty acid oxidation.

They protect against liver injury by reducing oxidative stress, inflammation, and apoptosis in hepatocytes. Additionally, licochalcones modulate bile acid metabolism and enhance cholesterol efflux, potentially contributing to their beneficial effects on lipid profiles. In skin health, licochalcones, particularly Licochalcone A, demonstrate significant benefits through multiple mechanisms. They reduce skin inflammation by inhibiting the production of pro-inflammatory cytokines and chemokines in keratinocytes and other skin cells.

They protect against UV-induced damage by scavenging ROS and activating Nrf2-mediated antioxidant defenses. Licochalcones inhibit melanogenesis (pigment production) by downregulating tyrosinase activity and expression, potentially reducing hyperpigmentation. Additionally, they enhance skin barrier function by promoting the expression of barrier proteins and lipids, and they exhibit antimicrobial activities against skin pathogens, including Propionibacterium acnes and Staphylococcus aureus. In neurological function, licochalcones demonstrate neuroprotective effects through multiple mechanisms.

They protect neurons from oxidative stress and inflammation, which are key factors in neurodegenerative diseases. They modulate neurotransmitter systems, potentially affecting mood, cognition, and stress responses. Some studies suggest that licochalcones may inhibit the aggregation of amyloid-β and tau proteins, key pathological features of Alzheimer’s disease. Additionally, they may enhance brain-derived neurotrophic factor (BDNF) expression, supporting neuronal survival and plasticity.

In cardiovascular health, licochalcones improve endothelial function by increasing nitric oxide (NO) production through activation of endothelial nitric oxide synthase (eNOS). They also demonstrate vasodilatory effects and inhibit platelet aggregation and thrombus formation, potentially reducing the risk of thrombotic events. Additionally, they improve lipid profiles by reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides while increasing high-density lipoprotein (HDL) cholesterol. Licochalcones inhibit the oxidation of LDL, a key step in atherosclerosis development.

The pharmacokinetics of licochalcones are characterized by relatively low oral bioavailability, estimated at approximately 5-15% in humans. This limited bioavailability is due to several factors, including poor water solubility, extensive first-pass metabolism, and potential efflux by transporters like P-glycoprotein. In the liver, licochalcones undergo phase I metabolism (primarily hydroxylation by cytochrome P450 enzymes) and phase II metabolism (glucuronidation, sulfation, and glutathione conjugation), forming metabolites that are more water-soluble and readily excreted in urine. The plasma half-life of licochalcones is relatively short, estimated at approximately 2-6 hours in humans, necessitating multiple daily doses for sustained therapeutic effects.

The biological effects of licochalcones are thus a combination of their direct actions through multiple mechanisms and the activities of their metabolites, with their anti-inflammatory, antioxidant, antimicrobial, and anticancer activities being particularly significant for their potential health benefits.

Optimal dosage ranges for licochalcones are not well-established due to limited clinical studies specifically evaluating licochalcones as supplements. Most research has been conducted in preclinical settings (cell culture and animal models) or with licorice extracts containing licochalcones along with other bioactive compounds. Based on the available research and considering licochalcones’ biological activities, the following dosage ranges can be considered: For standardized licochalcone extracts (rare as commercial supplements), the estimated dosage range is 50-200 mg daily, though this is primarily based on preclinical studies and limited human data. For licorice root extracts standardized to contain licochalcones, typical dosages range from 250-1000 mg daily, corresponding to approximately 5-50 mg of total licochalcones depending on the standardization level.

For topical applications (particularly for skin conditions), products containing 0.05-0.2% licochalcone A are commonly used, with application 1-2 times daily. It’s important to note that licorice extracts contain multiple bioactive compounds, including glycyrrhizin, which can cause adverse effects such as hypertension, hypokalemia, and edema at high doses. Therefore, deglycyrrhizinated licorice (DGL) extracts, which have reduced glycyrrhizin content but retain licochalcones, may be preferred for oral supplementation. Additionally, the bioavailability of licochalcones is relatively low (approximately 5-15% in humans), which may necessitate higher doses or enhanced delivery formulations for therapeutic effects.

For most health applications, starting with a lower dose (50-100 mg daily for licochalcone extracts or 250-500 mg daily for licorice root extracts) and gradually increasing as needed and tolerated is recommended. Divided doses (2-3 times daily) may be preferred due to the relatively short half-life of licochalcones, though specific pharmacokinetic data in humans is limited.

