Yashtimadhu-Licorice (Glycyrrhiza glabra)

Yashtimadhu-Licorice (Glycyrrhiza glabra)
By Dr. Hemant Vinze M. S.
Introduction

Yashtimadhu-licorice (Glycyrrriza glabra) contains many pharmacologically active phytochemicals. When isolated from the extract they display their pharmacological actions. However the pharmacological features of yashtimadhu-licorice (Glycyrrriza glabra) root powder or extract have some different pharmacological features. Also, the powder and the extract are less toxic and have lesser side effects than the pure phytochemicals. Hence here I describe the pharmacology of root powder and root extract of yashtimadhu-licorice (Glycyrrriza glabra).  

General Pharmacology
Pharmacokinetics 

After oral administration of yashtimadhu-licorice (Glycyrrriza glabra) in humans, its constituents are hydrolyzed by intestinal bacteria. They are then absorbed and transported to the liver. In the liver the constituents are metabolized to glucuronide and sulfate conjugates which are subsequently rehydrolyzed reabsorbed. This entero-hepatic recycling significantly delays terminal clearance from plasma. Some phytochemicals such as glycyrrhizin were found unchanged in the urine after 24 hours suggesting they are partly absorbed. Therefore pharmacokinetics of yashtimadhu-licorice (Glycyrrriza glabra) after oral administration is more relevant. [1], [2], [3], [4]
In China roasted licorice is used for allergic and inflammatory disorders where as in India un-roasted yashtimadhu licorice (Glycyrrhiza glabra) is used for medicinal purpose. In a study Majima T et al compared the pharmacological effects of  roasted and un-roasted   
licorice (Glycyrrhiza glabra). Although roasted licorice (Glycyrrhiza glabra) contained less amount of glycyrrhizin than un-roasted licorice (Glycyrrhiza glabra), the inhibitory potency of roasted licorice on immunoglobulin E (IgE)-mediated ear- swelling in mice was much greater compared with un-roasted licorice (Glycyrrhiza glabra). Thus roasted yashtimadhu-licorice (Glycyrrhiza glabra) is a better anti-allergic and immunomodulatory agent than un-roasted yashtimadhu- licorice (Glycyrrhiza glabra) [5]
When yashtimadhu- licorice (Glycyrrhiza glabra) is roasted with or without honey and subsequently extracted with 95% ethanol, the glycyrhizin was converted into glycyrrhetenic acid. When such an extract is administered orally, higher blood levels of pharmacologically active agents is achieved. [6] 
The solubility of phytochemicals from yashtimadhu-licorice (Glycyrrhiza glabra) is less compared to their solubility in alkaline solvents. The concentration of phytochemicals in alkaline extracts is more; therefore the pharmacological activity       of alkaline extract is better than that of aqueous extract. [7]
Roasting of Yashtimadhu-licorice (Glycyrrhiza glabra) with honey enhances immune function, cough relieving property, property of eliminating phlegm and detoxification. Honey in this process did not have effect on cough, expectoration and detoxification. Honey altered the pharmacological properties of alkaloids: liquitrin apioside, liquiritin, isoliquiritin, licuraside and glycyrrhizin. This modification caused by honey displays better pharmacological activity. [8] 
Roasted yashtimadhu-licorice (Glycyrrhiza glabra) has neuroprotective effects against ischemic damage by maintaining by superoxide dismutase 1 (SOD 1) levels. In addition, the difference in protective ability between raw and roasted licorice  may be associated with glycyrrhetinic acid (GA) and glycyrrhetinic acid monoglucuronide (GM)  [9]
Laminaria is a genus of 31 species of brown algae commonly called "kelp". One of them is Laminaria japonica.  The results of a study showed that Licorice-Laminaria japonica extract markedly increased the plasma concentration of glycyrrhetinic acid (GA) on single dose or multiple dose administration. However Laminaria japonica did not affect the pharmacokinetics of liquiritigenin or isoliquiritigenin. The data from the intestinal perfusion model showed that Laminaria japonia markedly increased the absorption of glycyrrhizic acid (GL) in the duodenum and jejunum, but did not affect the intestinal absorption of glycyrrhetinic acid (GA). Laminaria japonica also           enhanced the metabolism of GL to GA in the large intestine. [10] 

Anti-inflammatory activity

Yashtimadhu-licirice (Glycyrrhiza glabra) has been used to treat many inflammatory conditions. The anti-inflammatory activity was attributed to licorice and licorice metabolites. Recent studies on licorice extract showed that three triterpenes and thirteen flavonoids exhibited evident anti-inflammatory actions by decreasing TNF-α, MMPs, PGE2 and free radicals. More pharmacokinetic studies using different models and different doses are necessary for clinical use of Yashtimadhu-licorice (Glycyrrhiza glabra) extract and purified compounds. [11]
In many other studies six flavonoids, (1) 5-(1, 1-dimethylallyl)-3, 4, 4-trihydroxy-2-methoxychalcone, (2) licochalcone, (3) licochalcone A, (4) echinatin,                            (5) glycycoumarin and (6) glyuralin were quantified in different species of                    Glycyrrhiza. When tested for pharmacological activities these compounds showed anti-inflammatory, antioxidant and free radical scavenging activities. [12]

