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YNP College of Pharmacy, At post Asangaon, Raipada Road, Taluka: Dahanu, District: Palghar (401103), Maharashtra, India..
Licorice (Glycyrrhiza) species roots and rhizomes have long been utilized as a natural sweetener and herbal remedy around the world. Although clinical and experimental research indicates that licorice root has a number of health-enhancing pharmacological qualities, including anti-inflammatory, antiviral, antimicrobial, antioxidative, anticancer activities, immunomodulatory, hepatoprotective, and cardioprotective effects, it is primarily used in traditional medicine to treat peptic ulcers, hepatitis C, and pulmonary and skin conditions. Triterpene saponins, flavonoids, isoflavonoids, and chalcones are among the many components that have been identified from licorice; glycyrrhizic acid is typically thought to be the primary biologically active component. The main active ingredient found in liquorice roots, one of the most popular herbal remedies for liver problems, is glycyrrhizin. The herb has anti-inflammatory, spasmolytic, laxative, anti-depressive, anti-ulcer, and anti-diabetic properties. The phytochemical, pharmacological, and pharmacokinetic data, as well as the therapeutic and side effects of licorice and its bioactive components, are presented in this review. Despite all of the study on licorice, it appears that additional clinical trials are required to prove the therapeutic properties of this medicinal plant based on its traditional uses.
Since ancient times, plants have been a vital source of remedies for both humans and animals. Due to their effectiveness, safety, and little side effects, herbal medications are also much sought after for primary healthcare in the developed world. Additionally, they provide treatments for age-related conditions that are not currently treated by mainstream medicine, such as osteoporosis, immunological problems, memory loss, etc. Due to the export of crude extracts and pharmaceuticals, India has a pitiful share of the global market despite its rich traditional knowledge, legacy of herbal remedies, and abundant biodiversity. Approximately 80% of the world's population uses traditional medicines for primary healthcare, but the WHO has not conducted a thorough evaluation of them either. In recognition of their broad range of biological and therapeutic activities, high safety margins, and lower costs, herbal medicines are much sought after as a main health care source in both developed and developing nations. It is acknowledged that using traditional medicine can teach us about possible future medications. Numerous compounds utilized in conventional medicine have been found by researchers to have come from "ethnomedical" plant sources. Many powerful and potent medications are derived from plants, which are utilized medicinally in various nations(1). Because of their extensive pharmacological advantages, many plants have been utilized for generations as spices and medicines. Because they are an enriched source of several bioactive chemicals, these plants have a variety of useful qualities. These plants and their extracts are used by humans as nutritious food additives(2).
Fig no. 1: Liqourice plant with flowers.
One of the many plants that are mentioned in traditional medical texts from different civilizations is licorice. Glycyrrhiza spp. is the scientific name for this plant, which is a member of the Fabaceae family and has several varieties and subspecies. G. glabra, G. korshinskyi, and G. uralensis are a few of the most prevalent species. Dioscorides, an ancient Greek botanist, created the term Glycyrrhiza, which meaning sweet (Glycos) root (Rhiza)(3). The main component of licorice, which is the root of Glycyrrhiza glabra, is glycyrrhizin. In Asian, American, and European nations, this substance has been utilized as a sweetener and extra taste in candies, beverages, and meals, as well as in traditional plant-based medicine. Furthermore, glycyrrhizic is employed as a preferred natural sweetener because it is 50–100 times sweeter than sucrose and has a delayed sweetness onset(2). Currently, the extracts are utilized in the food and pharmaceutical industries, as well as in the production of functional meals and dietary supplements. For instance, the plant is frequently used in traditional Chinese medicine to treat bronchitis, arthritis, gastrointestinal issues, and cough(1).
History:
In traditional medicine, it is still frequently used to treat tremors, gastritis, peptic ulcers, and respiratory infections. G. glabra root is frequently used to make a tea that works wonders for quenching thirst. It has been said that the dried root cleans teeth. Additionally, it was one of the significant plants listed in the Assyrian Herbal (2000 BC). It was used to treat ulcers and quench thirds, according to Hippocrates (400 BC). Dioscorides and Theophrastus also referenced the medication. Liquorice is used as a laxative, sweetener, expectorant, anti-tussive, and demulcent in the traditional Siddha medical system(1,4).