Licochalcones have relatively low oral bioavailability, estimated at approximately 5-15% in humans based on limited studies. Several factors contribute to this limited bioavailability. Licochalcones have poor water solubility due to their chalcone structure and relatively high lipophilicity, which limits their dissolution in the gastrointestinal fluid. The compounds undergo extensive first-pass metabolism in the intestine and liver, primarily through phase I (hydroxylation) and phase II (glucuronidation, sulfation) reactions, which significantly reduce the amount of free licochalcones reaching the systemic circulation.

Additionally, licochalcones may be subject to efflux by intestinal transporters such as P-glycoprotein, further limiting their absorption. The absorption of licochalcones occurs primarily in the small intestine through passive diffusion, facilitated by their moderate lipophilicity. The prenyl groups in some licochalcones (particularly Licochalcone A) enhance their membrane permeability compared to non-prenylated chalcones. Some evidence suggests that a small portion may be absorbed via active transport mechanisms, though the specific transporters involved have not been fully characterized.

After absorption, licochalcones undergo extensive metabolism in the intestinal epithelium and liver. Phase I metabolism primarily involves hydroxylation by cytochrome P450 enzymes, particularly CYP1A2, CYP2C9, and CYP3A4. Phase II metabolism involves conjugation with glucuronic acid (glucuronidation) and sulfate (sulfation), forming conjugates that are more water-soluble and readily excreted in urine. These conjugates may be less biologically active than free licochalcones, though some evidence suggests they can be deconjugated in target tissues, releasing the active compounds.

The plasma half-life of licochalcones is relatively short, estimated at approximately 2-6 hours in humans based on limited studies, necessitating multiple daily doses for sustained therapeutic effects. Licochalcones demonstrate moderate distribution to various tissues, with some evidence suggesting they can cross the blood-brain barrier to some extent, which is particularly relevant for their potential neuroprotective effects. The prenyl groups in some licochalcones enhance their lipophilicity and may facilitate their accumulation in lipid-rich tissues. The bioavailability of licochalcones is influenced by various factors, including food matrix, processing methods, and individual factors such as gut microbiome composition, intestinal transit time, and genetic factors affecting metabolic enzymes.

Consumption with a high-fat meal may enhance the absorption of licochalcones by increasing bile secretion and improving their solubilization, though excessive fat may reduce absorption by slowing gastric emptying. The extraction method used to obtain licochalcones from licorice roots significantly affects their bioavailability. Traditional water extraction methods may not efficiently extract licochalcones due to their poor water solubility, while alcohol-based extractions (ethanol, methanol) are more effective. Supercritical fluid extraction using carbon dioxide can also efficiently extract licochalcones while avoiding the use of organic solvents.

For topical applications, licochalcones demonstrate good skin penetration due to their lipophilicity, particularly when formulated in appropriate vehicles such as emulsions, gels, or liposomes. The prenyl groups in some licochalcones enhance their ability to penetrate the stratum corneum, the outermost layer of the skin, and reach deeper skin layers where they can exert their biological effects.

Liposomal formulations – can increase bioavailability by 3-5 fold by enhancing cellular uptake and protecting licochalcones from degradation, Nanoemulsion formulations – can increase bioavailability by 4-6 fold by improving solubility and enhancing intestinal permeability, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, potentially increasing bioavailability by 3-5 fold, Phospholipid complexes – enhance lipid solubility and membrane permeability, potentially increasing bioavailability by 2-4 fold, Cyclodextrin inclusion complexes – improve aqueous solubility while maintaining stability, potentially increasing bioavailability by 2-3 fold, Solid dispersion techniques – enhance dissolution rate and solubility, potentially increasing bioavailability by 2-3 fold, Combination with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, potentially increasing bioavailability by 30-60%, Microemulsions – provide a stable delivery system with enhanced solubility, potentially increasing bioavailability by 3-5 fold, Co-administration with fatty meals – can increase absorption by stimulating bile secretion and enhancing lymphatic transport, potentially increasing bioavailability by 20-50%, Deglycyrrhizinated licorice (DGL) extracts – reduce glycyrrhizin content while retaining licochalcones, potentially allowing for higher doses without glycyrrhizin-related side effects

Licochalcones are best absorbed when taken with meals containing some fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. However, extremely high-fat meals should be avoided as they may slow gastric emptying and potentially reduce absorption. Due to the relatively short half-life of licochalcones (estimated at 2-6 hours based on limited studies), divided doses (2-3 times daily) may be beneficial for maintaining consistent blood levels throughout the day, though specific human pharmacokinetic data is limited. For anti-inflammatory applications, consistent daily dosing is recommended, with some evidence suggesting that divided doses throughout the day may provide more continuous protection against inflammation.