Antioxidant activity

Li YJ et al screened four species, Glycyrrhiza glabra, Glycyrrhiza inflata, Glycyrrhiza pallidiflora and Glycyrrhiza uralensis for antioxidant and free radical scavenging activity. They found that of 35 phytochemicals screened 21 showed a potent antioxidant and free radical scavenging activity. [13]
Pork patties contain 20% fat. Precooked pork patties become rancid soon due to oxidation of fat. Strange it may sound,   but licorice extract has been used to curtail lipid oxidation in pork and protect it during refrigeration and frozen storage.   
This shows that licorice has great potential as a natural antioxidative additive to extend the shelf-life of precooked pork. [14]

Immunomodulatory activity 

Yashtimadhu-licorice (Glycyrrhiza glabra) was used to treat many ailments in many countries in the east. The increasing use of complementary and alternative medicine has kindled the need for scientific evaluation of the mechanism of action of yashtimadhu-licorice (Glycyrrhiza glabra). Recent research showed that licorice      polysaccharides showed the immunomodulatory activity. The polysaccharides activate CD4 and CD8 immune cells. The polysaccharides also affected the production of various cytokines by increasing IL 2, IL 6, IL 7 levels and decreasing TNF α levels. [15]

Antibacterial activity

Diethyl carbonate extracts of root of licorice (Glycyrrhiza glabra) from Astrakhan region of Russia exhibited maximum antibacterial activity against Staphylococcus aureus, Escherichia coli and Bacillus subtilis.  This activity was superior to                   50% ethanol extracts of licorice (Glycyrrhiza glabra) from Astrakhan region of Russia and Calabria of Italy. Antibacterial activity was found to be directly proportional to the content of glycyrrhizin and 18-glycyrrhetinic acid in the extracts. The preliminary study showed, the content of these chemical compounds in extracts of root from Russia was higher than roots from Italy, which is presumed to be related to climate and geographic characteristics of Astrakhan region. This validates the Ayurvedic tenet (doctrine) which states that the medicinal properties of herbs depend on the geographical region where they grow and the season in which they grow. [16]
Nineteen flavonoids isolated from yashtimadhu-licorice (Gglycyrrhiza glabra) and other species of Glycyrrhiza were found to show antibacterial activities against methicillin sensitive/methicillin resistant Staphylococcus aureus, Micrococcus luteus, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.[17]      
A study was aimed to investigate antimicrobial potential of roots of yashtimadhu-licorice (Glycyrrhiza glabra). 
Researchers found that at concentration 500 μg/mL yashtimadhu-licorice (Glycyrrhiza glabra) exhibited a potent activity against Micobacterium tuberculosis. The phytochemical showing this activity was identified to be glabridin. At concentration of 29.16 μ g/mL glabridin exhibited activity against Micobacterium tuberculosis H(37)RaH(37)RV strains. A further study is necessary to develop a potent antitubercular agent from yashtimadhu- licorice (Glycyrrhiza glabra). Glabridin also exhibits antibacterial activity against Gram-positive and Gram- negative bacteria. [18]

In laboratory, the triterpene 18β-glycyrrhetinic acid was modified chemically to enhance its antibacterial activity. Compounds 22, 23, 25, 28, 29, 31 and 32 showed more potent inhibitory activity against Streptomyces scabies than the positive control,  streptomycin. The antibacterial activity of compound 29, against Bacillus subtilis, methicillin-sensitive/methicillin- resistant Staphylococcus aureus was greater than that of positive controls. The mode of antibacterial action of the derivatives involved the regulation of the expression of genes associated with peptidoglycans, the respiratory metabolism and the inherent virulence found in bacteria. [19]

Antiviral activity

Historical sources for the use of yashtimadhu-licorice (Glycyrrhiza glabra) and some other species of Glycyrrhiza include manuscripts from India, China and Greece. They mention the use of Glycyrrhiza species for ailments caused by viruses. Recently glycyrrhizin an active pharmacological agent was isolated from yashtimadhu-licorice    (Glycyrrhiza glabra). Glycyrrhizin showed antiviral activity against many virulent viruses and demonstrated reduction of mortality in influenza A virus pneumonia and virus encephalitis. Glycyrrhizin also showed antiviral activity against vaccinia virus, HIV-1, SARS related corona virus, respiratory syncytial virus, arboviruses, vesicular stomatitis virus and hepatitis B and C viruses. Glycyrrhizin and its derivatives reduced hepatocellular damage in chronic hepatitis B and C infections. Glycyrrhizin reduced the risk of development of hepatocellular carcinoma in hepatitis C virus induced cirrhosis. The mechanisms of antiviral activity include:
1. Reduced transport of viruses to cell membrane
2. Iintroduction of sialyl group in cell membrane (sialylation), thus preventing attachment of virus to cell membrane and preventing the penetration of virus in the cell
3. Induction of interferon gamma in T-cells
4. Inhibition of phosphorylating enzymes 
Well! There might be many more mechanisms involved!! Further research is necessary in this regard. [20]

