Milk thistle, Silybum marianum, hepatoprotective, silymarin, seeds, antioxidant

Milk thistle (Silybum marianum, Asteraceae) seeds have been used for over 2000 years
as remedy for several diseases especially for liver and still widely used. The active
constituents of milk thistle seed are three flavonolignans viz. silibinin, silychristin, and
silidianin collectively known as silymarin extracted from milk thistle seeds, available
commercially as standardized extract. Milk thistle seed extract (silymarin) and its
constituents (mainly silibinin) act as antioxidant and hepatoprotective; effective in
treating toxin poisoning, hepatitis, cirrhosis, fibrosis of liver; stimulate liver
regeneration. However, human studies regarding management of alcoholic cirrhosis and
hepatitis are equivocal. Milk thistle seed has anti-inflammatory, immunomodulatory,
lipid and biliary effects. It also has antiviral, antitumor and other therapeutic
properties. Milk thistle preparations are safe, well tolerated and cause no serious side
effects except mild gastrointestinal and allergic reactions. Milk thistle seed is a very
promising herbal drug. More research is warranted to substantiate its broad ranging
phytotherapeutic effects. 
Key words: Milk thistle, Silybum marianum, hepatoprotective, silymarin, seeds,
Milk thistle (Silybum marianum L. Gaert., Asteraceae) seeds have been used for
centuries as herbal medicine mainly for the treatment of liver diseases. The common
name, milk thistle, is derived from the ‘milky white’ veins on the leaves, which, when
broken open, yield a milky sap. The therapeutically active constituents of milk thistle
seeds are three isomeric flavonolignans namely silibinin (silybin), silychristin, and
silidianin collectively known as silymarin extracted from the dried milk thistle seeds.
Silibinin is the most biologically active. The seeds also contain other flavonolignans,
betaine, apigenin, silybonol, proteins, fixed oil and free fatty acids, which may
contribute to the health giving effects of milk thistle seeds. [1, 2] Present review
attempts to provide a brief overview of the recent advances in the pharmacological and
therapeutic aspects of milk thistle seeds.

Botanical descriptions
Milk thistle is an annual or biennial plant. It is erect, stout, 5-10 feet tall with large
prickly leaves, large purple flowering heads and strongly spinescent stems .
When broken the leaves and stems exude a milky sap. The glabrous leaves are dark
green, oblong, sinuate-lobed or pinnatified with spiny margins. The leaves have milkwhite
veins. White veins give the leaves, which initially form a flat rosette, a diffusely
mottled appearance. During flowering season, from June to September each stem bears
a terminal head containing a single, large, purple, slightly fragrant flower ending in
sharp spines. The reddish purple flowers are ridged with sharp spines. The achenes, 6-
7 mm in length and transversely wrinkled, are dark in colour, grey flecked with a yellow
ring at the apex. Attached to the achene is a long white pappus. The fruits are glossy
brown or grey with spots. 
Traditional cultivation and usage
Milk thistle was once cultivated in Europe as vegetable. The de-spined leaves were used
in salads and as spinach. The stalk, root and flowers were also consumed. He roasted
seeds were used as coffee substitute. Preparations of milk thistle seeds have been used
medicinally from as early as fourth century B.C. and first reported by Theophrastus.
Traditionally the seeds have been used in Europe as galactogogue in nursing mothers,
bitter tonic, and antidepressant, in liver complications (including gallstones), dyspepsia,
spleenic congestions, varicose veins, diabetes, amenorrhea, uterine hemorrhage and
menstrual problems. Its use as liver protectant can be traced back to Greek and Roman
references of first century A.D.