For antimicrobial applications, consistent daily dosing is recommended, with some evidence suggesting that higher doses may be more effective for acute infections, while lower doses may be sufficient for preventive purposes. For liver health and detoxification, taking licochalcones between meals may enhance their hepatoprotective effects by reducing competition with food components for absorption, though more research is needed. Some evidence suggests that evening dosing may be particularly beneficial for liver detoxification due to circadian rhythms in liver function, though more research is needed. For metabolic regulation, consistent daily dosing is recommended, with some evidence suggesting that taking licochalcones before meals may help reduce postprandial glucose and lipid spikes, though more research is needed.

For skin conditions, topical applications of licochalcone-containing products are typically recommended 1-2 times daily, with morning and evening applications being most common. For acne and oily skin, more frequent application (2-3 times daily) may be beneficial, while for sensitive or dry skin, less frequent application (1 time daily) may be sufficient. Enhanced delivery formulations like liposomes or nanoemulsions may have different optimal timing recommendations based on their specific pharmacokinetic profiles, but generally follow the same principles of taking with food for optimal absorption. The timing of licochalcone supplementation relative to other medications should be considered, as licochalcones may interact with certain drugs, particularly those metabolized by the same enzymes or transported by the same transporters.

In general, separating licochalcone supplementation from other medications by at least 2 hours is recommended to minimize potential interactions. For individuals taking medications that may interact with glycyrrhizin (such as diuretics, corticosteroids, or antihypertensives), deglycyrrhizinated licorice (DGL) extracts are recommended to minimize potential interactions while still providing licochalcones.

• Gastrointestinal discomfort (mild to moderate, common)
• Nausea (uncommon)
• Headache (uncommon)
• Allergic reactions (rare, particularly in individuals with allergies to licorice or related plants)
• Skin rash (rare, with oral consumption; more common with topical application in sensitive individuals)
• Hypertension (uncommon, primarily associated with glycyrrhizin in licorice extracts rather than licochalcones themselves)
• Hypokalemia (uncommon, primarily associated with glycyrrhizin in licorice extracts rather than licochalcones themselves)
• Edema (uncommon, primarily associated with glycyrrhizin in licorice extracts rather than licochalcones themselves)
• Mild dizziness (rare)
• Fatigue (rare)

• Hypertension (due to potential glycyrrhizin content in licorice extracts, though deglycyrrhizinated licorice extracts may be suitable)
• Hypokalemia (due to potential glycyrrhizin content in licorice extracts, though deglycyrrhizinated licorice extracts may be suitable)
• Heart failure (due to potential glycyrrhizin content in licorice extracts, though deglycyrrhizinated licorice extracts may be suitable)
• Kidney disease (due to potential glycyrrhizin content in licorice extracts, though deglycyrrhizinated licorice extracts may be suitable)
• Liver disease (severe cases, due to potential effects on liver enzymes)
• Pregnancy and breastfeeding (due to insufficient safety data and potential hormonal effects of licorice compounds)
• Individuals scheduled for surgery (discontinue 2 weeks before due to potential effects on blood pressure and electrolyte balance)
• Individuals with known allergies to licorice or related plants in the Fabaceae family
• Individuals with hormone-sensitive conditions (due to potential estrogenic effects of some licorice compounds)
• Individuals with known hypersensitivity to licochalcones or related compounds

• Antihypertensive medications (may reduce efficacy due to potential glycyrrhizin content in licorice extracts, though deglycyrrhizinated licorice extracts may have minimal interaction)
• Diuretics (may enhance potassium loss due to potential glycyrrhizin content in licorice extracts, though deglycyrrhizinated licorice extracts may have minimal interaction)
• Corticosteroids (may enhance potassium loss and increase risk of hypokalemia due to potential glycyrrhizin content in licorice extracts)
• Digoxin (increased risk of digoxin toxicity due to potential hypokalemia from glycyrrhizin content in licorice extracts)
• Cytochrome P450 substrates (may affect the metabolism of drugs that are substrates for CYP1A2, CYP2C9, and CYP3A4)
• Anticoagulant and antiplatelet medications (may enhance antiplatelet effects, potentially increasing bleeding risk)
• Oral contraceptives (may reduce efficacy due to potential effects on hormone metabolism)
• Hormone replacement therapy (may interfere with or enhance effects due to potential estrogenic activity of some licorice compounds)
• Antidiabetic medications (may enhance blood glucose-lowering effects, potentially requiring dose adjustment)
• Monoamine oxidase inhibitors (MAOIs) (theoretical interaction due to potential effects on neurotransmitter metabolism)

Based on limited studies and considering the potential for side effects, particularly from glycyrrhizin in licorice extracts, the upper limit for licochalcone supplementation is generally considered to be 200 mg daily for isolated licochalcone extracts or 1000 mg daily for standardized licorice root extracts. For licorice root extracts, it’s important to consider the glycyrrhizin content, as the European Scientific Committee on Food has established an upper limit of 100 mg/day for glycyrrhizin consumption. Deglycyrrhizinated licorice (DGL) extracts, which have reduced glycyrrhizin content but retain licochalcones, may allow for higher doses without glycyrrhizin-related side effects. For topical applications, products containing up to 0.2% licochalcone A are generally considered safe for most individuals, though skin sensitivity testing is recommended before widespread application.

