ADIS DRUG EVALUATION BioDrugs 2001; 15 (7): 465-489

1173-8804/01/0007-0465/$22.00/0

Adis International Limited. All rights reserved.

Silymarin: A Review of its Clinical

Properties in the Management of
Hepatic Disorders
Keri Wellington and Blair Jarvis
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

R. Agarwal, AMC Cancer Research Center & Foundation, Denver, Colorado, USA; H. Allain, Laboratoire
de Pharmacologie Exprimentale et Clinique, Universit de Rennes I, Rennes, France; J. Barnes, School of
Pharmacy, University of London, London, England; J. Chick, Royal Edinburgh & Associated Hospital
Outpatients Department, Edinburgh, Scotland; L. Favari, Pharmacology and Toxicology Department,
Centro de Investigacin y de Estudios Avanzades del I.P.N., Mexico; P. Ferenci, 1st Department of
Gastroenterology and Hepatology, University of Vienna, Vienna, Austria; P.C. Hayes, Department of Clinical
and Surgical Sciences, Edinburgh University, Edinburgh, Scotland; Y. Mizushima, First Department of
Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan; B. Nalpas, Unite
DHepatologie-Inserm U 370, Hpital Necker, Paris, France; A. Pars, Alcohol and Liver Units, Hospital
Clnici Provincial, Barcelona, Spain; J.D. Phillipson, School of Pharmacy, University of London, London,
England; M.G. Roma, Instituto de Fisiologa Experimental, CONICETUniversidad Nacional de Rosario,
Rosario, Argentina; D. Schuppan, Department of Medicine I, University of Erlangen-Neurnberg, Erlangen,
Germany; C. Soto, Pharmacology and Toxicology Department, Centro de Investigacin y de Estudios
Avanzades del I.P.N., Mexico; F. Stickel, Department of Medicine 1, University of Erlangen-Neurnberg,
Erlangen, Germany; H. Tilg, Department of Medicine, University Hospital Innsbruck, Innsbruck, Austria;
M. Velussi, Centro Antidiabetico, Ospedale Monfalcone, Gorizia, Italy.

Data Selection
Sources: Medical literature published in any language since 1966 on Silymarin, identified using Medline and EMBASE, supplemented by
AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles.
Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were Silymarin and Silybin and Silibin and Silibinin. EMBASE search terms were Silymarin
and Silybin and Silibin and Silibinin. AdisBase search terms were Silymarin and Silybin and Silibin and Silibinin. Searches were last
updated 18 Jul 2001.
Selection: Studies in patients with liver disease or Amanita mushroom poisoning who received silymarin or silybin. Inclusion of studies
was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodol-
ogy were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: liver disease, cirrhosis, Amanita mushroom poisoning, hepatitis, viral hepatitis, type 2 diabetes mellitus,
pharmacodynamics, pharmacokinetics, therapeutic use.

Contents

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
2. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
2.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
2.2 Antioxidant Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
2.2.1 Studies in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472
2.2.2 In Vitro and Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
466 Wellington & Jarvis

2.3 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474

3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
3.3 In Patients With Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
4.1 Cirrhosis of the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
4.1.1 Effects on Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
4.1.2 Effects on Liver Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
4.2 Cirrhosis and Type 2 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
4.3 Amanita Mushroom Poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
4.4 Viral Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
4.5 Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
6.1 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
6.1.1 Adjunctive Treatment of Hepatic Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . 483
6.1.2 Acute Mushroom Poisoning Caused by Amanita spp. . . . . . . . . . . . . . . . . . . . 483
6.2 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
7. Place of Silymarin in the Management of Hepatic Disorders . . . . . . . . . . . . . . . . . . . . . . 484
7.1 Alcoholic Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
7.2 -Amanitin Poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
7.3 Exposure to Toxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
7.4 Viral Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
7.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486

Summary
Abstract 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 -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 end-
point, 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 pla-
cebo) 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, -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,

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Silymarin: A Review 467

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 prop-
erties 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 pos-
sessing.
Pharmacodynamic Silymarin is a standardised extract from the seeds and fruits of the milk thistle
Properties 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 stim-
ulation of polymerase I and rRNA transcription (thereby increasing the synthetic
rate of structural and functional proteins), blockage of the uptake of toxins such
as -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 phys-
iological 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 lympho-
cytes 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 perme-
ability which has been associated with an increase in membrane stability against
oxidative stress [e.g. oxidative stress from -amanitin, phalloidin, carbon tetra-

Adis International Limited. All rights reserved. BioDrugs 2001; 15 (7)

468
Pharmacokinetic Profile
Therapeutic Efficacy
Adis International Limited. All rights reserved.
Wellington & Jarvis
chloride, paracetamol (acetaminophen), ethanol (alcohol) and metals, among oth-
ers]. 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.
Following oral administration of silymarin 560mg to 6 healthy volunteers, max-
imum plasma concentrations of total silybin (both diastereomers of free and con-
jugated 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 con-
jugates. 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.
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. How-
ever, subanalysis in 1 of the studies demonstrated that long term treatment with
silymarin 420 mg/day significantly increased the 4-year patient survival rate com-
pared 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 -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 im-
proved 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 re-
ceived silymarin alone, only 1 patient died and that was because of a suicidal
BioDrugs 2001; 15 (7)
Silymarin: A Review 469

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 phos-
phatase and cholinesterase or on prothrombin time.
Furthermore, there were no between-group differences in liver function pa-
rameters 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 func-
tion 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 Alzheimers disease.
Tolerability 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. How-
ever, 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 organophos-
phates.
Dosage and The German Commission E indications for silymarin are for treatment of acute
Administration 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 nutri-
tional supplementation to promote healthy liver function.
Silymarin can be administered either as capsules or tablets containing sily-
marin 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.

Adis International Limited. All rights reserved. BioDrugs 2001; 15 (7)

470 Wellington & Jarvis

1. Introduction tutes between 60 and 70% of the drug and is the

Milk thistle (also known as Marian thistle, St.
Marys thistle and Our Ladys thistle) extracts have
been used for over 2000 years as a general medic-
inal herb, and since the 16th century they have been
used mainly as a medicament for hepatobiliary dis-
eases.[1]
Silymarin is a standardised extract from the seeds
and fruits of the milk thistle Silybum marianum
Gaertn. (also known as Carduus marianus L.) and
contains, as its main constituents, the flavono-
lignans silybin (synonymous with silibinin, and
sometimes incorrectly called silybinin), isosilybin,
silydianin and silychristin (fig. 1).[2,3] The major
component of silymarin is silybin, which consti-
major active component. Silymarin is extracted
from the crude plant material with >96.7% ethyl
acetate[5] and the content of silymarin is calculated
by spectrophotometry.[6]
During the 1960s there was a revival in interest
in silymarin and subsequently there have been a
range of studies evaluating its hepatoprotective
properties as well as its use in the treatment of liver
disease of varying aetiology.[7] In this review, the
therapeutic effects of silymarin in patients with a
range of liver disorders will be evaluated.
2. Pharmacodynamic Profile
The pharmacodynamic profile of silymarin has
been well studied, and in vitro, animal and human