With a variety of applications in tobacco, cosmetics, food, and pharmaceuticals, licorice is one of the most commercially valuable plants in the world. The phytochemical and pharmacological analysis of licorice has been carefully investigated. The chalcone structure of isoliquiritigenin (2',4',4-trihydroxychalcone, ISL), which is isolated from licorice root, has a potent anticancer action. Other key compounds in this plant with anti-atherogenic, anti-cancer, anti-diabetic, anti-microbial, antispasmodic, anti-inflammatory, and anti-asthmatic qualities include glycyrrhizin, glycyrrhizinic acid, isoliquiritin, and glycyrrhizic acid. In China, licorice has also been shown to alleviate weariness and disability. Licorice also has anti-inflammatory properties that lessen allergic reactions and shield the liver from harm. The World Health Organization states that licorice is used as an expectorant for coughs and bronchial catarrh and as a demulcent for sore throats. The taxa that have been investigated thus far have not been found to have any potentially hazardous chemicals. However, there are known negative effects, including as long-term use of high dosages that cause serious illnesses(5).
Taxonomical data:
This plant is cultivated in Russia, UK, USA, Italy, France, Germany, Spain, China and Northern India (Punjab and Sub-Himalayan tracts). It is distributed in Southern Europe, Syria, Iran, Afghanistan, Russia, China, Pakistan and Northern India. Large scale commercial cultivation is seen in Spain, Sicily and England(4). G. glabra is a typical herbaceous perennial, growing to 1 m in height, presenting pinnate leaves with a length of 7 to 15 cm. The flowers are purple to pale whitish blue, being arranged in a hermaphrodite inflorescence, whereas the fruit is an oblong legume with 2 to 3 cm of length and containing several seeds. The genus Glycyrrhiza (Fabaceae) consists of about 30 species, such as G. glabra, G. uralensis, G. inflata, G. aspera, G. korshinskyi, or G. eurycarpa. Like the other plants of Fabaceae, G. glabra is able to fix nitrogen, due to symbiosis with bacteria of the genus Rhizobium, at the root level, being suitable for sandy and clay soils, though preferring humid soils(1,6).
|
Sr. no |
Taxonomical Hierarchy |
Taxonomical Name |
|
1. |
Kingdom |
Plantae |
|
2. |
Division |
Angiospermae |
|
3. |
Class |
Dicotyledoneae |
|
4. |
Sub-Class |
Magnolidae |
|
5. |
Order |
Rosales |
|
6. |
Superorder |
Rosanae |
|
7. |
Family |
Leguminosae |
|
8. |
Genus |
Glycyrrhiza |
|
9. |
Species |
glabra Linn |
Glycyrrhiza glabra L. has various local names, including Jashtimadhu (Bangla), Muleti (Punjabi), MithiKathi (Sindhi), Khosha Walgi (Pushto), Rub-us-soos (Arabic), Bikhemahaka (Persian), and Moyo (Chitrali). Vernacular names include Liquorice (English), Bois doux (French), and Regalizia (Spanish). Pharmaceutical and trade names include Liquirtiae Radix. Radix Liquirtiae (Latin) includes rhizomes, rootlets, and stolons. Liquorice grows naturally in Baluchistan, Chitral, and the Hindu Kush Himalayan highlands. Chitral roots are thick and of similar quality to Chinese licorice, making them ideal for commercial utilization(7).
Phytochemical Profile:
Licorice contains essential elements such saponins, flavonoids and coumarins. Flavonoids and glycyrrhizin contribute to the spice’s unique golden hue and sweet flavor. Licorice root contains glycyrrhizin, a triterpenoid saponin found in potassium and calcium salts of 18β-glycyrrhizic acid (also known as glycyrrhizic or glycyrrhizinic acid and a glycoside of glycyrrhetinic acid) and ammonium salt in commercial preparations. Licorice root contains up to 15% glycyrrhizin, which can vary depending on extraction method and root source(8). Due to the continuous extraction of glycyrrhizin, Glycyrrhiza glabra L. has become an endangered medicinal plant.
Fig no.2: Liqourice Extracts having bioactive constituent.
A root-centric secondary metabolite, glycyrrhizin is a triterpenoid saponin with a variety of pharmacological characteristics, including anti-inflammatory, immunomodulatory, antiallergic, and antiulcer effects. It has also been shown to be useful against HIV. The entire plant is destroyed when the roots are harvested for high-value glycyrrhizin, endangering the plant’s existence and affecting biodiversity as a result(9,10).