Higher doses may significantly increase the risk of side effects and drug interactions, particularly in sensitive individuals or those with pre-existing conditions such as hypertension, hypokalemia, or heart failure. For general supplementation, doses exceeding these levels are not recommended without medical supervision. The safety profile of licochalcones warrants attention due to their diverse biological activities and potential for interactions with drugs and endogenous compounds. While licochalcones themselves demonstrate a favorable safety profile in preclinical studies, their presence in licorice extracts alongside glycyrrhizin adds complexity to safety considerations.

Glycyrrhizin can cause pseudoaldosteronism, characterized by hypertension, hypokalemia, and edema, through inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which normally prevents cortisol from binding to mineralocorticoid receptors. This effect is dose-dependent and reversible upon discontinuation of licorice consumption. The long-term safety of licochalcone supplementation has not been fully established, with most safety data derived from preclinical studies and limited human trials. Acute toxicity studies in animals have shown relatively low toxicity, with no significant adverse effects observed at doses equivalent to several times the recommended human doses.

However, the potential for cumulative effects with long-term use remains a consideration. The diverse biological activities of licochalcones, including their effects on drug-metabolizing enzymes, add complexity to safety considerations. Licochalcones may inhibit certain cytochrome P450 enzymes, potentially affecting the metabolism of drugs that are substrates for these enzymes. Additionally, their effects on other biological pathways, such as NF-κB signaling and Nrf2 activation, while generally beneficial, may have context-dependent effects that should be considered in specific health conditions.

The safety of licochalcones during pregnancy and breastfeeding has not been established, and some licorice compounds have been associated with adverse pregnancy outcomes, including preterm birth and developmental effects. Therefore, licochalcone supplementation is not recommended during these periods. For most individuals, obtaining licochalcones through moderate consumption of licochalcone-containing foods and supplements as part of a balanced approach is likely safer than high-dose isolated licochalcone supplements. Deglycyrrhizinated licorice (DGL) extracts may be preferred for oral supplementation to minimize glycyrrhizin-related side effects while still providing licochalcones.

Licochalcones as isolated compounds are not specifically regulated by the FDA. They are not approved as drugs and are not generally available as standalone dietary supplements. Licorice root extracts containing licochalcones are regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under this framework, manufacturers are responsible for ensuring the safety of their products before marketing, but pre-market approval is not required.

Manufacturers cannot make specific disease treatment claims but may make general structure/function claims with appropriate disclaimers. The FDA has not evaluated the safety or efficacy of licochalcones specifically. However, the FDA has issued guidance regarding glycyrrhizin content in licorice products due to potential adverse effects at high doses, including hypertension, hypokalemia, and edema. While this guidance does not specifically address licochalcones, it is relevant for licorice-derived supplements that may contain both glycyrrhizin and licochalcones.

For topical applications, licochalcone-containing products are regulated as cosmetics unless they make drug claims. If they claim to treat or prevent disease or to affect the structure or function of the body, they would be regulated as drugs and would require FDA approval. Synthetic licochalcone derivatives being developed as pharmaceutical drugs would be regulated as new drug entities and would require full FDA approval through the standard drug development and approval process, including clinical trials demonstrating safety and efficacy.

Eu: Licochalcones as isolated compounds are not specifically regulated in the European Union. Licorice root extracts containing licochalcones are primarily regulated as food supplements under the Food Supplements Directive (2002/46/EC). The European Food Safety Authority (EFSA) has evaluated several health claims related to licorice and has generally not found sufficient evidence to approve specific claims. The European Commission has established an upper limit for glycyrrhizin consumption at 100 mg/day, which is relevant for licorice-derived supplements that may contain both glycyrrhizin and licochalcones. For topical applications, licochalcone-containing products are regulated under the Cosmetic Products Regulation (EC) No 1223/2009 unless they make medicinal claims. Synthetic licochalcone derivatives being developed as pharmaceutical drugs would be regulated under the centralized procedure by the European Medicines Agency (EMA) or through national authorization procedures.