To evaluate efficacy of yashtimadhu-licorice (Glycyrrhiza glabra) against Herpes simplex virus, Vero cells were incubated in different concentrations of aqueous extract of yashtimadhu- licorice (Glycyrrhiza glabra). Incubation of HSV- 1 with licorice root extract prior to infection was also performed. The result showed that yashtimadhu- licorice (Glycyrrhiza glabra) has antiviral activity against herpes simplex virus (HSV- 1).  [21]

Antifungal activity

For centuries root of yashtimadhu-licorice (Glycyrrhiza glabra) has been used to treat various fungal infections.             
Recently 18-β glycyrrhetenic acid (18-β GA) has been extracted from root of Glycyrrhiza species. From patients suffering from recurrent candidial vulvovaginitis, Candida albicans strains were isolated. The in vitro growth of               Candida albicans strains was markedly reduced, in a pH dependent manner by low doses (6.2 μg/mL) of 18-β glycyrrhetenic acid. The results demonstrate that 18-β glycyrrhetenic acid is a promising biological alternative for the topical treatment of recurrent candidial vulvovaginitis. [22]   
                            
Actions on the Skin

Glycyrrhizin and glycyrrhetinic acid found in yashtimadhu-licorice (Glycyrrhiza glabra) potentiate the action of aldosterone and facilitate transport of sodium in epithelium and skin. [23]
Yashtimadhu-licorice (Glycyrrhiza glabra) is used to treat various allergic disorders of the skin. Its anti-itching, anti-scratching behavior and inhibition of IgE production are now well evaluated both in vitro and in vivo. RBL-2H3 cells have high affinity for IgE receptors. They can be activated to secrete histamine. Liquiritigenin and 18β-         glycyrrhetinic acid inhibit the degranulation of RBL-2H3 cells and block histamine release. Liquiritigenin and 18β- glycyrrhetinic acid inhibit the passive cutaneous anaphylactic reaction. Liquiritigenin and 18β-glycyrrhetinic acid also inhibit the production of IgE in ovalbumin-induced bronchial asthma.  [24]            


Actions on Wound healing

To evaluate wound healing property of Yashtimadhu-licorice (Glycyrrhiza glabra), incised wounds of 3 cm length were inflicted over the skin of back of 20 male albino rats. The wounds were treated with topical application of cream containing the extract of Yashtimadhu-licorice (Glycyrrhiza glabra). There was no significant effect of the cream on the tensile strength of the wound. [25]
A group of researchers studied the healing effect of yashtimadhu-licorice (Glycyrrhiza glabra) extract on open skin wounds in adult Newzeland rabits of both sexes. Creams of 5%, 10% and 15% (W/W) hydroalcoholic extracts of yashtimadhu-licorice (Glycyrrhiza glabra) in eucerin base were applied twice a day to treat the wounds. The results demonstrated that the wounds treated with yashtimadhu-licorice (Glycyrrhiza glabra) extract healed faster than the ones not treated with the extract. [26]
In a study the vacuum dried ethanolic extract of root of yashtimadhu-licorice (Glycyrrhiza glabra) was evaluated for its wound healing property. The extract demonstrated significant wound healing property. The wound healing property        of yashtimadhu-licorice (Glycyrrhiza glabra) was attributed to the antioxidant activity of the extract. [27]    
The commonest organism that interferes with wound healing is Staphylococcus aureus. Different concentrations of extracts of root of yashtimadhu-licorice (Glycyrrhiza glabra) were studied for anti-staphylococcal activity and their                 effect on wound healing. Irrigation of wounds of oral mucosa, twice daily with 1 ml of 60 g /100 of yashtimadhu-licorice (Glycyrrhiza glabra) root extract was found to be most effective in the treatment of wounds of oral mucosa.  [28]          
A burn is still one of the most devastating injuries in emergency medicine; more so if the wounds are infected with Pseudomonas aeruginosa organisms. When these wounds were treated with topical application of 1 % and 2 % gel containing Glycyrrhiza glabra, there was significant reduction of edema, redness and itching after two weeks. There was increase in the deposition of collagen content. However licorice extract (10%) was not an effective dressing in healing of third degree burns infected with Pseudomonas aeruginosa organisms. [29]