O
12 OH
O 13
HO OCH3
O
OCH3

OH OH
O
OH O 12 OH
Silybin 13
HO O OH
a,b = diastereomers O
a = -H12; -H13
b = -H12; -H13
OH

OH O
Isosilybin
a,b = diastereomers
a = -H12; -H13
b = -H12; -H13

HO
OH
OH
O
O CH3O
OCH3 OH
HO O OH HO O
O

OH OH

OH O OH O

Silychristin Silydianin

Fig. 1. The main components of the herbal extract silymarin. 60 to 70% of the silymarin mixture, isolated from the fruits and seeds
of Silybum marianum (the milk thistle), comprises silybin which exists as a diastereomeric pair and is the major active metabolite.
Silybin and isosilybin are both present as a pair of diastereomers epimeric at C12 and C13.[2-4]

Adis International Limited. All rights reserved. BioDrugs 2001; 15 (7)

Silymarin: A Review
Table I. Pharmacological properties of silymarin (or silybin) as
demonstrated in vitro
Silybin 10 mg/ml significantly inhibited histamine release from
human blood basophils induced by anti-immunoglobulin E and
f-met peptide (p < 0.05 vs control)[10]
Silymarin 25 and 50 mg/L significantly inhibited ligand-induced
activation of human epidermal growth factor receptor with no
change in its protein levels (p < 0.001 vs vehicle)[11]
Silybin 25 mg/L significantly inhibited lymphocyte blastogenesis
induced by anti-CD3 monoclonal antibody in human
lymphocytes (p < 0.025 vs cultures without silybin)[12]
Silymarin 0.05 mol/L significantly reduced paracetamol
(acetaminophen)-induced toxicity in human epidermal cell line
A431 and hepatoblastoma cell line Hep G2 (p < 0.05 vs
paracetamol alone)[13]
Silymarin and silybin 100 mol/L inhibited cell growth and DNA
synthesis in prostate, breast and cervical human carcinoma
cellsa[14]
Silybin inhibited -glucuronidase isolated from human intestinal
bacteria (IC50 = 0.8 mg/ml)[15]
Silybin inhibited leukotriene B4 (IC50 = 15 mol/L) in rat Kupffer
cells and, to a lesser extent, prostaglandin E2 (IC50 = 45 mol/L)
in human granulocytes[16,17]
Hepatoprotective effect is not mediated by cytochrome P450
2E1-mediated activation of paracetamol or carbon tetrachloride
in rat hepatocytes[18]
Silymarin 50 mol/L blocked the TNF family-induced activation
of NF-B in a dose- and time-dependent manner (without
affecting AP-1 activation)a,b[19]
Silymarin 50 mol/L blocked the translocation of p65 to the
nucleus without compromising its ability to bind to DNAa,b[19]
Silymarin 50 mol/L suppressed TNF-induced production of
reactive oxygen intermediates and lipid peroxidationa,b[19]
Silymarin 50 mol/L inhibited TNF-induced activation of
nitrogen-activated protein kinase kinase and c-Jun N-terminal
kinasea,b[19]
Silybin 10-4 mol/L inhibited rat hepatic stellate cell proliferation
and transformation by 75% versus controla[20]
Silybin 50 mg/L tripled the rate of ribosomal RNA synthesis
compared with controls in rat liver nucleia[21]
Silymarin 100 mol/L inhibited Fe2+ascorbate-induced swelling,
oxygen uptake and malondialdehyde formation (all of which are
an expression of lipid peroxidation) in isolated rat liver
mitochondriaa[22]
Silybin and silychristinc inhibited beef heart cyclic AMP
phosphodiesterase with IC50s of 28 and 18 mol/L,
respectively[23]
a Statistical analysis not reported.
b In human histiocytic lymphoma U-937 cells.
c One of the constituents of silymarin.
AMP = adenosine monophosphate; AP-1 = activating protein-1;
IC50 = concentration required for 50% inhibition; NF-B = nuclear
factor-B; TNF = tumour necrosis factor.
Adis International Limited. All rights reserved.
471
studies have demonstrated that it has hepatoprotec-
tive effects with minimal toxicity. There have been
a number of reviews concerning the pharmacolog-
ical action of silymarin[2,7-9] and so the following
is presented as an overview of the pharmacody-
namic properties of silymarin.
Tables I and II summarise the pharmacody-
namic properties of silymarin and/or silybin.
2.1 Mechanism of Action
The hepatoprotective mechanisms of action of
silymarin involve a number of different biochemi-
cal events. Silymarin increases the synthesis of ri-
bosomal RNA (rRNA) species through stimulation
of polymerase I and rRNA transcription[8,42] which
leads to an increase in the rate of synthesis of both
structural and functional proteins. This stimulation
may enable cells to counteract the loss or func-
tional impairment of transporters and enzymes that
occurs in many pathological conditions.
Silymarin blocks the interaction of -amanitin
(the principle toxin from Amanita phalloides, the
deathcap mushroom) with cellular components, in-
cluding its basolateral transport systems (thus
preventing uptake) and its nuclear receptors (thus
preventing inhibition of polymerase II and the con-
comitant blockade of protein synthesis).[2]
A number of studies have demonstrated the abil-
ity of silymarin to stabilise cellular membranes.
For instance, silymarin was shown to have a stabil-
ising effect on cell membranes against osmotic
stress and ionic detergents in vitro.[43,44] It was also
shown to influence phospholipid metabolism by
inhibition of phosphatidylcholine and phospha-
tidylethanolamine, thus reducing membrane turn-
over and improving membrane integrity.[45-47]
2.2 Antioxidant Activity
Antioxidant activity is an important mechanism
of action of hepatoprotective agents, as free radical
damage is purported to play a key role in the hep-
atotoxic effect of various substances as well as in
the pathogenesis of such processes as inflamma-
tion, ischaemia and reperfusion, atherosclerosis
and aging.[2] It is also thought to play a major role
in the pathogenesis of liver diseases.[48-51] Lipid
BioDrugs 2001; 15 (7)
472
Table II. Pharmacological properties of silymarin (or silybin) as
demonstrated in animals
Silymarin 200 mg/kg significantly increased the redox state and
the total glutathione content of the liver, intestine and stomach of
the rat (p < 0.05 vs control)[24]
Silybin 100 mg/kg significantly prevented phalloidin-induced
hepatotoxicity in mice (p < 0.05 vs phalloidin alone)[25,26]
Silybin significantly prevented iron-induced hepatotoxicity in rats
(p < 0.01 vs control)[27]
Silymarin 100 mg/kg significantly reduced thallium
(10 mg/kg)-induced hepatotoxicity in rats (p < 0.01 vs thallium
alone)[28]
Silymarin 150 mg/kg significantly prevented carbon
tetrachloride-induced liver damage in rats (p < 0.005 vs
controls)[29]
Pretreatment with silymarin 200 mg/kg significantly reduced
hepatic lipid peroxidation induced by acute ethanol (alcohol)
intoxication in rats (p < 0.02 vs control)[30]
Silymarin 100 mg/kg significantly stimulated the synthesis of
hepatoprotective bile salts in rats (p < 0.05 vs control)[31]
Silymarin 70 mg/kg significantly increased the concentration of
RNA and DNA in the liver and bone marrow of rats after
whole-body gamma irradiation (p < 0.01 vs unprotected
animals)[32]
Silymarin 50 mg/kg protected against glutathione depletion and
hepatic lipid peroxidation induced by paracetamol
(acetaminophen) in ratsa[33]
Silymarin 200 mg/kg or silybin 5 mg/kg protected against
phenylhydrazine-induced hepatic lipid peroxidation and
haemolysis in ratsa[34,35]
Silybin 200 mg/kg significantly prevented cisplatin (5
mg/kg)-induced renal damage in rats (p < 0.01 vs control)
without compromising cisplatins antitumour activity[36,37]
Silymarin 100 mg/kg was significantly more effective than
ranitidine 50 mg/kg at preventing gastric ulceration induced by
cold-restraint stress in rats (p < 0.01 vs ranitidine)[38]
Silymarin 100 mg/kg significantly reduced post
ischaemia-reperfusion mucosal injury in rats (p < 0.005 vs
control)[39]
Silymarin 660 mg/kg significantly inhibited the development of
diet-induced hypercholesterolaemia in rats (p < 0.05 vs
control)[40]
Pretreatment with silymarin 500 mg/kg prevented death from a
lethal dose of microcystin-LR (0.08 mg/kg) in micea[41]
a Statistical analysis not reported.
peroxidation is a chain reaction initiated by the at-
tack of free radicals on cell membrane lipids result-
ing in lipidic free radicals that, in the presence of
oxygen, are oxygenated to form reactive peroxides.
The 2 main physiological defences against free rad-
icals are superoxide dismutase (SOD) and the glu-
tathione system. Both these defence mechanisms
Adis International Limited. All rights reserved.
Wellington & Jarvis
are subject to depletion during a period of toxic
substance overload.[2]
The ability of silymarin to protect against oxi-
dative stress-induced hepatocellular damage (such
as lipid peroxidation of membranes and subsequent
membrane degradation) is associated with its
free radical scavenging properties and its ability
to enhance endogenous antioxidant defences, such
as those mediated by SOD or the glutathione sys-
tem.[1,52]
The antioxidant activity of silymarin has been
extensively examined in vitro and in animal and
human studies.
2.2.1 Studies in Humans
A number of studies focused on the effect of
silymarin (or silybin) on SOD activity in lympho-
cytes and erythrocytes.[48,49,53] Copper, zinc (Cu,
Zn) SOD is considered to be the main component
of the intracellular defence mechanism of human
cells against oxidative stress.[48] In patients with
alcoholic liver disease (fatty degeneration and
micronodular cirrhosis), SOD activity was found
to be significantly lower (39 U/ml) than in healthy
patients (79 U/ml, p < 0.001).[48] Three studies
showed that silymarin 280 or 420 mg/day for 1
month significantly (p < 0.01 vs baseline values)
increased, by 103%, SOD activity of lymphocytes
and erythrocytes in patients with histologically
proven micronodular cirrhosis (see also section
4.1).[48-50] In 2 further studies, silymarin 10 mg/L
increased SOD expression in lymphocytes from
patients with liver cirrhosis.[51,53]
Silymarin has also been shown to increase pa-
tient serum levels of glutathione and glutathione
peroxidase. In a double-blind clinical trial, 36 pa-
tients with chronic alcoholic liver disease were
randomised to receive silymarin 420 mg/day in 3
divided doses or placebo for 6 months.[54] Average
alcohol consumption over the preceding 8 years
exceeded 60 g/day in men and 30 g/day in women.
Patients did not have symptoms of encephalopathy,
malnutrition or other associated disease, and viral
and immunological markers were negative. Micro-
nodular cirrhosis was confirmed by liver biopsy.
The efficacy of silymarin was determined by the
change in levels of serum markers for hepatic lipid
BioDrugs 2001; 15 (7)
Silymarin: A Review 473