Uk: Licochalcones as isolated compounds are not specifically regulated in the United Kingdom. Licorice root extracts containing licochalcones are regulated as food supplements. They are not licensed as medicines and cannot be marketed with medicinal claims. The Medicines and Healthcare products Regulatory Agency (MHRA) has not issued specific guidance on licochalcones. For topical applications, licochalcone-containing products are regulated as cosmetics unless they make medicinal claims. The UK follows similar guidance to the EU regarding glycyrrhizin content in licorice products.

Canada: Licochalcones as isolated compounds are not specifically regulated in Canada. Licorice root extracts containing licochalcones are regulated as Natural Health Products (NHPs) under the Natural Health Products Regulations. Several products containing licorice root extract have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims. Health Canada has established a maximum daily dose of 5 g of licorice root (corresponding to approximately 75-100 mg of glycyrrhizin) for oral use, which is relevant for licorice-derived supplements that may contain both glycyrrhizin and licochalcones. For topical applications, licochalcone-containing products are regulated as cosmetics unless they make therapeutic claims, in which case they would be regulated as NHPs.

Australia: Licochalcones as isolated compounds are not specifically regulated in Australia. Licorice root extracts containing licochalcones are regulated as complementary medicines by the Therapeutic Goods Administration (TGA). Several products containing licorice root extract are listed on the Australian Register of Therapeutic Goods (ARTG). The TGA has established a maximum daily dose of 5 g of licorice root (corresponding to approximately 75-100 mg of glycyrrhizin) for oral use, which is relevant for licorice-derived supplements that may contain both glycyrrhizin and licochalcones. For topical applications, licochalcone-containing products are regulated as cosmetics unless they make therapeutic claims, in which case they would be regulated as therapeutic goods.

Japan: Licochalcones as isolated compounds are not specifically regulated in Japan. Licorice root extracts containing licochalcones may be regulated as Foods for Specified Health Uses (FOSHU) if they meet specific criteria and have supporting evidence for their health claims. Licorice is also recognized as a Kampo medicine (traditional Japanese herbal medicine) and is included in many approved Kampo formulations. The Ministry of Health, Labour and Welfare has not issued specific guidance on licochalcones. For topical applications, licochalcone-containing products are regulated as quasi-drugs or cosmetics depending on their claims and ingredients.

China: Licochalcones as isolated compounds are not specifically regulated in China. Licorice root is officially listed in the Chinese Pharmacopoeia and is widely used in Traditional Chinese Medicine (TCM). Licorice root extracts containing licochalcones may be regulated as health foods and would require approval from the China Food and Drug Administration (CFDA) before marketing with health claims. The CFDA has not issued specific guidance on licochalcones. For topical applications, licochalcone-containing products are regulated as cosmetics unless they make therapeutic claims, in which case they would be regulated as drugs.

Korea: Licochalcones as isolated compounds are not specifically regulated in South Korea. Licorice root extracts containing licochalcones may be regulated as health functional foods and would require approval from the Ministry of Food and Drug Safety (MFDS) before marketing with health claims. Licorice is also recognized in traditional Korean medicine and is included in many approved herbal formulations. The MFDS has not issued specific guidance on licochalcones. For topical applications, licochalcone-containing products are regulated as cosmetics unless they make therapeutic claims, in which case they would be regulated as drugs.

Medium

Isolated licochalcones are not typically available as consumer supplements but are primarily used in research settings. Research-grade licochalcone A (>95% purity) typically costs $200-$500 per gram, making it prohibitively expensive for regular supplementation. Standardized licochalcone extracts (rare as commercial supplements) typically cost $2.00-$5.00 per day for effective doses (50-200 mg daily). Licorice root extracts containing licochalcones typically cost $0.50-$2.00 per day for basic extracts (250-1000 mg daily, corresponding to approximately 5-50 mg of total licochalcones depending on the standardization level) and $2.00-$4.00 per day for premium, standardized formulations or enhanced delivery systems.

Deglycyrrhizinated licorice (DGL) extracts, which have reduced glycyrrhizin content but retain licochalcones, typically cost $0.75-$2.50 per day for effective doses (500-1500 mg daily). Topical products containing licochalcones (particularly licochalcone A) typically cost $15-$50 per product (e.g., creams, serums, lotions), with each product lasting approximately 1-3 months depending on usage frequency and application area. Enhanced delivery formulations (such as liposomes, nanoemulsions, or phospholipid complexes) typically cost $3.00-$7.00 per day, though these may provide improved bioavailability that could justify the higher cost.

The value of licochalcone supplementation varies significantly depending on the specific health application, the form of supplementation, and individual factors. For anti-inflammatory support, licochalcones offer moderate to high value. Preclinical studies have demonstrated potent anti-inflammatory effects through multiple mechanisms, including NF-κB inhibition and modulation of pro-inflammatory cytokine production. For individuals with inflammatory conditions, licochalcone-containing supplements may provide valuable support, particularly when combined with lifestyle modifications.