Present day cultivation and usage
Milk thistle is indigenous to Kashmir (India), Southern Europe, Southern Russia, North
Africa, and Asia Minor. It was introduced to most areas of Europe, North and South
America and Southern Australia and cultivated mainly in dry rocky soils of European
countries, Australia, Canada, China, North and South America as medicinal plant. It is
also grown widely as ornamental plant for its attractive foliage. The seeds are collected
ripe during late summer. Presently milk thistle seed, its purified extracts and its active
constituents are mainly used in liver diseases. It is the most widely used
hepatoprotective agent, in chronic inflammatory hepatic disorders including hepatitis,
jaundice, alcohol abuse, fibrosis, cirrhosis and fatty infiltration; in hepatotoxicity by
mushroom poisoning and by industrial pollutants. It is also widely used as
nutraceuticals agent. In homoeopathy the seed tincture has been used in liver
disorders, jaundice, gall stones, peritonitis, haemorrhage, bronchitis and varicose veins.
Extracts, tablets or capsules containing standardized extract of milk thistle seeds are
available commercially.
Phytotherapeutic applications
The seeds of milk thistle can be consumed raw (usually freshly milled), made into a tea
or used as a hydro-alcoholic extract for medicinal use. Silymarin is included in the
pharmacopoeia of many countries. Average adult dose of powdered seed is 12-15 g/day;
as dry standardized seed extract (silymarin): 200-400 mg/day; as liquid seed extract: 4-
9 ml/day. Silymarin is very poorly soluble in water, so milk thistle seed is not much
effective in the form of tea. Extracts from the seed are generally marketed as tablet and
encapsulated form for oral use, usually containing concentrated seed extract
standardized to 70-80 % of silymarin. Silymarin is also administered by parenteral
route. The effects of silymarin (the standardized extract from milk thistle seed) are
discussed below.
Milk thistle seed’s therapeutic and health promoting efficacy involves a variety of
molecular mechanisms. Its primary activities are of use as antioxidant and

Antioxidant: Silymarin has been reported to act as an excellent antioxidant,
scavenging free radicals (reactive oxygen species) and inhibiting lipid peroxidation
thereby protecting cells against oxidative stress. It augments the non-enzymatic and
enzymatic antioxidant defense systems of cells involving reduced glutathione,
superoxide dismutase and catalase. It can protect the liver, brain, heart and other vital
organs from oxidative damage for its ability to prevent lipid peroxidation and
replenishing the reduced glutathione levels. Silibinin exhibits membrane protective
properties and it may protect blood constituents from oxidative damage.
Hepatoprotection: Use of milk thistle seeds as liver protectant dates back to the first
century. Antioxidant activity is one of the important factors in hepatoprotection.
Antihepatotoxic potential: Silymarin protects liver cells against many hepatotoxins in
humans and animals. Some mushrooms (e. g. Amanita phalloides, the death cup
fungus and A. virosa) contain two toxins: phalloidine and α-amanatine which destroy
hepatocyte cell membrane and block hepatic protein synthesis leading to severe liver
damage and death. Silymarin effectively prevents both of these effects by blocking the
toxin’s binding sites, increasing the regenerative capacity of liver cells. Silibinin was
found to be an effective measure against liver damage if it is administered intravenously
within 24 hours after mushroom ingestion. In one study, 60 patients with severe
Amanitia poisoning were treated with infusions of 20 mg/kg of slibinin with excellent
results showing no death of the patients treated. Sliymarin is often used as supportive
therapy in food poisoning due to fungi.
Silymarin also offers liver protection against tetracycline, d-galactosamine and thalliuminduced
liver damage and erythromycin estolate, amitryptiline, nortryptiline and tertbutyl
hydroperoxide exposure of neonatal hepatocytes. It reduces liver damage due to
long term treatment with phenothiazine or bytyrophenone. Silibinin significantly
inhibits concanavalin A-induced liver disease. It also provides heparoprotection against
poisoning by phalloidin, halothane, thioacetamide, acetaminophen and carbon
tetrachloride. It also protects liver from ischaemic injury, iron overload and radiation.
Silymarin is used for the treatment of several liver diseases characterized by
degenerative necrosis and functional impairment including chronic liver disorders. The
German Commission E endorses use silymarin for the treatment of liver diseases,
including hepatitis A, alcoholic cirrhosis, and chemically induced hepatitis.