Actions on mouth

The phytochemicals glycyrrhizin, glabridin, licochalcone A, licoricidin and licorisoflavan A, found in yashtimadhu- licorice (Glycyrrhiza glabra), show beneficial effects in the treatment of oral diseases such as gingivitis, recurrent aphthous ulcers, oral candidiasis, periodontitis, dental caries and oral bacterial infections. Yashtimadhu-licorice (Glycyrrhiza glabra) is also useful for preventing oro-dental diseases. [30]
That sucking sweet candies rot teeth is well-known. The bacteria (Streptococcus mutans) attach to teeth and metabolize sugars from food and drink, produce acid that leads to formation of plaque. The combination of acid and plaque leads to tooth decay. Furthermore the bacteria form a protective biological layer i.e. a “biofilm” around themselves so that the process of decay continues unabated. Trans-chalcone found in yashtimadhu-licorice (Glycyrrhiza glabra) root blocks the action of a key enzyme that allows the bugs to thrive in oral cavity.
The Chinese dentists have been using yashtimadhu-licorice (Glycyrrhiza glabra) to prevent and treat dental decay. In the U.S. licorice candy flavored with anise oil is used for this purpose.
In a recent study participant volunteers consumed licorice lollipops for 21 days. The results demonstrated that there was significant reduction of Streptococcus mutans in saliva of volunteers. [31], [32], [33], [34]
Oral infections and dental caries are serious health problems. In a study yashtimadhu-licorice (Glycyrrhiza glabra) was found to exhibit anti-bacterial activity against six oral pathogenic organisms. [35] 
About two-thirds of cancer patients undergo radiotherapy. They develop inflammation of oral mucosa (mucositis) as a major complication of radiotherapy, causing morbidity, mortality and decreasing the quality of life. Topical application   twice daily of aqueous extract of Glycyrrhiza glabra from the first day of starting of radiotherapy alleviated the mucositis. [36]   


Actions on Endocrine System

Glabridin a major isoflavan found in root extract of licorice exhibited estrogen receptor (ER) agonism. Animals fed on licorice extract showed an increase in creatine kinase (CK) activity a known marker for estrogen responsive genes, which was higher than expected from the levels of glabridin in the extract. This led the researchers to search for other estrogen agonist chemicals in the extract. The results indicated that glabrene and isoliquiritigenin exhibited estrogen receptor (ER) affinity. The stimulatory effects of glabrene in vivo were tissue specific and similar to those of estradiol. [37]
The affinity of yashtimadhu-locorice (Glycyrrhiza glabra) for glucocorticoid and mineralocorticoid receptors has been reported since long. However the affinity for mineralocorticoid receptors is one fourth that  of aldosterone and for glucocorticoid receptors one fifth that of dexamethasone. The affinity, though low, is sufficient to cause mineralocorticoid-like side effects, when  yashtimadhu-locorice (Glycyrrhiza glabra) is administered in large amount. [38]
Sodium retention associated with administration of yashtimadhu-locorice (Glycyrrhiza glabra) is due to a direct mineralocorticoid-like effect, despite the fact that it does not occur in patients or animals with severe adrenal insufficiency. The sodium retention is due to the inhibition of an enzyme 11-β-hydroxysteroid dehydrogenase. Congenital deficiency of this enzyme produces a syndrome of apparent mineralocorticoid excess. In both conditions there is a defect in the renal conversion of cortisol to cortisone. [39]
An 11-year-old boy had hypoparathyroidism and Addison’s disease. He was treated with calcitrol, calcium, hydrocortisone and 9- α-fluorocortisol. During treatment he developed mineralocorticoid excess and growth retardation. Pseudohyperaldosteronism persisted even after 9- α-fluorocortisol was stopped and dose of htdrocortisone was reduced. The boy reported of taking daily 300-400 g licorice corresponding to 600-800mg glycyrrhizic acid because of salt craving. After complete withdrawal of licorice all symptoms of hypermineralocorticoidism diminished and growth velocity increased. It was evident that licorice caused hypermineralocorticoidism and growth retardation.  [40]  
A 42-year-old woman having un-diagnosed Addison’s disease, self treated for several years with soy sauce and licorice sticks. She described an unusual diet of consuming 46 g of salt per week and soy sauce and licorice sticks. There was a family history of Type 1 diabetes mellitus. She presented with a history of decreased energy, malaise and postural dizziness of four week duration. Physical examination was unremarkable. Subsequent investigations confirmed the diagnosis of Addison’s disease. In this case the net effect was potentiation of glucocorticoid action on renal mineralocorticoid receptors in the context of failing adrenocortical steroid production. [41]
In a study 36 healthy volunteers (15 women and 21 men) consumed 100 g of licorice (equivalent to 150 mg glycyrrhetinic acid) daily in a 9-week, open- treatment trial. Blood and 24-hour urine samples were collected for hormone analysis 4 weeks before and 4 weeks after licorice consumption and 4 weeks after cessation of licorice intake.
The results showed that licorice induced a moderate decrease in the serum concentrations of dehydroepiandrostenedione sulphate in men. The relative change in serum levels of dehydroepiandrostenedione sulphate differed between genders. No significant changes were observed in the serum levels of testosterone. The urine excretion of androgens did not change. [42]   
Licorice and glycyrrhetinic acid increase DHEA and deoxycorticosterone levels in vitro and in vivo by inhibiting the enzyme 11 β- hydroxysteroid dehydrogenase type 2. [43]
Excessive ingestion of licorice induces a syndrome of hypokalemia and hypertension that reflects increased activation of renal mineralocorticoid receptors by cortisol.[44]