When compared to other natural anti-inflammatory compounds, licochalcone-containing supplements are moderately priced and offer a reasonable option for general support. For skin conditions (acne, rosacea, eczema), licochalcones offer high value. Clinical studies have demonstrated significant improvements in skin inflammation, redness, and overall skin condition with topical licochalcone A applications. When compared to other topical treatments for these conditions, licochalcone-containing products are moderately priced and often offer a more favorable side effect profile, particularly for sensitive skin.

The long-term cost-effectiveness is enhanced by the relatively low amount of product needed per application and the potential to reduce the need for more expensive treatments. For antimicrobial support, licochalcones offer moderate value. Preclinical studies have demonstrated significant antimicrobial effects against various pathogens, including bacteria, fungi, viruses, and parasites. For individuals seeking natural antimicrobial support, licochalcone-containing supplements may provide valuable assistance, particularly as a complementary approach alongside conventional treatments when needed.

When compared to other natural antimicrobial compounds, licochalcone-containing supplements are moderately priced and offer a reasonable option for general support. For liver health and detoxification, licochalcones offer moderate to high value. Preclinical studies have demonstrated hepatoprotective effects through multiple mechanisms, including antioxidant activity, anti-inflammatory effects, and modulation of lipid metabolism. For individuals with liver concerns, licochalcone-containing supplements may provide valuable support, particularly when combined with lifestyle modifications.

When compared to other natural compounds for liver health, such as silymarin (milk thistle), licochalcone-containing supplements are similarly priced and may offer complementary benefits through different mechanisms. For metabolic regulation, licochalcones offer moderate value. Preclinical studies have demonstrated beneficial effects on glucose metabolism, insulin sensitivity, and lipid profiles through multiple mechanisms, including AMPK activation. For individuals with metabolic concerns, licochalcone-containing supplements may provide valuable support, particularly when combined with diet and exercise.

When compared to other natural compounds for metabolic health, licochalcone-containing supplements are moderately priced and offer a reasonable option for general support. When comparing the cost-effectiveness of different sources of licochalcones: Licorice root extracts offer the best value for most health applications, providing licochalcones along with other beneficial compounds that may have synergistic effects. However, the glycyrrhizin content in standard licorice extracts may limit the maximum safe dose, particularly for individuals with hypertension or other conditions affected by glycyrrhizin. Deglycyrrhizinated licorice (DGL) extracts offer a good balance of cost and efficacy for oral supplementation, providing licochalcones without the potential side effects of glycyrrhizin.

This allows for higher doses if needed, potentially enhancing therapeutic effects. Topical products containing licochalcones offer excellent value for skin conditions, with clinical evidence supporting their efficacy and a favorable side effect profile. The cost per application is relatively low, and the potential to reduce the need for more expensive treatments enhances long-term cost-effectiveness. Enhanced delivery formulations offer improved bioavailability, which may justify their higher cost for individuals with absorption issues or those seeking maximum therapeutic effects.

However, the cost-benefit ratio should be carefully considered, as the improvement in bioavailability may not always justify the significantly higher cost. For most individuals, standard licorice extracts or DGL extracts (for those with glycyrrhizin concerns) offer the best balance of cost and efficacy for general health applications. These should be selected based on quality considerations, including standardization methods, extraction techniques, and third-party testing for purity and potency.

Pure licochalcones have moderate stability, with a typical shelf life of 1-2 years when properly stored at -20°C under inert gas. At room temperature, their stability is significantly reduced, with a shelf life of approximately 3-6 months when protected from light, heat, and moisture. The α,β-unsaturated carbonyl group in licochalcones is particularly susceptible to oxidation and Michael addition reactions, which can lead to degradation. Different licochalcones have varying stability profiles depending on their specific substitution patterns.

Licochalcone A, the most abundant and well-studied licochalcone, tends to be more stable than some other licochalcones due to its specific substitution pattern, particularly the prenyl group at position 3′ of the B-ring, which provides some steric hindrance against nucleophilic attack on the α,β-unsaturated carbonyl group. Standardized licorice extracts containing licochalcones typically have a shelf life of 1-2 years from the date of manufacture when properly stored in airtight, opaque containers at room temperature or below. The stability of licochalcones in these extracts may be enhanced by the presence of other compounds with antioxidant properties. Deglycyrrhizinated licorice (DGL) extracts, which have reduced glycyrrhizin content but retain licochalcones, typically have a similar shelf life to standard licorice extracts when properly stored.