Alcoholic liver disease/cirrhosis: Ethanol metabolism involves formation of free radicals
leading to oxidative stress in liver. Silymarin successfully opposes alcoholic cirrhosis
with its antioxidant and hepatoprotective mechanisms restoring the normal liver
biochemical parameters. Silymarin also ameliorates cytolysis in active cirrhosis
patients. However use of silymarin is inadvisable in decompensated cirrhosis.
Hepatitis: In patients with acute viral hepatitis, silymarin shortens treatment time and
shows improvement in serum bilirubin, and serum liver enzymatic levels. Biochemical
values are restored to normal sooner in silymarin-treated patients. In chronic active
hepatitis silymarin treatment improves liver function tests. Histological improvement is
observed in sliymarin-treated patients with chronic hepatitis. Silymarin causes stable
remission of alcoholic hepatitis normalizing the liver biochemical parameters. [10]
Liver fibrosis: Liver fibrosis can result in remodeling of liver architecture leading to
hepatic insufficiency, portal hypotension and hepatic encephalopathy. The conversion
of hepatic stellate cells into myofibroblast is condidered as central event in fibrogenesis.
Sliymarin treatment markedly inhibits this process in liver fibrosis patients showing
antifibrotic potential.
Liver tissue regeneration: Silymarin stimulates liver tissue regeneration by increasing
protein synthesis in the injured liver. In in vivo and in vitro experiments performed in
the liver of rats from which part of the organ (liver) was removed, silibinin produces a
significant increase in the formation of ribosomes and in DNA synthesis, as well as an
increase in protein synthesis. Interestingly, the increase in protein synthesis is induced
by silibinin only in injured livers, not in healthy ones.
There are a number of systematic reviews regarding the applications of milk thistle
seeds in liver diseases but most of the human studies done to date are of such variable
design, quality and results that no definitive conclusions about degrees of effectiveness
in the treatment or prevention of alcoholic cirrhosis and hepatitis can yet be made.
Better quality clinical trials are necessary.
Anti-inflammation:Milk thistle seed and its active extract silymarin have antiinflammatory
and anti-arthritic effects due to excellent antioxidant property, scavenging
free radicals which act as pro-inflammatory agents. Silymarin was found to be more
effective in cases of developing arthritis compared to developed arthritis. Silymarin and
silibinin hinder inflammatory process by inhibiting neutrophil migration and Kuppfer
cell inhibition. They also inhibit the formation of inflammatory mediators viz.
prostaglandins and leukotrienes especially (by inhibiting 5-lipoxigenase pathway) and
release of histamine from basophils. Therefore, milk thistle seed may possess antiallergic
and anti-asthmatic activities.
Immunomodulation: Sliymarin’s immunomodulatory activity in liver disease patients
may also be involved in its hepatoprotective action. Sliymarin protects experimental
rodents from ultraviolet radiation-induced immunosupression. [14] Silibinin inhibits
activation of human T-lymphocyte, human polymorpho-nuclear leucocyte. Silymarin
significantly suppresses the inflammatory mediators, expression of histocompatibility
complex molecules and nerve cell damage. Long term administration of sliymarin
improves immunity by increasing T-lymphocytes, interleukins and reducing all types of
immunoglobulins. Sliymarin can be useful in development of therapeutic adjuvant in
which immunosupression is required including autoimmune and infectious diseases.