peroxidation, i.e. glutathione, glutathione peroxi- 150 Silymarin

dase, Cu, Zn SOD activity of erythrocytes and lym- Placebo
**
phocytes, and SOD expression by lymphocytes.[54]
During treatment with silymarin, patient serum
levels of glutathione and glutathione peroxidase 100

Change from baseline (%)

were significantly increased compared with the **
corresponding serum levels of patients receiving
placebo (p < 0.05; fig. 2). Similarly, SOD activity
of erythrocytes and lymphocytes was significantly 50 * *
higher than that of patients receiving placebo (p <
0.01; fig. 2).[54] However, the relevance of these
improvements in antioxidant function to hepatic
0
processes is not known.
The damaging potential of reactive oxygen spe-
cies is often mediated by lipid peroxidation that
*
leads to the breakdown of cellular membranes;[17] 50
thus, the ability of silymarin to scavenge these re-
da e

ne

de
xi on

SO

SO
io

hy
se
ro thi

th

de
active oxygen species is a potentially important

e
pe luta

ta

yt

yt

al
lu

oc

oc

di
G

on
hr

ph
feature of the drug. Silybin inhibited human neu-
yt

al
m
Er

trophil hypochlorous acid (HOCl) production and
leukotriene production but not reactive oxygen
(O2-) production by human granulocytes taken
from healthy volunteers at plasma concentrations
normally achieved after a dose of silybin 240mg
(0.4 to 1.3 mol/L).[17]
Silymarin 800 mg/day for 90 days significantly
reduced serum levels of malondialdehyde, the end-
product of linoleic acid oxidation in cell mem-
branes, in a randomised, double-blind, placebo-
controlled trial involving patients who had been
taking butyrophenone or phenothiazine psy-
chotropic drugs for at least 5 years.[55] 60 women
who had serum AST or ALT levels at least twice
the normal value were included in the study. Pa-
tients were excluded if they had any other hepatic
diseases, altered renal function, cardiac and circu-
latory insufficiency, diabetes mellitus, major extra-
hepatic diseases, or alcohol or opiate abuse. Pa-
tients were randomised to 4 different groups:
treatment with a psychotropic drug (butyrophenone
or phenothiazine) and silymarin 800 mg/day, treat-
ment with a psychotropic drug and placebo, treat-
ment with silymarin 800 mg/day alone (suspension
of the psychotropic drug), administration of pla-
cebo alone (suspension of the psychotropic drug).
M
Ly
Fig. 2. Effect of silymarin on serum markers for lipid peroxidation
and the antioxidant system in patients with chronic alcoholic
cirrhosis. 36 patients with histologically confirmed micronodular
cirrhosis were randomised to receive silymarin 420 mg/day in
3 divided doses (n = 17) or placebo (n = 19) for 6 months in a
double-blind manner.[54] SOD = superoxide dismutase. * p <
0.05, ** p < 0.01 vs placebo.
Serum levels of malondialdehyde were lower in
the group treated with silymarin 800 mg/day and
psychotropic drugs after 90 days compared with
the group that received placebo while being treated
with psychotropic drugs. A treatment versus time
statistical analysis proved significantly in favour
of the silymarin group (p = 0.005); patients given
silymarin had an average reduction from baseline
of serum malondialdehyde levels of 7% compared
with an increase of 9.8% in placebo recipients.[55]
However, there was no significant difference
between reductions of serum malondialdehyde
levels in silymarin and placebo recipients in the 2
groups that had suspended treatment of psy-
chotropic drugs. Both groups had a mean reduction
from baseline of serum malondialdehyde levels of
about 22%.[55] Similarly, there was no significant

Adis International Limited. All rights reserved. BioDrugs 2001; 15 (7)

474
between-group difference in reductions from base-
line of serum levels of AST and ALT in these pa-
tient groups.
Elevated levels of malondialdehyde in patients
who received long term treatment with pheno-
thiazines have previously been demonstrated in a
study examining lipid peroxidation products in
cerebrospinal fluid.[56]
2.2.2 In Vitro and Animal Studies
Silymarin, as reviewed by Valenzuela and Garrido,
has demonstrated regulatory action on cell mem-
brane permeability which has been associated with
an increase in membrane stability against oxidative
stress.[8] Oxidative stress is induced by such toxins
as -amanitin, phalloidin, carbon tetrachloride
(CCl4), N-acetyl-p-benzoquinone imine [NAPQI,
the reactive metabolite of paracetamol (acetamin-
ophen)], ethanol (alcohol) and metals, among oth-
ers. Once the level of oxidative stress exceeds the
antioxidant capacity of the cellular defence system,
the cell dies. Silymarin has been shown to protect
against hepatotoxicity induced by many toxins in
animals (table II) because of its antiperoxidative
activity, as well as its stimulating effect on RNA
polymerase I and its subsequent enhancement of
protein biosynthesis.[57] Furthermore, in cells ob-
tained from rat stomachs, silybin, silychristin and
silydianin inhibit the formation of prostaglandins,
which are associated with lipid peroxidation.[58]
In contrast, the hepatoprotective ability of sily-
marin, in isolated rat hepatocytes, does not involve
inhibition of cytochrome P450 2E1-mediated acti-
vation of paracetamol and CCl4.[18] Similarly,
silymarin and silybin did not affect the covalent
binding of paracetamol. Conversely, silymarin (but
not silybin) counteracted glutathione depletion
caused by allyl alcohol. These results imply that
the effects of silymarin are mediated indirectly
through glutathione rather than through a protec-
tive effect of the drug per se.[18]
2.3 Other Effects
Silymarin has also been shown to significantly
(p < 0.01) reduce glucagon-stimulated C-peptide
levels in patients with cirrhosis and type 2 diabetes
mellitus compared with placebo (see section 4.2).[59]
Adis International Limited. All rights reserved.
Wellington & Jarvis
Furthermore, silymarin has shown significant
antifibrinogenic[20,60] and anti-inflammatory[61,62]
activity in animals, as well as in vitro inhibition of
carcinoma cell growth and DNA synthesis (tables
I and II).[14] Its antifibrinogenic properties are
probably mediated via the inhibition of stellate cell
proliferation and their further transformation into
myofibroblasts, expression of collagen and mes-
senger RNA of the profibrinogenic cytokine trans-
forming growth factor -1 (TGF-), and inhibition
of Kupffer cells, a well recognised source of fibrin-
ogenic mediators.[16,20] The anti-inflammatory
properties of silymarin have been associated with
its capability to inhibit the production of leuko-
triene B4 by Kupffer cells at concentrations close
to those reached after oral administration (table I).[16]
3. Pharmacokinetic Properties
Few pharmacokinetic studies have been per-
formed on silymarin because it is a crude extract
containing a number of compounds, of which
silybin, isosilybin, silydianin and silychristin make
up the majority (fig. 1).[2,3] Silybin (which is a mix-
ture of 2 diastereomers) constitutes between 60 and
70% of the drug and is the major active component.
Hence, the few studies which have involved the
administration of silymarin to healthy volunteers
usually report the pharmacokinetic parameters of
silybin. Furthermore, as shown by Schulz et al.,[63]
different commercially available preparations of
silymarin have variable content, dissolution and
oral bioavailability of silybin.
3.1 Absorption and Distribution
Following oral administration of single dose
silymarin 560mg to 6 healthy volunteers, maxi-
mum plasma concentrations (Cmax) of total silybin
(both diastereomers of free and conjugated silybin)
of 0.34 mg/L were reached (tmax) within 1.32 hours
(table III), and the area under the plasma concen-
tration-time curve (AUC0-24h) was 1.14 mg/L h.[64]
In a further study, 4 single different doses of
silymarin (280, 420, 560 and 700mg) were given
to 6 healthy volunteers.[66] Cmax ranged from 0.52
to 1.38 mg/L with tmax ranging from 0.6 to 4.6 hours
with an average of about 1.7 hours. AUC0-16h val-
BioDrugs 2001; 15 (7)
Silymarin: A Review 475

Table III. Pharmacokinetic properties of silybin (the major active principle of silymarin) in healthy volunteers after administration of various
single doses of silymarin
Reference Regimen Cmax tmax AUC t12 CLR Excretion (% of
(no. of volunteers) (mg/L)a (h) (mg/L h)a (L/h) dose in urine)
Barzaghi et al.[65] (8) SIBb 360mg 0.10 1.40 0.26 NR NR NR
Lorenz et al.[64] (6) SIL 560mgc 0.34 1.32 1.14 6.32 NR 1-2
Weyhenmeyer et al.[66] SIL 280mg 0.52 NRd 2.56 NR 1.59 3.72
(6)
SIL 420mg 0.96 NRd 3.91 NR 1.79 4.4
SIL 560mg 1.02 NRd 5.77 NR 1.91 5.15
SIL 700mg 1.38 NRd 6.81 NR 1.88 4.87
a Total silybin (free silybin plus silybin conjugates after hydrolysis with glucuronidase/arylsulfatase).
b Administered as silymarin but the dosage was reported as silybin equivalents.
c Equivalent to silybin 240mg.
d Average tmax over all dosages 1.7 hours (range 0.6-4.6 hours).
AUC = area under the plasma concentration-time curve; CLR = renal clearance; Cmax = maximum plasma concentration; NR = not reported;
SIB = silybin; SIL = silymarin; t12 = elimination half-life; tmax = time to reach Cmax.