Actions on the eye

The growth of abnormal blood vessels in the eye is a leading cause of loss of vision in people with wet form of macular degeneration (MD). In macular degeneration (MD) the blood vessels grow into retina and leak blood and fluid causing retinal edema which damages the macula. A new study in China has found that isoliquiritigenin (ISL) found in yashtimadhu-locorice (Glycyrrhiza glabra) can suppress angiogenesis in retina, cornea of laboratory mice. A topical formulation of isoliquiritigenin (ISL) applied to cornea suppressed the abnormal blood vessel growth in cornea while intravitreal injection had same effect on mice with retinal angiogenesis. Thus yashtimadhu-locorice (Glycyrrhiza glabra) can be useful for the treatment of macular degeneration. [45], [46]

Actions on Musculoskeletal System

A study showed that glabridin and glabrene found in yashtimadhu-locorice (Glycyrrhiza glabra) stimulated creatine kinase (CK) specific activity in diaphysial bone and epiphyseal cartilage in prepubertal female rats. Glabridine also stimulated creatine kinase (CK) specific activity in ovariectomised female rats. Glabridine shows greater similarity to estradiol- β, and greater potential, with or without Vitamin D, to modulate bone disorders in post-menopausal women. The study suggested that yashtimadhu-locorice (Glycyrrhiza glabra) can be useful for prevention and treatment ofosteoporosis in perimenopausal women. [47]

Actions on Nervous System

Corticotrophin releasing factor (CRF) and β-endorphin (beta- EP) containing neurons are present in the hypothalamus and at the paraventricular nucleus (PVN). Steroid hormones alter the plasma level of these neurotransmitters. Glycyrrhizic acid (GCA) found in yashtimadhu-locorice (Glycyrrhiza glabra) inhibits the enzyme 11 β- hydroxysteroid dehydrogenase (11 HSD) which is needed for the inactivation of the steroid pathway. A study showed that rats treated with glycyrrhizic acid (GCA) did not show any changes in the number of β-endorphin (beta- EP) containing neurons. [48]