In liquid formulations (such as tinctures or liquid extracts), licochalcones have reduced stability compared to solid forms, with a typical shelf life of 6-12 months when properly stored in airtight, opaque containers. The presence of alcohol in these formulations may help preserve licochalcones by inhibiting microbial growth and providing some protection against oxidation. In topical formulations (such as creams, lotions, or gels), licochalcones typically have a shelf life of 1-2 years when properly formulated with appropriate preservatives and antioxidants and stored in airtight, opaque containers. The stability in these formulations depends significantly on the specific formulation, pH, and presence of other ingredients that may interact with licochalcones.

Enhanced delivery formulations (such as liposomes, nanoemulsions, or phospholipid complexes) may have different stability profiles depending on the specific formulation. These formulations often provide some protection against degradation, potentially extending the shelf life of licochalcones, but they may also introduce additional stability considerations related to the delivery system itself.

For pure licochalcones (primarily used in research), storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability. Protect from light, heat, oxygen, and moisture, which can accelerate degradation. For standardized licorice extracts containing licochalcones, store in airtight, opaque containers at room temperature or below (preferably 15-25°C). Refrigeration (2-8°C) can extend shelf life but may not be necessary if other storage conditions are optimal.

Avoid exposure to direct sunlight, heat sources, and high humidity, which can accelerate degradation. For deglycyrrhizinated licorice (DGL) extracts, follow the same storage recommendations as for standard licorice extracts. These extracts may be more sensitive to moisture due to the processing required to remove glycyrrhizin, so particular attention should be paid to maintaining airtight conditions. For liquid formulations containing licochalcones, store in airtight, opaque containers at room temperature or below (preferably 15-25°C).

Refrigeration (2-8°C) can extend shelf life but may not be necessary if other storage conditions are optimal. Avoid exposure to direct sunlight and heat sources. For topical formulations containing licochalcones, store in airtight, opaque containers at room temperature or below (preferably 15-25°C). Avoid exposure to direct sunlight, heat sources, and high humidity.

Do not freeze, as this may affect the formulation’s texture and stability. For enhanced delivery formulations, follow specific storage recommendations for each formulation. These may include refrigeration, protection from light, or other special considerations depending on the delivery system. After opening, all licochalcone-containing products should be used within the recommended time frame specified by the manufacturer, typically 1-3 months for liquid formulations and 3-6 months for solid formulations.

Proper sealing of containers after each use is important to minimize exposure to air and moisture. For long-term storage of research-grade licochalcones, aliquoting into smaller portions before freezing is recommended to minimize freeze-thaw cycles, which can accelerate degradation.

Exposure to oxygen – leads to oxidation, particularly of the α,β-unsaturated carbonyl group, forming epoxides, diols, and other oxidation products, Exposure to UV light and sunlight – causes photodegradation, particularly isomerization of the trans-chalcone to the cis-chalcone, which is less stable, High temperatures (above 30°C) – accelerates decomposition and oxidation, Moisture – promotes hydrolysis of the carbonyl group and facilitates other degradation reactions, pH extremes – licochalcones are most stable at slightly acidic to neutral pH (5-7), with increased degradation in strongly acidic or alkaline conditions, Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Nucleophilic compounds – can react with the α,β-unsaturated carbonyl group through Michael addition reactions, Enzymatic activity – certain enzymes, particularly oxidases and reductases, can degrade licochalcones, Microbial contamination – can lead to enzymatic degradation of licochalcones, Freeze-thaw cycles – can accelerate degradation, particularly in liquid formulations

Synthesis Methods

Natural Sources

Quality Considerations

Licochalcones themselves were not identified or isolated as specific compounds until the late 20th century, so their direct historical usage as isolated compounds is limited to recent scientific and medical applications. However, licochalcones have been unknowingly consumed for millennia through licorice root (Glycyrrhiza species), which has a long and rich history of medicinal use across multiple cultures and traditional medicine systems. The earliest documented use of licorice root dates back to ancient civilizations. Archaeological evidence suggests that licorice was used medicinally in ancient Egypt as early as 2600 BCE.

A bundle of licorice roots was found in the tomb of King Tutankhamun (ca. 1350 BCE), indicating its value in ancient Egyptian society. Ancient Egyptian papyri, including the Ebers Papyrus (ca. 1550 BCE), mention licorice as a remedy for various ailments, including respiratory conditions, liver problems, and as a general tonic.

In ancient Mesopotamia, Assyrian and Babylonian texts from around 2300 BCE mention licorice for treating coughs, liver and kidney diseases, and as a general health tonic. The ancient Greeks and Romans also valued licorice highly. Theophrastus (371-287 BCE), often called the ‘father of botany,’ described licorice in his botanical writings. Hippocrates (460-370 BCE), the ‘father of medicine,’ recommended licorice for respiratory conditions and as a wound healing agent.