Licorice (Glycyrrhiza glabra L., Fabaceae) includes numerous natural bioactive compounds. Licorice roots contain water-soluble chemicals (5-15% glucose, mannitol, and sucrose), starch (25-30%), glycyrrhizin (10-16%), amines (1-2% asparagine, betaine, and choline), and sterols (stig-masterol and β-sitosterol) accounting for 50% of their dry weight. Licorice phytochemicals were tested for their whitening and antioxidant properties in treating pigmented skin disorders. Licorice root extracts contain bioactive compounds such as liquiritigenin, isoliquiritigenin, liquiritin, isoliquiritin, liquiritin apioside, licuraside glucoliquiritin apioside, and glabridin, which can protect the skin from oxidative stress and alleviate atopic dermatitis symptoms effectively(11).
Table no. 2: Chemical Constituent present in liqourice
|
Sr.no |
Phytoconstituent Chemical |
Source of Constituent |
|
1. |
Triterpenoids saponin (4-20%) |
Liqourice Root |
|
2. |
Flavonoids and chalcones (liquiritin, liquiritigenin, rhamnoliquiritin, neoliquiritin, chalcones isoliquiritin, isoliquiritigenin, neoisoliquiritin, licuraside, glabrolide and licoflavonol) |
Root of G. inflata , G. uralensis |
|
3. |
Isoflavonoid (glabridin, galbrene, glabrone, shinpterocarpin, lico isoflavones A and B, formononetin, glyzarin, kumatakenin) |
In Liqourice roots |
|
4. |
Coumarins (liqcoumarin, glabrocoumarone A and B, herniarin, umbelliferone, glycyrin) |
Roots and Rhizomes |
|
5. |
Fatty acids (C2–C16) and phenols (phenol, guaiacol), with saturated linear γ-lactones (C6–C14) |
In Liqourice roots |
Pharmacology action:
In traditional medicine, G. glabra was used to treat a variety of liver ailments. Later modern pharmacological investigations revealed that secondary metabolites derived from licorice reduced serum liver enzyme levels and improved tissue pathology in hepatitis patients. Glycyrrhizic acid significantly reduced serum aminotransferases and improved liver histology. Recent investigations have shown that the aqueous extract of G. glabra has a substantial effect on improving liver functions in acute liver disorders when administered in a single dose per day of 2 mg/kg body weight. Another study found that glycyrrhetinic acid protects against carbon tetrachloride-induced hepatotoxicity and retrorsine-induced liver damage(6).
These days, asthma is a prevalent respiratory condition. When treating asthma, corticosteroids are frequently used to reduce inflammation. Long-term usage of these medications, however, may have numerous negative health repercussions. Licorice has been used to treat bronchial asthma for a very long time. Lic A, one of the active ingredients in licorice, is thought to have anti-asthma properties. Thymic stromal lymphopoietin (TSLP) is a cytokine that is primarily responsible for asthma. Nuclear factor kappa B (NF-kB) can regulate TSLP expression. By preventing the activation of the IkB kinase complex, Lic A was found to prevent NF-kB from being activated by tumor necrosis factor α (TNFα). Flavonoids in licorice have been shown in numerous trials to reduce eosinophilic lung , raise interferon gamma activity, and lower levels of immunoglobulin (IgE), interleukin (IL)-13, IL-5, and IL-3. Ganoderic acid, another substance extracted from licorice, has an anti-asthma action by inducing TNFα. The effects of glycyrrhizin, an active ingredient in licorice, on the histopathologic characteristics of the lung in BALB/c mice were investigated. According to the study’s findings, the treatment group that received glycyrrhizin showed improvement in all known lung histopathologic alterations in the asthma mouse model. Thus, the active ingredients of licorice, Lic A and glycyrrhizic acid, can be utilized to treat asthma(2).
Non-steroidal anti-inflammatory drugs (NSAIDs) are increasingly being used to treat a variety of illnesses and inflammatory conditions; nevertheless, these medications have a number of adverse effects. Concurrently, there is growing interest in natural remedies for inflammation, which are frequently linked to less side effects(10). Liquorice root (Glycyrrhiza) extract contains glycyrrhetinic acid, which has anti-inflammatory properties similar to glucocorticoids and mineralocorticoids. It has been used for over 2000 years to aid ulcer healing in the stomach and mouth. Studies show that glycyrrhizic acid suppresses all inflammatory factors. It suppresses cyclooxygenase activity, prostaglandin production, and platelet aggregation(1),(12).
The combination of glycyrrhizic acid and other medications creates a synergistic effect that protects against influenza virus infection. The regulating effects of glutamyl-tryptophan (EW) and glycyrrhizic acid, as well as their combination, on influenza A (H3N2) virus infection in mice (1 or 10 LD50). The study found that combining glycyrrhizic acid (10 mg/kg body weight) with EW (0.1 μg/kg, 10 μg/kg, and 1,000 μg/kg) had significant antiviral effects, reducing lung oedema and inflammatory cell infiltration. The combination of glycyrrhizic acid with ribavirin, a broad-spectrum antiviral medication, dramatically reduced lung consolidation in mice infected with the H1N1 influenza virus. The combination of 40 mg kg−1 d−1 ribavirin and 50 mg kg−1 d−1 glycyrrhizin was found to offer 100% protection to infected mice (5 times LD50 of influenza H1N1 virus infection), indicating that the combination may have therapeutic efficacy(13,14).