ues ranged from 2.56 to 6.81 mg/L h (table III)
and the relationship between dose, AUC and Cmax
was shown to be linear.[66]
3.2 Metabolism and Elimination
Between 75 and 90% of the administered dose
of silybin is metabolised to glucuronide and sul-
phate conjugates which are partly hydrolysed and
cycled enterohepatically.[66,67] The AUC of the 2
diastereomers of silybin differ by a ratio of 4 : 1
implying stereoselective absorption, distribution
or metabolism.[67]
The plasma elimination half-life of total silybin
is approximately 6 hours (table III). Between 1 and
5% of an oral dose of silymarin is excreted un-
changed in the urine.[2,64-66] Both silybin and
silychristin are predominantly excreted in the bile
as glucuronides and sulphates. Between 20 and
40% of the administered dose of silybin is recov-
erable, in conjugated form, from the bile.[2] The
remaining proportion of silybin is excreted in the
faeces.
The biliary elimination of silybin reached
steady state 2 days after administration of sily-
marin 420 mg/day, in 3 divided doses, and stopped
within 3 days of the final dose in cholecystec-
tomised patients with T-tube drainage.[2] Maxi-
mum concentrations of silybin, as glucuronide or
sulphate conjugates, in the bile up to 24 hours after
oral administration of silymarin 140mg ranged be-
tween 10 and 50 mg/L, with a peak time to these
concentrations of between 2 and 9 hours.[2,68]
3.3 In Patients With Cirrhosis
Plasma levels of silybin in 9 patients with com-
pensated liver cirrhosis were found to be similar to
those in healthy volunteers.[69] Cmax values ranged
from 0.024 to 0.118 mg/L and the mean AUC0-12h
value was 0.252 mg/L h after oral administration
of a single dose of silymarin (reported as 336mg
equivalent of silybin).
4. Therapeutic Efficacy
The therapeutic efficacy of oral silymarin has
been evaluated in a number of comparative studies
in patients with liver disease of various aetiology.
However, only a few studies focused on clinical
outcomes such as patient mortality. The majority
of studies examined changes in indices of liver
function.
The efficacy of the drug has primarily been in-
vestigated in patients with alcoholic liver cirrhosis.
However, intravenous silybin has been evaluated
in patients with acute poisoning by the deathcap
mushroom Amanita phalloides. Silymarin has also
been studied in patients with alcoholic cirrhosis

Adis International Limited. All rights reserved. BioDrugs 2001; 15 (7)