The Roman naturalist Pliny the Elder (23-79 CE) mentioned licorice in his ‘Natural History,’ noting its effectiveness for coughs, asthma, and stomach ulcers. The Greek physician Dioscorides included licorice in his pharmacopeia ‘De Materia Medica’ (ca. 70 CE), recommending it for respiratory conditions, stomach ulcers, and kidney problems. In traditional Chinese medicine (TCM), licorice root (known as ‘gan cao’) has been used for over 2,000 years and is mentioned in the Shennong Ben Cao Jing (Divine Farmer’s Materia Medica), one of the oldest Chinese pharmacopeias, compiled around 200 CE.

In TCM, licorice is considered one of the most important herbs and is used in more than half of all TCM formulations, often as a harmonizing agent that enhances the effects of other herbs while reducing their potential toxicity. It is traditionally used for treating coughs, reducing inflammation, supporting digestive health, and as an ‘adaptogen’ to help the body resist various stressors. In Ayurvedic medicine, the traditional medical system of India dating back over 3,000 years, licorice (known as ‘yashtimadhu’ or ‘mulethi’) is classified as a ‘rasayana’ herb, which means it is believed to promote longevity and rejuvenation. It is traditionally used for treating respiratory conditions, supporting adrenal function, promoting digestive health, and enhancing voice quality.

In traditional Japanese Kampo medicine, which evolved from TCM, licorice (known as ‘kanzō’) is used in many formulations for similar purposes as in TCM. In traditional Korean medicine, licorice (known as ‘gamcho’) is also widely used in herbal formulations. In medieval Europe, licorice continued to be valued for its medicinal properties. The influential Persian physician Avicenna (980-1037 CE) included licorice in his ‘Canon of Medicine,’ which became a standard medical text in European universities for centuries.

During the Middle Ages, European monasteries often cultivated licorice in their medicinal herb gardens. By the 15th century, licorice was being cultivated commercially in England, particularly around Pontefract in Yorkshire, where the famous Pontefract cakes (small, stamped lozenges of licorice) were first produced. The scientific discovery and characterization of licochalcones began in the late 20th century. Licochalcone A, the most abundant and well-studied licochalcone, was first isolated and identified from Glycyrrhiza inflata in the 1970s, with its structure fully elucidated in the 1980s.

Detailed studies of its biological activities began in the 1990s, when researchers discovered its potential antimicrobial, anti-inflammatory, and anticancer properties. In the early 2000s, research on licochalcones expanded to include their effects on metabolic regulation, skin health, and neuroprotection. The development of more sophisticated analytical techniques allowed for the identification and characterization of additional licochalcones (B, C, D, E) and the elucidation of their structure-activity relationships. In recent years, there has been growing interest in licochalcones for various health applications, particularly in dermatology.

Licochalcone A has been incorporated into several commercial skincare products for its anti-inflammatory and skin-soothing properties, particularly for conditions such as acne, rosacea, and sensitive skin. Additionally, research on licochalcones’ potential as antimicrobial, anticancer, and anti-inflammatory agents has continued to expand, with numerous preclinical studies demonstrating their diverse biological activities. Today, while isolated licochalcones are primarily used in research settings, licorice extracts containing licochalcones are available as dietary supplements and are incorporated into various topical formulations for skin health. The modern understanding of licochalcones’ presence in traditional licorice preparations and their potential health benefits represents a fascinating intersection of traditional herbal medicine and contemporary scientific research.

Preclinical investigations into licochalcones’ anticancer effects, particularly for liver, colon, and oral cancers, Studies on licochalcones’ anti-inflammatory effects and potential applications in inflammatory conditions such as inflammatory bowel disease and arthritis, Investigations into licochalcones’ antimicrobial effects against various pathogens, including drug-resistant bacteria, fungi, and parasites, Research on licochalcones’ metabolic effects and potential applications in obesity, metabolic syndrome, and non-alcoholic fatty liver disease, Studies on licochalcones’ neuroprotective effects and potential applications in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, Investigations into licochalcones’ hepatoprotective effects and potential applications in liver diseases, Research on the development of enhanced delivery systems for licochalcones to improve their bioavailability and therapeutic efficacy, Studies on the potential synergistic effects of licochalcones with conventional drugs for various conditions, Investigations into the effects of different licochalcones (A, B, C, D, E) and their structure-activity relationships, Limited clinical trials evaluating licochalcone-containing topical products for various skin conditions, including acne, rosacea, and eczema