The loss of dopaminergic neurons causes Parkinson’s disease, a neurological condition that significantly impairs patients quality of life and is characterized by symptoms like tremor, lack of motility control, involuntary movements, and stiffness in the muscles. The effectiveness of licorice as an adjuvant therapy in patients with Parkinson’s disease was examined in a randomized double-blind clinical trial. When compared to the control group that only received the conventional treatment, six months of licorice syrup administration could considerably improve tremor, daily activity, and rigidity.
Fig no 3: Affected Parts in Brain of Parkinson suffering individuals.
Schizophrenia is a persistent mental condition characterized by psychotic symptoms, hallucinations, and delusions. It impacts cognitive function, emotional regulation, and interpersonal communication. Antipsychotic medications used for these patients can cause hyperprolactinemia due to dopamine blockade in the hypothalamus. In a 16-week RCT, ninety-nine schizophrenic women were treated with a peony-licorice decoction in addition to antipsychotics. Compared to the control group, antipsychotic-related hyperprolactinemia and unintentional movement symptoms improved dramatically. Further research is needed to understand the link between licorice and dopaminergic brain pathways(3,15).
Prostate cancer is the most frequent non-cutaneous cancer among men. The most common conventional treatments for prostate cancer include radiation therapy, androgen deprivation therapy, and chemotherapy. Herbal remedies have become increasingly popular in western countries. A recent study found that ISL effectively suppressed prostate cancer cells LNCaP and C4-2 in a dose-dependent manner. Furthermore, it reduces mitochondrial membrane potential [Psi(m)] and ROS levels without affecting intraepithelial carcinoma-6 cells. C4-2 cells were inhibited by aberrant AMP reliant/stimulated ERK and protein kinase pathways(5,16).
Marketed example:
Licorice is used in goods ranging from traditional candy twists to skincare and health supplements in the confectionery, pharmaceutical, herbal medicine, and cosmetic industries. Products made from Glycyrrhiza glabra, which is used for its sweetening, flavoring, and medicinal qualities, dominate the worldwide market.
Fig no. 4: Candy twist flavoured with liqourice . Fig no.5: Soft liqourice Candy
Fig no. 6: Liquorice Capsules. Fig no. 7: Liqourice roots powder. Fig no.8: Liqourice Extracted Oil.
Toxicological studies:
Toxicological results, mutagenicity, genotoxicity, carcinogenicity and developmental toxicity, cytotoxicity, side effects, and drug interactions were the primary categories used to categorize the hazardous effects of licorice and glycyrrhizin.
Acute toxicity:
Depending on the kind of salt tested, the acute toxicity values of glycyrrhizin salts have been reported to range from 412 mg/kg (potassium glycyrrhizinate, IV) to 12700 mg/kg (crude ammonium glycyrrhizate, oral). Additionally, data indicates a significant difference in LD50 values following IV or IP administration compared to oral exposure (Federation of American Societies for Experimental and United, 1974). This difference may be due to first-pass metabolism and lower absorption in the oral treatment. The first toxicity analysis described from a single exposure over a 14-day period is the acute toxicity test. Rats and mice are the most often utilized species. The results are used to assess the chemical's intrinsic toxicity [approximate fatal dosage (LD50), target organ, interspecies sensitivity, and dose selection for longer-term investigations]. It is crucial to understand that the LD50 value is influenced by numerous circumstances and is not a consistent number. The animal's age, weight, and strain all have a role. Additionally, animal caging and the kind of nutrition may have an impact. The chemical may be classified as dangerously toxic (<1 mg/kg), extremely toxic (1–50 mg/kg), very toxic (50–500 mg/kg), moderately toxic (500–5000 mg/kg), slightly toxic (5000–15,000 mg/kg), or practically non-toxic (>15,000 mg/kg) based on the LD50 values(8,10).