476
and type 2 diabetes mellitus,[59] primary biliary cir-
rhosis,[70] viral hepatitis[71-74] and in patients who
have been exposed to toxic substances.[75,76]
Studies in patients with alcoholic cirrhosis and
viral hepatitis were all randomised and double-
blind, apart from a randomised crossover trial in
alcoholic patients,[77] a noncomparative study in
patients with liver disease of varied aetiology (33%
of whom had cirrhosis)[78] and a small noncom-
parative study in patients with viral hepatitis.[79]
4.1 Cirrhosis of the Liver
There have been 5 randomised, double-blind
studies investigating the efficacy of silymarin in
patients with cirrhosis of the liver. The effects of
silymarin on patient survival were examined in 3
of these studies,[80-82] and changes in liver function
parameters were examined in the other 2 studies.[83,84]
4.1.1 Effects on Mortality
In none of the 3 studies did silymarin signifi-
cantly decrease mortality in patients with cirrhosis.
However, upon subanalysis, patient survival rate
was significantly increased in 1 study.[80]
Two studies of similar design that focused on
the long term survival of patients with cirrhosis had
contrasting conclusions regarding the benefits of
silymarin treatment.[80,81]
Treatment with silymarin did not significantly
affect the mortality rate of patients compared with
placebo during a 2-year randomised, double-blind,
multicentre trial involving 170 patients with alco-
holic (n = 91) or nonalcoholic (n = 79) cirrhosis of
the liver (diagnosis was performed within 2 years
before entry to the trial).[80] However, upon sub-
analysis, the 4-year survival rate was significantly
(p = 0.036) increased by silymarin compared with
placebo. Patients were randomised to receive
silymarin 420 mg/day in 3 divided doses or placebo
for 2 years, and then had the option of continuing
until the last trial entrant had completed 2 years of
treatment; the mean duration of treatment was 41
months. Liver function parameters were measured
and included serum levels of transaminases, biliru-
bin, alkaline phosphatase, albumin and serum -
glutamyl transferase (GGT) activity.[80] The sever-
ity of the underlying disease was classified using
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Wellington & Jarvis
the Child-Turcotte criteria. The degree of alcohol
consumption during the study was determined by
serial determinations of GGT levels. However, al-
though it was reported that 26 and 33 patients in
the silymarin and placebo groups, respectively,
continued to drink, the degree of consumption was
not reported.[80]
Of the 87 patients treated with silymarin and the
83 who received placebo, 91 had active cirrhosis
(shown by liver biopsy) and 28 had cirrhosis with
alcoholic hepatitis. No biopsy could be obtained
from the remainder of the patients because of co-
agulation disorders. Among the silymarin group,
47 patients were classified Child-Turcotte A, 37
Child-Turcotte B and 3 Child-Turcotte C. Among
the placebo group, 42, 32 and 9 patients were clas-
sified Child-Turcotte A, B and C, respectively.[80]
23% (20 of 87, including 4 dropouts) of patients
receiving silymarin treatment died during the 2-
year trial compared with 33% (27 of 83, including
2 dropouts) in the placebo group (p = 0.07). A fur-
ther 8 and 12 patients given silymarin or placebo,
respectively, died during the extended study. Al-
though there was no significant difference in mor-
tality rates between all patients receiving silymarin
and all patients receiving placebo, 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; fig. 3, table IV).
However, there was no statistical difference be-
tween the silymarin and control groups in patients
with nonalcoholic cirrhosis, i.e. 34% versus 47%
died (fig. 3, table IV).
Furthermore, there was no significant between-
group difference in liver function parameters
throughout the trial. However, the cumulative 4-
year survival rate was significantly in favour of the
silymarin group (58%) compared with the placebo
group (38%; p = 0.036).[80]
16 patients who received silymarin died of liver-
related complications compared with 32 in the pla-
cebo group. Liver-related deaths included end-
stage liver failure, upper gastrointestinal tract
haemorrhage and hepatocellular carcinoma. Upon
subanalysis, the 4-year survival rate among pa-
tients classified as Child-Turcotte A was signifi-
BioDrugs 2001; 15 (7)
Silymarin: A Review
100
80 *
Patient survival rate (%)
60
40
20
0 penicillamine or corticosteroids or if they had a life
Alcoholic cirrhosis Nonalcoholic cirrhosis
Fig. 3. Efficacy of silymarin among patients with liver cirrhosis
in a randomised, double-blind, multicentre study. Survival rate
among 170 patients with alcoholic (n = 91) or nonalcoholic (n =
79) cirrhosis who were given silymarin 420 mg/day in 3 divided
doses (n = 46 and 41, respectively) or placebo (n = 45 and 38,
respectively) for a mean duration of 41 months. Among patients
with alcoholic cirrhosis, 10 vs 19 patients died in the silymarin
and placebo groups, respectively. Among patients with nonal-
coholic cirrhosis, 14 vs 18 patients died in the silymarin and
placebo groups, respectively.[80] * p = 0.01 vs placebo.
cantly improved with silymarin compared with
placebo; i.e. 78% versus 33% survived (p = 0.03).
However, in patients originally rated Child-Turcotte
B or C, 4-year survival rates were not significantly
different in the 2 groups.[80]
During the 2-year study period, 14 silymarin
recipients and 10 placebo recipients withdrew be-
cause of adverse effects (2 in each group), concom-
Table IV. Effect of oral silymarin (SIL) versus placebo (PL) on survival rate in patients with alcoholic liver disease; all trials were
randomised and double-blind
Reference (duration)
Bunout et al.[82] (mean 15mo)
Ferenci et al.[80] (mean 41mo)
Pars et al.[81] (2y)
a Number of doses was not reported.
b Silymarin was administered in 3 divided doses.
NR = not reported; * p = 0.01 vs PL (total deaths).
Adis International Limited. All rights reserved.
477
itant major nonhepatic disease, location change or
Silymarin
Placebo noncompliance.[80]
