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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