Liver lipidaemic control: It was found that silymarin and silibinin reduce the
synthesis and turnover of phospholipids in the liver. Silibinin neutralizes ethanolinduced
inhibition of phospholipids synthesis and the reduction in glycerol
incorporation into lipids of isolated hepatocytes. Furthermore, silibinin stimulates
phosphatidylcholine synthesis and increases the activity of choline phosphate
cytidyltransferase in rat liver both in normal conditions and after galactosamine
intoxication. Silymarin significantly inhibits hepatic lipid peroxidation and may
diminish triglyceride synthesis in liver. Impairments in the liver lipid profile caused as a
result of prolonged effect of ethanol, anti-tubercular drugs (isoniazid, rifampacin), and
liver toxicants (acetaminophen, halothane, microcystin) are effectively improved by
Blood (plasma) lipidaemic control:Administration of silymarin to type II
hyperlipidemic patients resulted in slightly decreased total cholesterol and high-density
lipoprotein levels in blood plasma. Silymarin reduces plasma levels of cholesterol and
low-density lipoprotein levels in hyperlipidaemic rats, whereas silibinin does not reduce
plasma levels of cholesterol in normal rats; however, it reduces total phospholipid
levels. Biliary cholesterol and phospholipid concentrations in rats are also slightly
reduced. Silymarin-induced reduction of biliary cholesterol and phospholipids in both
rat and human may be in part due to decreased liver cholesterol synthesis. Silymarin
could represent a novel agent in the prevention and therapy of hypercholesterolemia
and atherosclerosis.
Biliary effect:  Silymarin undergoes excessive enterohepatic circulation, which allows a
continuous loop between intestine and liver. It prevents the disturbance of bile
secretion, thereby increasing bile secretion, cholate and bilirubin excretion.
Anti-viral effect:Although silymarin does not affect viral replication it has beneficial
role in viral hepatitis by its inhibitory action on inflammatory and cytotoxic processes
induced by viral infection. Silibinin strongly inhibits growth of both HepG2 (hepatitis B
virus negative; p53 intact) and Hep3B (hepatitis B virus positive; p53 matured) cells
with relatively more cytotoxicity in Hep3B cells which is associated with apoptosis
induction. Silymarin also showed inhibitory activity against other viruses in different
cell lines.
Antitumor and anticarcinogenic effects: Silymarin significantly inhibits tumor
growth and also cause regression of established tumors. It is associated with in vitro
anti-proliferative, pro-apoptopic and anti-angiogenic efficacy in prostate tumor.
Silymarin feeding during the promotion phase of 4-nitroquinoline-1-oxide-induced rat
tumorigenesis exerts chemopreventive activity against tongue squamous cell carcinoma.
The cancer chemopreventive and anticarcinogenic effects of silymarin in long term
animal tumorigenesis models and in human prostate, breast, and cervical carcinoma
cells are also reported. Treatment with silibinin results in a highly significant inhibition
of both cell growth and DNA synthesis with loss of cell viability in case of cervical
carcinoma cells.
It is well demonstrated that ultraviolet light-induced immunosuppression and oxidative
stress play an important role in the induction of skin cancers. Topical or dietary
administration of silymarin to mouse skin prevents photocarcinogenesis by significantly
inducing apoptosis, increase in catalase activity and induction of cylo-oxygenase and
ornithine decarboxylase activity. Similar results are also obtained in other chemical induced
skin carcinogenesis models. Prevention of ultraviolet light-induced
immunosuppression and oxidative stress by silymarin may be associated with the
prevention of photocarcinogenesis.
Silibinin significantly induces growth inhibition, a moderate cell cycle arrest and a
strong apoptotic cell death in small cell and non-small cell human lung carcinoma cells.
Silibinin inhibits the growth of human prostate cancer cells both in vitro and in vivo.
Silymarin and silibinin have strong anti-angiogenesis effect on the colon cancer cell line
and effective against chemical-induced bladder carcinogenesis in mice and
hepatocellular carcinoma in rats.
Neuroprotection:Silymarin was found to be useful in prevention and treatment of
neurodegenerative and neurotoxic processes due to its antioxidant effects. Silymarin
can effectively protect dopaminergic neurons against lipopolysaccharide-induced
neurotoxicity in brain .
Cardioprotection:During cancer therapy, the use of certain chemotherapeutic agents
like doxorubicin is limited by cardiotoxicity that is known to be mediated by oxidative
stress and apoptosis induction. Silibinin has such cardioprotective properties due to its
antioxidant and membrane protective actions.
