, Volume 15, Issue 7, pp 465–489 | Cite as

Silymarin: A Review of its Clinical Properties in the Management of Hepatic Disorders

  • Keri WellingtonEmail author
  • Blair Jarvis
Adis Drug Evaluation



The mechanisms of action of silymarin involve different biochemical events, such as the stimulation of the synthetic rate of ribosomal RNA (rRNA) species through stimulation of polymerase I and rRNA transcription, protecting the cell membrane from radical-induced damage and blockage of the uptake of toxins such as α-amanitin.

Studies in patients with liver disease have shown that silymarin increases Superoxide dismutase (SOD) activity of lymphocytes and erythrocytes, as well as the expression of SOD in lymphocytes. Silymarin has also been shown to increase patient serum levels of glutathione and glutathione peroxidase.

Silybin 20 to 48 mg/kg/day has shown promise as a clinical antidote to acute Amanita (deathcap mushroom) poisoning.

Primary efficacy data from 3 trials which examined the therapeutic potential of silymarin in patients with cirrhosis, and included patient survival as an endpoint, demonstrated that silymarin had no significant beneficial effect on patient mortality. However, upon subanalysis, silymarin 420 mg/day had a significantly beneficial effect on patient survival rate (compared with patients receiving placebo) in 1 randomised, double-blind trial in patients with alcoholic cirrhosis.

Silymarin 420 mg/day was also shown to improve indices of liver function [AST, ALT, γ-glutamyl transferase and bilirubin] in patients with liver disease of various aetiology, including those exposed to toxic levels of toluene or xylene; however, it was largely ineffective in patients with viral hepatitis.

Reports of adverse events while receiving silymarin therapy are rare. However, there have been accounts of nausea, epigastric discomfort, arthralgia, pruritus, headache and urticaria. Silymarin has also been reported to have possibly caused a mild laxative effect.

Conclusion: The antioxidant properties of silymarin (a mixture of at least 4 closely related flavonolignans, 60 to 70% of which is a mixture of 2 diastereomers of silybin) have been demonstrated in vitro and in animal and human studies. However, studies evaluating relevant health outcomes associated with these properties are lacking. Although silymarin has low oral absorption, oral dosages of 420 mg/day have shown some therapeutic potential, with good tolerability, in the treatment of alcoholic cirrhosis. Moreover, silybin 20 to 48 mg/kg/day has shown promise as an antidote for acute mushroom poisoning by Amanita phalloides; however, further studies paying attention to the amount of ingested mushroom and time elapsed before administration of treatment are needed to clarify its role in this indication. Studies in patients with the early onset of liver disease may demonstrate the liver regeneration properties that silymarin is promoted as possessing.

Pharmacodynamic Properties

Silymarin is a standardised extract from the seeds and fruits of the milk thistle Silybum marianum and contains, as its main constituents, the flavonolignans silybin, isosilybin, silydianin and silychristin. The major component of silymarin is silybin (which is a mixture of 2 diastereomers), which constitutes between 60 and 70% of the drug and is the major active component.

The mechanisms of action of silymarin involve different biochemical events, such as increasing the synthesis of ribosomal RNA (rRNA) species through stimulatio of polymerase I and rRNA transcription (thereby increasing the synthetic rate of structural and functional proteins), blockage of the uptake of toxins such as α-amanitin from Amanita phalloides (the deathcap mushroom), and protecting the cell membrane from osmotic stress and radical-induced damage.

Superoxide dismutase (SOD) and the glutathione system are the 2 main physiological defence mechanisms against free radicals, both of which are subject to depletion during a period of toxic substance overload.

Two studies showed that silymarin 420 mg/day significantly increased the SOD activity of lymphocytes and erythrocytes, as well as SOD expression in lymphocytes of patients with histologically proven micronodular cirrhosis.

In 2 further studies, silymarin 10 mg/L significantly increased SOD expression in lymphocytes from patients with liver cirrhosis. Silymarin 420 mg/day has also been shown to significantly increase serum levels of glutathione and glutathione peroxidase and SOD activity of erythrocytes and lymphocytes compared with placebo in patients with chronic alcoholic liver disease. Furthermore, silymarin 800 mg/day significantly reduced serum levels of malondialdehyde, the end-product of linoleic acid oxidation in cell membranes, in a double-blind, placebo-controlled trial involving 60 patients who had been taking psychotropic drugs for at least 5 years.

Among patients with liver cirrhosis and concomitant type 2 diabetes mellitus, silymarin significantly reduced glucagon-stimulated C-peptide levels compared with placebo.

Silymarin has also demonstrated regulatory action of cell membrane permeability which has been associated with an increase in membrane stability against oxidative stress [e.g. oxidative stress from α-amanitin, phalloidin, carbon tetrachloride, paracetamol (acetaminophen), ethanol (alcohol) and metals, among others]. Furthermore, silybin, silychristin and silydianin inhibit the formation of prostaglandins, which are associated with lipid peroxidation. Silymarin has also shown significant anti-inflammatory and antifibrotic activity in animal models as well as in vitro inhibition of carcinoma cell growth and DNA synthesis.

Pharmacokinetic Profile

Following oral administration of silymarin 560mg to 6 healthy volunteers, maximum plasma concentrations of total silybin (both diastereomers of free and conjugated silybin) of 0.34 mg/L were reached within 1.32 hours, and the area under the plasma concentration-time curve was 1.14 mg/L · h. Between 75 and 90% of the administered dose of silybin is metabolised to glucuronide and sulphate conjugates. The plasma elimination half-life of total silybin is approximately 6 hours, and between 1 and 5% of an oral dose of silymarin is excreted unchanged in the urine. Between 20 and 40% of the administered dose of silybin is recovered, in conjugated form, in the bile. Plasma levels of silybin in patients with compensated liver cirrhosis were found to be within the normal range compared with those obtained in healthy volunteers.