Actions on Cardiovascular System 

 A case report
A 40-year old-female developed severe hypertension and hypokalemic metabolic alkalosis due to prolonged licorice ingestion. On detailed investigation this was proved to be a case of pseudo-hyperaldosteronism induced by licorice. [49]
(For details ref. to glycyrrhizic acid above)
A 38-year-old woman was hospitalized for hypertension and hypokalemic alkalosis. Her history revealed that she was taking 200 g licorice per day. This was proven to be the cause for her hypertension and hypokalemic alkalosis. A licorice provocation test produced all the expected clinical and biochemical abnormalities. The condition was attributed to glycyrrhizic acid in yashtimadhu-locorice (Glycyrrhiza glabra). [50]
A 50-year-old woman was admitted in a hospital for hypertension and hypokalemia-induced limb paresis due to chronic ingestion of licorice. She was treated with potassium sparing diuretic spironolcctone. Her blood pressure and electrolyte status returned to normal within a month after cessation of licorice intake. [51]
A study revealed that hypertension induced by licorice was due to inhibition of renin-angiotensin system. Some healthy normotensive individuals consume licorice up to 100 g per day. The reason for this consumption is unknown. In the study regular moderate intake of licorice at doses of 50-100 g per day was found to raise blood pressure (Systolic 5-6 mm of Hg and Diastolic 3-4 mm of Hg). Consumption of 100 g of licorice could raise blood pressure significantly. Licorice raised the blood pressure with a linear dose-responsive relationship. [52], [53], [54]
That the cause of hypertension induced by licorice can be due to inhibition of the enzyme 11 β- hydroxysteroid dehydrogenase (11 HSD) which results in pseudo-hyperaldosteronism is now well established.
Licorice induced increase in blood pressure is more profound in subjects with essential hypertension than in healthy individuals. A study revealed that licorice also induced pseudo-hyperaldosteronism by inhibiting rennin-angiotensin-aldosterone system. The relative change in serum aldosterone levels differed between the genders, men being more responsive than women, but not between patients with hypertension and healthy subjects.  [55], [56], [57]   
Aqueous and ethanolic extracts of licorice demonstrated scavenging activity against nitric oxide radicals, superoxide, hydroxyl, ABTS [2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)], (DPPH 2’ 2-diphenylpicrylhydrazyl) and some free radicals involved in oxidative stress. This suggests that licorice shows anti-atherosclerosis activity. [58]  
In another study licorice was administered to hypercholesterolemic patients and normolipidemic subjects at 0.1 g per day. Licorice lowered high levels of cholesterols in hypercholesterolemic patients. In both groups licorice reduced plasma susceptibility of LDL against oxidation and prevented atherosclerosis. [59]
Russo et al described two cases of hypertensive encephalopathy which resulted in pseudohyperaldosteronism syndrome due to the regular daily intake of low doses of licorice. The phytochemical identified to be responsible for this condition was glycyrrhizic acid. The condition is reversible on cessation of licorice intake. [60]
A 56-year-old lady presented with severe headache which she described as “thunderclap headache”, visual disturbance and generalized tonic-clonic seizures. Her blood pressure was markedly elevated but improved within 24 hours. Her cranial CT scan and laboratory study of lumbar puncture were normal but cranial MRI revealed abnormalities in the occipital lobes consistent with posterior reversible encephalopathy syndrome (PRES). She had hypokalemia. There was no evidence of restricted diffusion or vasoconstriction.  On direct questioning she revealed she had been habitually eating, in recent months, licorice sweets every day. Three weeks later follow-up MRI showed complete resolution.
Posterior reversible encephalopathy syndrome (PRES) is a medical emergency. Prompt recognition, early institution of supportive care and removing potential triggers are associated with good clinical outcome. [61]
A similar case of posterior reversible encephalopathy syndrome (PRES) of 49-year-old woman with very high blood pressure  (210/100 mm of Hg), arterial pH 7.64 and serum potassium 2.7 was reported by van Beers EJ et al. She was a chronic smoker but quit smoking 2 weeks before the event however started consuming large amounts of licorice. Her CT imaging showed minor bleeding in the left Sylvian fissure and bilateral occipital edema suggestive of PRES. She was advised to abandon the use of licorice and was given supportive, symptomatic treatment. Her blood pressure then settled to 106/60 mm of Hg. After the treatment of 10 days her repeat CT scan was completely normal. [62]

Actions on RS

Yashtimadhu-licorice (Glycyrrhiza glabra) is a common ingredient in many polyherbal formulations used for the treatment of respiratory infections. Now licorice is proved to inhibit infection of human respiratory syncytial virus (HRSV). Recently glycyrrhizin and 18 β-glycyrrhetinic acid (18 β-GA) constituents of yashtimadhu-licorice (Glycyrrhiza glabra) have been identified to be effective against human respiratory syncytial virus (HRSV). [63]
In another study some phytochemicals from yashtimadhu-licorice (Glycyrrhiza glabra) were tested for antibacterial activity against upper respiratory tract organisms such as Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis. Among the compounds tested licoricidin exhibited the highest antibacterial activity against all tested microorganisms with MIC of 12.5 micro g/mL [64]

Actions on GI System

Infection due to Helicobacter pylori erode gastric and duodenal mucosa cause peptic ulcer. In a group receiving three drug regime, bismuth was replaced by yashtimadhu-licorice (Glycyrrhiza glabra). The researchers claim that healing of the ulcers and pain relief was better than with bismuth. [65]
An international team of researchers from England, Italy, France and Sri Lanka showed that yashtimadhu-licorice (Glycyrrhiza glabra) exerts bactericidal effect on Helicobacter pylori. [66], [67], [68]
For centuries yashtimadhu-licorice (Glycyrrhiza glabra) has been used for stomach (GI) troubles. Licorice tea has the ability to strengthen the mucosal lining of stomach and digestive system. It also prevents acid reflux.
To prepare yashtimadhu-licorice (Glycyrrhiza glabra) boil 15Gms of licorice root in 500 mL of water for 15 minutes. Sip slowly half a cup at a time. Use it half an hour before meals. Do not use this tea for more than two weeks. Many products sold as licorice tea do not contain enough of licorice. They are merely “licorice flavored” drinks. This is said to be an effective treatment for peptic ulcer. [69], [70]. [71]  
A special extract of licorice known as deglycyrrhizinated licorice (DGL) is a remarkable natural medicine for the treatment of peptic ulcer and gastro-esophageal reflux disease. [72]

Actions on the Liver

Two novel oleanane-type saponins, licorice-saponin P2 and licorice-saponin Q2, demonstrated a significant hepatoprotective activity. In in vitro study they lowered the elevated ALT and AST levels in primary hepatocytes of rats, injured by D-galactosamine. [73]
In a study, single or repeated administration of extract of root of licorice to Sprague-Dawley rats at doses 3138 or 6276 mg/kg/animal or its constituent glycyrrhizin at doses of 240 or 480 mg/kg/animal were found to protect liver against CPY toxicity and carcinogenicity. [74]