In another randomised, double-blind, multi-
centre trial involving 200 alcoholic patients with
histologically or laparoscopically proven liver cir-
rhosis (3 months prior to enrolment), silymarin
had no effect on survival or the clinical course of
liver cirrhosis.[81] Chronic alcoholism was defined
as an ethanol intake of over 80 g/day in men and
60 g/day in women. Patients were excluded if they
had ever been treated with colchicine, malotilate,
expectancy of <6 months. Patients were also ex-
cluded if they had other known aetiologies for liver
cirrhosis such as hepatitis B virus, primary biliary
cirrhosis, cryptogenic cirrhosis or autoimmunity.
However, a number of patients in both groups had
antihepatitis C antibodies. Stored sera of 75 pa-
tients was tested at the completion of the trial for
antibodies against hepatitis C virus; 29 patients (13
receiving silymarin and 16 placebo recipients)
tested positive. Although the degree of alcohol
consumption during the trial was determined by
questionnaire and urine assessment every 3 months,
these data were not reported. However, it was re-
ported that 39 and 28 silymarin or placebo recipi-
ents, respectively, continued to drink.[81]
Patients were randomised to receive silymarin
450 mg/day in 3 divided doses (n = 103) or placebo
(n = 97) for 2 years. The primary and secondary
efficacy variables were time to death and progres-
sion of liver failure, respectively.[81]
Treatment regimen (mg/day) Results at end-point
[no. of patients evaluated] no. of patients who died no. of patients who died
from hepatic causes from nonhepatic causes
SIL 280a [25] 5 NR
PL [34] 5 NR
SIL 420b [46] 6* 4*
PL [45] 14 5
SIL 450b [57] 9 6
PL [68] 13 1
BioDrugs 2001; 15 (7)
478
15 of 57 evaluable patients who received
silymarin died during the trial compared with 14 of
68 evaluable patients who received placebo (table
IV). End-stage liver failure was the cause of death
in 9 patients receiving silymarin and 13 patients
receiving placebo (table IV). Survival was similar
in both groups; the 5-year (intention-to-treat) sur-
vival rate in silymarin-treated patients was 71%
compared with 76% in the placebo group.[81] 57
patients dropped out of the trial: 15 failed to show
up after their first visit and 42 left during the first
2 years because of adverse events (2 in the
silymarin group and 1 placebo recipient), noncom-
pliance or voluntary withdrawal.
Similarly, silymarin did not change the clinical
progress or affect the patient mortality rate in a
randomised, double-blind study involving 72 pa-
tients with alcoholic liver disease.[82] Patients re-
ceived silymarin 280 mg/day or placebo for an
average of 15 months. Five patients in each group
died from hepatic causes during the trial (table IV).
There were no significant between-group differ-
ences in liver function parameters (serum levels of
bilirubin, alkaline phosphatase, albumin and GGT
and prothrombin time [PT]) before or at the con-
clusion of the trial (table V).[82]
4.1.2 Effects on Liver Function
The remaining studies investigated the ability of
silymarin to normalise parameters of liver function
(AST, ALT, GGT, bilirubin, alkaline phosphatase,
albumin and PT) which become abnormal during
liver-related diseases.
In a randomised, double-blind trial, silymarin
was significantly (p < 0.05) better at reducing ele-
vated serum indices of liver function than placebo
in patients with chronic alcoholic liver disease.[83]
36 patients were randomised to receive silymarin
420 mg/day in 3 divided doses or placebo for 6
months. Average alcohol consumption over the
preceding 8 years exceeded 60 g/day in men and
30 g/day in women. Patients did not have symp-
toms of encephalopathy, malnutrition or other as-
sociated diseases, and viral and immunological
markers were negative. Micronodular cirrhosis
was confirmed by histological examination.[83]
Adis International Limited. All rights reserved.
Wellington & Jarvis
During the course of silymarin treatment, mean
patient serum levels of bilirubin (which were
mildly elevated at baseline) normalised, and AST,
ALT (both of which had high normal levels at base-
line) and GGT levels decreased significantly com-
pared with baseline values (table V). However, al-
cohol consumption decreased significantly (p <
0.001) in both groups, which in itself would result
in an improvement of liver function parameters.
There was also a significant difference (p < 0.05)
between the treatment groups of the above values,
except for ALT levels, at the conclusion of the trial.
PT and serum levels of albumin remained un-
changed and normal in both groups throughout the
trial. Repeat liver biopsies did not demonstrate sig-
nificant differences between groups at end-point.
Clinical outcomes including morbidity and fre-
quency of hospitalisation were not reported.[83]
Similarly, in a randomised, double-blind, pla-
cebo-controlled trial involving 97 consecutive pa-
tients with liver disease induced by alcohol,
silymarin 420 mg/day significantly (p < 0.001) im-
proved serum levels of AST (which became nor-
mal) and ALT compared with placebo (table V).[84]
Patients with elevated serum levels of AST and
ALT (2 to 3 times higher than the upper normal
limit) received either silymarin 420 mg/day (n =
47) or placebo (n = 50) for 4 weeks. Alcohol intake
was not allowed during the trial, although how
many patients abstained was not reported.[84] The
effects of treatment on morbidity were also not re-
ported.
In a 6-month randomised crossover trial involv-
ing 27 patients with laparoscopy-biopsy confirmed
compensated active cirrhosis (and with AST and
ALT values 2 to 10 times the upper normal limit),
silymarin 420 mg/day or ursodeoxycholic acid 600
mg/day had no significant effect on patient serum
levels of ALT, AST or bilirubin.[77] Compared with
baseline values, serum GGT levels were signifi-
cantly (p < 0.01) decreased by ursodeoxycholic
acid but not by silymarin (table V). Serum trans-
aminases decreased in both treatment groups over
the 6-month period but the differences between
baseline and end-point were not significant (table
BioDrugs 2001; 15 (7)
Silymarin: A Review 479