Therapeutic Efficacy

Cirrhosis of the Liver: The effect of silymarin on the survival of patients with liver cirrhosis has been examined in 3 randomised, double-blind studies, none of which demonstrated a significantly beneficial effect on patient mortality. However, subanalysis in 1 of the studies demonstrated that long term treatment with silymarin 420 mg/day significantly increased the 4-year patient survival rate compared with placebo in a randomised, double-blind trial involving 170 patients with alcoholic (n = 91) or nonalcoholic (n = 79) cirrhosis of the liver. Furthermore, among patients with alcoholic cirrhosis, 22% (10 of 46) of the silymarin group died compared with 42% (19 of 45) of the control group (p = 0.01).

In a randomised, double-blind trial investigating the ability of silymarin to normalise parameters of liver function in patients with liver disease, treatment was significantly better with silymarin than with placebo. 36 patients were randomised to receive silymarin 420 mg/day in 3 divided doses or placebo for 6 months. During the course of silymarin treatment, mean patient serum levels of bilirubin normalised and AST, ALT and γ-glutamyl transferase (GGT) decreased significantly compared with baseline values.

Similarly, in a randomised double-blind trial involving 97 consecutive patients with liver disease induced by alcohol, silymarin 420 mg/day significantly improved serum levels of AST and ALT compared with placebo.

In a 6-month trial involving 27 patients with compensated active cirrhosis, silymarin 420 mg/day had no significant effect on patient serum levels of ALT, AST or bilirubin.

Patients With Cirrhosis and Type 2 Diabetes Mellitus: Compared with placebo, silymarin 600 mg/day for 12 months reduced lipid peroxidation of liver cell membranes and decreased the endogenous production of insulin and the need for exogenous insulin in a randomised, nonblind study involving 60 patients with type 2 diabetes mellitus and alcoholic liver cirrhosis.

Amanita Mushroom Poisoning: Among 175 patients with acute Amanita poisoning who were treated with silymarin (as silybin), only 8.6% died (data were published as case reports). However, 131 of the patients were also receiving benzylpenicillin (penicillin G) treatment. Of the remaining 44 patients who received silymarin alone, only 1 patient died and that was because of a suicidal intake of mushroom. Most patients received intravenous silybin 20 to 48 mg/kg/day. However, 5 patients were given oral silymarin as well as intravenous silybin; 1 patient received only oral silymarin 1.4 to 4.2 g/day.

Viral Hepatitis: Silymarin was largely ineffective in the treatment of viral hepatitis. In 59 patients with uncomplicated acute viral hepatitis A or B, silymarin 420 mg/day significantly lowered serum levels of bilirubin and AST compared with placebo over a treatment period of between 21 and 28 days. There were no significant between-group effects on serum levels of GGT, ALT, alkaline phosphatase and cholinesterase or on prothrombin time.

Furthermore, there were no between-group differences in liver function parameters in 3 trials involving 187 patients with acute or chronic viral hepatitis who were given silymarin 420 mg/day or placebo for between 5 weeks and 1 year.

Other Studies: Silymarin significantly improved serum indices of liver function in 49 patients who had been exposed to toxic levels of toluene or xylene. However, it had no significant effect on tacrine-induced elevated serum levels of ALT or AST in a 12-week, randomised, double-blind, placebo-controlled trial among 222 patients with Alzheimer’s disease.


In 2 trials involving 295 patients with liver cirrhosis, 9 patients (4 of whom withdrew from treatment) who received silymarin 420 or 450 mg/day complained of adverse events compared with 6 receiving placebo. Adverse events included nausea, epigastric discomfort, arthralgia, pruritus, headache and urticaria. However, assessment of tolerability was often not included in the trial designs.

Silymarin 420 mg/day for 30 days was reported to have caused a mild laxative effect in 4 of 24 patients who were being treated for exposure to organophosphates.

Dosage and Administration

The German Commission E indications for silymarin are for treatment of acute mushroom poisoning, adjunctive treatment of hepatic cirrhosis with or without a history of ethanol abuse or concurrent chronic hepatitis C infection, adjunctive treatment of acute viral hepatitis due to hepatitis A or B infection, and as a nutritional supplementation to promote healthy liver function.

Silymarin can be administered either as capsules or tablets containing silymarin extract (usually 70 or 140mg) or as an infusion of milk thistle fruits. The German Commission E recommends a daily dosage of 12 to 15g of crude herb or 200 to 400mg of silymarin calculated as silybin.

Adult patients with hepatic cirrhosis, regardless of prior history of ethanol abuse or concurrent hepatitis C infection, may receive silymarin 420 mg/day before meals. Patients should also abstain from any alcohol consumption.

Silybin dihemisuccinate, a derivative of silybin, is used as a clinical antidote for acute Amanita mushroom poisoning. The initial dosage should consist of silybin dihemisuccinate 5 mg/kg by intravenous infusion over the course of 1 hour followed by 20 mg/kg/day by continuous infusion for 6 days.

Because of insufficient data, silymarin should be used during pregnancy only when the benefits to the mother outweigh the risks to the fetus. Furthermore, it is unknown if silymarin is excreted in breast milk and a decision should be made whether to discontinue breast feeding when taking silymarin.

Silymarin should not be administered to children under 12 years of age unless the benefits outweigh the risks.


Silymarin Amanita Silybin Thioctic Acid Alcoholic Liver Cirrhosis 
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© Adis International Limited 2001

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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