Actions on metabolism

Phytochemicals (1) Hispaglabridin A (2) Hispaglabridin B (3) Glabridin (4) 4’-O-Methylglabridin (5) two chalcones (6)Isoliquiritigenin (7)Formononetin isolated from yashtimadhu-licorice (Glycyrrhiza glabra) prevent oxidation of LDL. Among these compounds glabridin shows strong antioxidative capacity. As oxidztion of LDL is a key event in the formation of atherosclerotic lesion, it is clear that by virtue of their antioxidative property these compounds may be beneficial to prevent and attenuate atherosclerosis.  [75]
Another study showed that supplementation of licorice root extract at 0.1g/day for one month,   
(1) reduced patient’s plasma susceptibility to oxidation by 19 %  
(2) increased susceptibility of LDL oxidation by 55 %
(3) increased chondroitin sulphate binding ability by 25 %
(4) reduced plasma total cholesterol levels by 5 %   
(5) reduced plasma LDL levels by 9 %
(6) reduced plasma triglyceride levels by 14 %          
Administration of licorice extract to normolipidemic subjects also inhibited LDL oxidation. [76]

Actions on diabetes

The effects of low dose licorice and glycerrhizine were investigated on hyperkalemia due to hyporeninemic hypoaldosteronism in eight subjects with non-insulin-dependent diabetes mellitus. The data of the study supported the assumption that licorice extract can be use safely in the therapy for treating hyperkalemia due to selective hypoaldosteronism in diabetes mellitus subjects. [77]

Actions on Urinary System

That glycyrrhizic acid found in yashtimadhu-licorice (Glucyrrhiza glabra) and yashtimadhu-licorice (Glucyrrhiza glabra) itself induce hypertension is well known. In glycyrrhizic acid-induced hypertension, antagonism of both aldosterone and endothelin receptors normalizes blood pressure and improves renovascular function. This may represent a new approach in cardiovascular disease associated with impaired 11 β-hydroxysteroid dehydrogenase type 2 (11 β-HSD 2) activity. [78]

Actions on Male Reproductive System

Glycyrrhetinic acid (GA) is the active metabolite of glycyrrhizic acid. The anti-inflammatory activity of glycyrrhetinic acid (GA) inhibits the proliferation of tumor cells. A study showed that glycyrrhetinic acid (GA) could inhibit the growth of androgen dependent prostate cancer cell. Furthermore glycyrrhetinic acid (GA) significantly reduced the production of prostate-specific antigen. Thus glycyrrhetinic acid (GA)/ yashtimadhu-licorice (Glycyrrhiza glabra) can be useful in prevention and treatment of prostate-cancer.  [79] 

Actions on Female Reproductive System

 In many countries, perimenopausal and menopausal women consume yashtimadhu-licorice (Glycyrrhiza glabra) extract as herbal supplement or natural alternative to pharmaceutical hormone replacement therapy (HRT). Among various phytochemicals of yashtimadhu-licorice (Glycyrrhiza glabra)      Glabridin, Calicisin, Mehoxychalcone, Vestitol,Glyasperin C, Glycyumarin, Glycoricone, Liquiritigenin and Isoliquiritigenin show estrogenic activity. But they have low binding ability to estrogen receptors. Among them Glabridin, Glyasperin C, and Glycoricone show partial estrogen antagonism.  
(Copyright 2015 Elsevier Inc) [80]
Risks associated with hormone replacement therapy in menopausal women led researchers to seek herbal supplements. They found yashtimadhu-licorice (Glycyrrhiza glabra) as one. The herb demonstrates estrogenic activity. Thus yashtimadhu-licorice (Glycyrrhiza glabra) can be useful as natural agent for hormone replacement therapy in menopausal women.  [81]  

Antitumor Activity

In experimental studies, methanol extract of yashtimadhu-licorice (Glycyrrhiza glabra) was found to be cytotoxic to human keratinocytes (HaCaT), lung adenocarcinoma (A549) and liver carcinoma (HepG2) cells. [82]
In another study mixed extract of yashtimadhu-licorice (Glycyrrhiza glabra) and purified compounds isolated from yashtimadhu-licorice (Glycyrrhiza glabra) were found to demonstrate anticancer activity. It was found that they show anticancer activity by inhibition of cell proliferation, induction of cell cycle arrest, apoptosis, autophagy, differentiation and suppression of metastasis, angiogenesis and sensitization of chemotherapy or radiotherapy. A combined treatment of yashtimadhu-licorice (Glycyrrhiza glabra) or licorice compounds and conventional chemotherapy drugs remarkably enhanced anticancer effects of chemotherapy drugs and reduced their side effects. [83]    