Table V. Effect of oral silymarin (SIL) on liver function, as determined by extrahepatic biochemical parameters in patients with liver
disease of various aetiology: results from clinical trialsa
Reference (duration) No. of Treatment regimen Results: percentage change from baseline to end-point in serum levels of
patients (mg/day) liver function indices
evaluated AST ALT GGT bilirubin albumin alkaline
phosphatase
In patients with alcoholic liver cirrhosis
Bunout et al.[82] 19 SIL 280b 13c NR 11 14 13c 17c
(mean 15mo) 29 PL 32c NR 23 6 11c 14c
Fehr et al.[83] 17 SIL 420d 39*c 36c 58* 49*e 15c 6c
(6mo) 19 PL 19c 16c 24 14 7c 15c
Pars et al.[81] 57 SIL 450d 15 NC 18 13 11c 5
(2y) 68 PL 30 21 50 NC 17c NC
In patients with hepatic cirrhosis
Lirussi et al.[77] 27 SIL 420d 15 23 4 NC NR 9
(6mo) 27 URS 600f 30 21 53 NC NR 14

Tanasescu et al.[74] 30 SIL 420d NR 6 8 31 NR 1
(4mo)g 30 PL NR 24 22 16 NR 11
In patients with chronic active hepatitis

Tanasescu et al.[74] 30 SIL 420d NR 27* 26 30 NR 28
(4mo)g 30 PL NR 2 19 9 NR 13
In patients with chronic persistent hepatitis

Tanasescu et al.[74] 27 SIL 420d NR 16 27 16 NR 19
(4mo)g 30 PL NR 7 13 15 NR 4
In patients with acute viral hepatitis
Magliulo et al.[71] 28 SIL 420d 93*e 92e 59 72* NR 51c
(mean 24.9d) 29 PL 89e 89 52 46 NR 28c
In patients with acute or subacute alcohol-induced liver disease
Salmi et al.[84] 47 SIL 420b 30**e 41** NR 41 5c 9
(4wk) 50 PL 5 3 NR 4 2c 15c
[77]
a All trials were randomised and double-blind except for Lirussi et al which was randomised, nonblind and crossover.
b Number of daily doses not reported.
c Normal serum level at start of trial.
d Administered in 3 divided doses.
e Serum level normalised at end-point.
f Administered in 2 divided doses.
g Units of measurement of liver indices were not reported and, therefore, it is unknown if the values were abnormal at the start of the trial.
GGT = -glutamyl transferase; NC = no change; NR = not reported; PL = placebo; URS = ursodeoxycholic acid; = increase; = decrease;
* p < 0.05, ** p < 0.001 vs PL; p < 0.05, p < 0.01 vs baseline value.

V).[77] However, patient numbers and the duration
of treatment are insufficient to draw any conclusions.
In a large (n = 998) noncomparative study in
patients with chronic liver disease of varied aetiol-
ogy, clinical and laboratory indices improved dur-
ing treatment with silymarin for 3 months.[78] Pa-
tients were diagnosed with fatty liver (47%), fatty
liver hepatitis (20%) and hepatic cirrhosis (33%).
Causative factors were alcohol (61%), hepatitis B
or C (12%), chemicals in the workplace (2%),
drugs (8%) or in 21% of patients the cause was
unknown. Approximately 60% of the patients had
concomitant illnesses such as cardiovascular ail-
ments, endocrinopathies or metabolic disorders,
and of these patients 50.5% were being treated
with 1 or several concurrent medications. Most

Adis International Limited. All rights reserved. BioDrugs 2001; 15 (7)