Miscellaneous effects:Silymarin helps to maintain normal renal function. Silibinin
reduces oxidative damage to kidney cells in vitro. In rats, silibinin prevents cisplatininduced
nephrotoxicity, but does not prevent cyclosporine-induced glomerular damage.
As an antioxidant, silymarin can protect the pancreas against certain forms of damage.
In a controlled trial of human diabetics treated with silymarin, patients experienced
decreases in blood glucose and insulin requirements. It exhibits anti-ulcer activity in
rats.  In one study of post parturient cattle given milk thistle seed meal, milk
production was increased and ketonuria reduced, as compared to controls. [19]
The value of silymarin in the treatment of psoriasis may be due to its ability to improve
endotoxin removal by the liver, inhibition of cyclic adenosine monophosphate
phosphodiesterase, and leukotriene synthesis. Abnormally high levels of cyclic
adenosine monophosphate and leukotrienes are observed in patients with psoriasis and
normalization of these levels may improve the condition.
Adverse effects
Human studies performed with milk thistle seeds indicated little need for concern with
adverse effects. Human studies demonstrate that milk thistle seed extract (silymarin) is
safe and well tolerated. It is generally nontoxic and causes no side effects when
administered to adults in a dose range of 200-900 mg/day in two or three divided
doses. Higher dose (> 1500 mg/day) could produce minor gastrointestinal disturbances
involving mild laxative effect which may be due to increased bile secretion and flow.
Mild allergic reactions (pruritus, urticaria, arthralgia) are observed, but rarely enough to
discontinue. Commonly noted adverse effects such as bloating, dyspepsia, epigastric
pain, flatulence, nausea, irregular stool and laxation are observed in 2-10 % of patients
in clinical trial. Headaches and dermatological symptoms are also noted.
Silymarin was found nontoxic in rats and mice after oral doses of 2500 or 5000 mg/kg
body weight without producing any unwanted symptoms. Similar reports were also
obtained for rabbits and dogs. No evidence of ante- or postnatal toxicity in animals was
reported. These data reveal that the acute toxicity of silymarin is very low. [3,7]
It was found that silymarin at higher concentrations have an inhibitory effect on both
phase I and phase II hepatic drug metabolizing (biotransformation) cytochrome enzyme
systems. But the plasma concentrations at therapeutic doses are very less as compared
to that needed for the inhibition. So it exhibits no beneficial or harmful drug
interactions at normal doses.
Safety of milk thistle seed in pregnancy and lactation was not studied in humans.
Traditionally has been considered safe in lactation, however, no clinical studies have
been performed. Safety in children also has not been studied yet. No known
contraindications have yet been reported.
Milk thistle (Silybum marianum) seeds have been used for over 2000 years as natural
remedy for the treatment of several diseases especially for liver and still widely used for
the same. The active constituents of milk thistle seed are three isomeric flavonolignans
viz. silibinin or silybin, silychristin, and silidianin collectively known as silymarin
extracted from the milk thistle seeds, available commercially as standardized extract.
Milk thistle seed extract (silymarin) and its constituents (mainly silibinin) act as
antioxidant and hepatoprotective and effective in treating toxin poisoning, hepatitis,
cirrhosis, and fibrosis of liver; stimulate liver regeneration. Although the human studies
regarding management of alcoholic cirrhosis and hepatitis are equivocal. Milk thistle
seed demonstrates anti-inflammatory, immunomodulatory, lipid and biliary effects. It
also has antiviral, antitumor and other therapeutic properties. Milk thistle seed
preparations are safe, well tolerated and cause no serious side effects in humans except
mild gastrointestinal and allergic reactions.
Milk thistle seed shows great promise to be a superior herbal drug. Its good safety
profile, better standardization and quality control, easy availability and low cost are
added advantages. More definitive research is warranted to corroborate its wide range of
phytotherapeutic effects. Further research on milk thistle seed may make a
breakthrough as a new approach in disease prevention in addition to liver

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