Chronic Toxicity:
Disodium glycyrrhizinate administered to B6C3F1 mice for 96 weeks at the maximum tolerable dose (male up to 0.15% and female up to 0.3% in drinking water) did not cause any tumorigenicity. For 45 days, male black mollyfish were treated to 1, 2, and 4 mg/L of G. glabra root extract. The NOAEL and first detected effect concentrations in this model were 1 and 4 mg/L, respectively. There were reports of liver toxicity in the fish that received treatment. Additionally, NOAEL has been established for subcutaneous injection of monoammonium glycyrrhizinate in rats at a dose of 25 mg/kg for a duration of 26 weeks .The severity of NOAEL varies with gender. Oral licorice consumption has been calculated to be 800 and 400 mg/kg/day, respectively(8).
Drug Interaction of Glycyrrhizin:
Drug metabolism is largely influenced by phase I metabolism, which is mediated by CYP 450 isoenzymes, phase II metabolism, which is primarily mediated by UDP glucuronosyltransferases, and phase III metabolism, which is mediated by transporter proteins. It is crucial to observe any alteration in these pathways in order to identify potential drug interactions during combination therapy.When used with medications having a narrow therapeutic index, licorice's effects on the CYP enzymes are significant. CYP3A4, 2B6, and 2C9 were inhibited by the isoflavan (glabridin) produced from licorice roots. Glycyrrhetinic acid inhibits the enzymes CYP3A, 2C9, and 2C19 both in vitro and in vivo. However, prior research using Vivid CYP450 Screening Kits and human investigations demonstrated that prolonged consumption of licorice and glycyrrhizin promotes CYP isoenzyme activity on rodent liver. It has been demonstrated that G. uralensis increases the possibility for cyclophosphamide teratogenicity by inducing CYP 2B activity. Due to G. glabra's stimulating actions on CYP isoenzymes, this pharmacokinetic interaction should be observed. Additionally, the substances (3R)-vestitol, 4-hydroxyguaiacol apioglucoside, and liquiritigenin 7,40-diglucoside that were extracted from the Glycyrrhiza species G. uralensis have an inhibitory impact on CYP3A(8).
Cytotoxicity:
Licorice ethanol extract had cytotoxic action (63% at 0.24 mg/mL) in Vero cells, according to MTT assay results. When CT25, HT29, and HEK293 cells are treated with complete extract of licorice (0, 20, 50, 100, and 200 μg/mL) for 24 hours, the viability of cancer cell lines is considerably reduced compared to non-cancerous cell lines, with IC50 values for CT26 and HT29 being approximately 50 μg/mL and HEK293 being approximately 200 μg/mL. Licorice extract has been demonstrated to promote apoptosis in malignant cells but not in non-cancerous cells. As the dose was increased, cell viability dropped. Additionally, ethanol extract of roasted licorice (2.5, 5, 7.5, and 10 μg/mL) decreased the viability of MDA-MB-231 cells in a dose and time-dependent manner without having any cytotoxic effects on normal cells such as hFOB1.19 human osteoblast cells and murine bone marrow-derived macrophages. In a model of MDA-MB-231 metastatic human breast cancer cells injected subcutaneously into the tibia of mice, the treatment of this extract (0.5, 1, and 2 mg/kg, gavage, daily for the first 5 days followed by weekly administration for 44 days) inhibited tumor growth and bone degradation(8).
CONCLUSION
This review peered at all of the phytochemical compounds that were separated from Glycyrrhiza glabra as well as its therapeutic qualities. The primary components identified from G. glabra extracts include glycyrrhizic acid, 18-β-glycyrrhetinic acid, glycyrrhizin, and licochalcones. Pharmacologically, G. glabra and its primary components have antibacterial, antiparasitic, antiviral, antitussive, immuno-enhancing, antioxidant, anti-inflammatory, and anticancer properties. Licorice is regarded as a useful medicinal herb for the treatment of respiratory and gastrointestinal issues in both conventional medical systems and contemporary phytotherapy. It is important to note that there are a number of pre-clinical studies on licorice and its purified secondary metabolites that discuss the pharmacological activities of these compounds and the underlying cellular and sub-cellular mechanisms. We have attempted to concentrate on clinical evidence in order to provide a collection of studies useful in clinical practice. Furthermore, licorice is thought to have a number of therapeutic uses in traditional medical systems, including headache, urogenital issues, and andrological illnesses, which have not yet been studied in clinical trials but may be the subject of future research. Further research is advised to elucidate the health advantages of this medicinal plant and its active ingredients in humans.
REFERENCES
Yukti Kadu, Mahendra Patel, Naresh Kumar Parmar, Komal Mane, Shailesh Kokani, An Integrative Study of Phytomorphological and Pharmacological profiling of Licorice, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 4, 4742-4751, https://doi.org/10.5281/zenodo.19878629
10.5281/zenodo.19878629