Toxicity

Hypertension, hypokalemia, life-threatening ventricular tachycardia, pseudohyperaldosteronism, hormonal disturbances, muscle fatigue, muscle cramping, muscle weakness,  photosensitivity, sunburns when exposed to sunlight, headache, edema of face and ankle, irregularities of menstruation, problems with libido in men, dark urine etc. [84], [85], [86]

Case Vignettes  

During the month of Ramadan (Islamic holy month) a 62-year-old male was admitted to a hospital, following ingestion of moderate amount of licorice. He had marked acid-base disturbances, changes of hypokalemia on ECG (EKG) and raised creatinine kinase- MB (rhabdomyolysis). Over a prolonged period of supportive treatment all parameters returned to normal. This shows that ingestion of modest to large quantity of licorice even for a short period can induce toxicity.  [87]
A 19-year-old girl who ingested a lot of licorice was admitted to a hospital with severe hypertension, hypokalemia and metabolic acidosis. Urine analysis showed inhibition of 11-beta-hydroxysteroid dehydrogenes. The active compound of licorice was found to be glycyrrhetinic acid. Three months after she stopped licorice she became normal. [88]   
A 65-year-old- woman was suffering from myalgia and encephalitis. She was taking alternative medicines, licorice tea and licorice as dietary supplement. She presented with hypertension and hypokalemia. She was advised to discontinue licorice tea and licorice as dietary supplements and discharged from the hospital. Follow up study showed reversal of her condition, normalization of blood pressure and hypokalemia with normal aldosterone: renin ratio. [89]
 A case of six and half year-old child with pseudohyperaldosteronism and hemorrhagic gastritis due to excessive and prolonged ingestion of licorice is reported in a pediatric journal. The unusual association of hemorrhagic gastritis with licorice is debated because licorice is known to relieve gastralgia and cure peptic ulcer. Furthermore hemorrhagic gastritis is never observed in the course of licorice intoxication or licorice poisoning. [90] 

Contraindications:

Hypertension, cardiac failure (CCF-congestive cardiac failure), acute left ventricular failure, electrolyte imbalance, pregnancy, kidney disorders, hepatic failure, water retention (edema), women on oral contraceptive pills (OCPs) 

Drug Interactions

Yashtimadhu-licorice (Glycyrrhiza glabra) can show interactions with antihypertensive drugs, hormone therapy, digestive juices and gut bacteria.

 Ayurvedic Uses 

1. Mukhapaaka (Glossitis, stomatitis, aphthous ulcers)
2. Kaasa, shwaasa (Sore throat, pharyngits, laryngitis, bronchitis, bronchial asthma)
3. Raajayakshmaa (Tuberculosis)
4. Twachaa roga/Warnya (Eczema, allergic dermatitis, skin color-lightener, reduce hyperpigmentation of the skin)
5. Keshya (Premature graying of hair, hair fall and baldness, improves thequality of hair)
6. Jwara (PUOs)
7. Amla pitta (Hyper acidity, peptic ulcer)
8. Grahanee (Diarrhea, dysentery, colitis)
9. Yakrit wyadhi, Kaamala (Hepatic disorders, jaundice) 
10. Sandhiwaata (Osteoarthritis)
11. Medhya (To improve imtelligence, memory)
12. Balya (To improve strength, immunity)
13. Rasaayana (Adaptogen, antiagind)
14. Chkshushya (Beneficial in ophthalmic disorders)
15. Shukrala (To increase sperm count, to improve male sub fertility)
16. Wrushya/ Waajeekara (Aphrodisiac) [91], [92]  

Modern uses 

1. Stomatitis, glossitis, dental caries, aphthous ulcers
2. Gastritis, peptic ulcer, Helicobacter pylori infection
3. Pharyngitis, laryngitis, bronchitis, sinusitis, allergic rhinitis
4. Chronic dysentery, ulcerative colitis, irritable bowel disease
5. Non alcoholic fatty liver disease (NAFLD)
6. Hyperlipidemia, dyslipidemia
7. Prevention and treatment of atherosclerosis
8. Chronic fatigue syndrome
9. Oligospermia, male subfertility
10. Benign prostatic hyperplasia and prostate cancer
10. Menopausal syndrome
11. Obesity
12. Osteoarthritis
13. Addison’s disease [93], [94]

Preparations: 

 Licorice Gel: for atopic dermatitis
Many formulations used for respiratory infections and as anti-tussive agents
Yashtimadhu Taila: Oil containing licorice (Glycyrrhiza glabra) used for skin disorders, for lightening skin color
Licorice Tea: Used as rasaayana (adaptogen), hormone replacement therapy fo menopausal women   
Yashtimadhughana/candy as lozenge to treat sore throat

 Dosages:

Children: 250 mg to 1.5 grams
Adults: 1-3 grams
Maximum adult dose: 6grams per day in divided doses
Usually taken 2doses with lukewarm water [95]

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