480
frequently, these were drugs acting on the coronary
arteries, or were antihypertensives, antidiabetics,
drugs for gout or analgesics. There were also a
number of drugs acting on the liver (in 2.2% of
patients), e.g. ornithine aspartate and lactulose.
Approximately 50% of patients received 1
silymarin 140mg capsule 3 times daily. A further
38% took 2 capsules per day and 9% received 1
daily dose of silymarin 140mg. The mean period of
observation was 107 days.[78]
The percentage of patients with normal serum
levels of AST, ALT, bilirubin and alkaline phos-
phatase increased by more than 25% (actual values
not reported). Furthermore, 40% of patients whose
initial amino terminal procollagen III peptide
(PIIINP) levels were elevated at the start of treat-
ment had normal PIIINP levels after 3 months of
therapy.[78] Low or falling PIIINP levels in patients
with chronic liver diseases are regarded as pro-
gnostically favourable, as this implies an increase
in connective tissue metabolism in the liver (nota-
bly the formation and deposition of collagen).[78]
Silymarin 420 mg/day did not significantly af-
fect serum levels of AST, alkaline phosphatase, to-
tal bilirubin or albumin in 27 patients with primary
biliary cirrhosis who had experienced a suboptimal
response to ursodeoxycholic acid 13 to 15 mg/kg/
day for 7 to 221 months.[70]
4.2 Cirrhosis and Type 2 Diabetes Mellitus
Silymarin reduced lipid peroxidation of liver
cell membranes and decreased the endogenous pro-
duction of insulin and the need for exogenous in-
sulin in patients with type 2 diabetes mellitus and
alcoholic liver cirrhosis in a randomised, nonblind
study.[59] 60 patients were randomised to receive
silymarin 600 mg/day in 3 divided doses or placebo
for 12 months. Inclusion criteria included type 2
diabetes mellitus for at least 5 years with treatment
by insulin only for at least 2 years, negative mark-
ers for hepatitis A, B and C, and nonaddiction to
alcohol for at least 2 years. Cirrhosis was con-
firmed by liver biopsy within the 4 years preceding
the trial.
During the course of treatment with silymarin,
patient fasting blood glucose levels, daily blood
Adis International Limited. All rights reserved.
Wellington & Jarvis
glucose levels, daily glucosuria, glycosylated
haemoglobin levels, glucagon-stimulated C-pep-
tide levels, insulin requirement, fasting insulin val-
ues and mean blood levels of malondialdehyde (see
section 2.1) decreased significantly (p < 0.01) com-
pared with baseline values and with the corre-
sponding values obtained from patients in the pla-
cebo group (fig. 4).[59]
No statistically significant variations in protein-
uria or serum levels of GGT, bilirubin, alkaline
phosphatase, creatinine or haemachrome were
found in the 2 treatment groups.[59]
4.3 Amanita Mushroom Poisoning
Although there have been no controlled clinical
trials examining the therapeutic potential of
silymarin in patients with acute Amanita poison-
ing, there have been a number of case reports.[85-88]
However, the quantity of mushroom ingested is of-
ten not reported and patients usually received a
number of concomitant medications without an ad-
equate control. Therefore, the benefit of silymarin
in patients with Amanita poisoning is often diffi-
cult to determine.
In a retrospective study, Hruby et al.[85] reported
18 cases of mushroom poisoning treated intrave-
nously with silybin 33 mg/kg/day. 17 of the 18 pa-
tients made a full recovery and showed normal lab-
oratory parameters upon discharge. One patient
died as a result of a suicidal intake of the mush-
room. The 18 patients, aged 2 to 60 years, had vary-
ing degrees of liver damage caused by deathcap
mushroom (Amanita phalloides) ingestion. Diag-
nosis of Amanita poisoning was made on the basis
of case history, typical clinical course, increased
aminotransferase activity and lengthened PT. Sup-
portive diagnosis by way of liver biopsy was car-
ried out in 4 patients. The average time between
ingestion and hospitalisation was 29 hours and
general supportive management, including admin-
istration of benzylpenicillin in 16 patients, was
started immediately upon admission. Benzyl-
penicillin dosage regimens were inconsistent and
in some of the patients benzylpenicillin treatment
was stopped because of allergy. In addition, 8 pa-
BioDrugs 2001; 15 (7)
Silymarin: A Review 481

Silymarin bin treatment among patients with light, medium

20 Placebo and severe liver damage was 33.8, 46 and 71.5
10 hours, respectively, indicating a favourable effect
of treatment with silymarin on the course of Ama-
Change from baseline (%)

0 nita poisoning. However, the actual amount of ab-

sorbed toxin was not calculated, thus a definitive
10 conclusion regarding the efficacy of silybin cannot
*
be made.[85]
20 *
In an unpublished study[87] involving 154 cases
* of Amanita poisoning, the efficacy of silybin and
30
* silybin in conjunction with benzylpenicillin was
40
examined. 128 patients were treated with silybin
* * 20 mg/kg/day (the route of administration and du-
50 ration of treatment were not reported) in conjunc-
tion with benzylpenicillin and 26 patients received
e

ria

lin

de
en
tid

bi

su

hy
su

lo

m
ep

in
og

de

silybin 20 mg/kg/day alone. Patients were grouped

co

ire
-p

g
em
lu

al
qu
C

in
G

di
re

st
ed

ha

according to severity of poisoning. Grades I and II

on
Fa
lin
at

al
d
ul

te

su

included patients with severe vomiting and diar-

im

la

In
sy
St

co

rhoea (grade I) and a moderate rise in transami-

ly
G

Fig. 4. Effect of silymarin on liver function indices in patients with

alcoholic cirrhosis and type 2 diabetes mellitus. 60 patients were
randomised to receive silymarin 600 mg/day or placebo for 12
months in a nonblind study. Mean daily insulin requirement,
glucosuria and glycosylated haemoglobin levels were recorded
every 30 days. The remaining indices of liver function were
recorded every 3 months until the trial conclusion.[59] * p < 0.01
vs placebo and vs baseline; p < 0.01 vs baseline.
tients received prednisolone and a further patient
was given thioctic acid 300 mg/day.[85]
17 patients were given an average dosage of sily-
bin 33 mg/kg/day intravenously for a mean dura-
tion of 81.6 hours. Two patients received oral
silymarin tablets in addition to silybin, while 1 pa-
tient was given oral silymarin 1.4 to 4.2 g/day
alone.[85]
The mean interval between mushroom inges-
tion and the commencement of silybin treatment
was found to correlate significantly (p < 0.05) with
the severity of liver damage. Patients were retro-
spectively divided into 3 groups according to the
severity of liver damage: light (n = 5), medium (n
= 5) and severe (n = 8). The mean interval between
mushroom ingestion and commencement of sily-
nases (grade II). Grade III included patients with a
large rise in serum bilirubin levels. Grade IV in-
cluded patients with large rises in serum levels of
transaminases, bilirubin and creatinine, and a de-
crease in PT. 68 patients were in grade III, 16 of
whom received silybin as monotherapy. No pa-
tients with grade IV toxicity (n = 11) received sily-
marin as monotherapy.
100% of the patients who received only silybin
(n = 26) recovered, whereas 15 of 128 patients
(12%) who received silybin as well as benzyl-
penicillin died; all of these were in grade III or
IV.[87] However, if only severe cases of poisoning
were taken into consideration, 19% of patients died.
In a small case report of a family of 3 with light
to moderate poisoning by deathcap mushrooms,[86]
silymarin and silybin therapy in conjunction with
benzylpenicillin and cortisone was associated with
a rapid symptomatic recovery, with laboratory pa-
rameters sufficiently improved to allow discharge
after 12 days. The 3 patients were given oral sily-
marin 70 mg/kg in 2 divided doses and 4 hours
later, intravenous silybin 36 to 48 mg/kg for 4 days.
Benzylpenicillin 10ml (dosage not stated) was ad-
ministered concomitantly every 8 hours and pred-
nisolone 100mg was administered every 6 hours.[86]

Adis International Limited. All rights reserved. BioDrugs 2001; 15 (7)

482
4.4 Viral Hepatitis
The efficacy of silymarin in patients with viral
hepatitis has been evaluated in 5 controlled trials
(2 of which were reported together[72]); results
from these trials are mixed.[71-74]
In a randomised, double-blind, multicentre
study involving 59 patients with uncomplicated
acute viral hepatitis A or B, silymarin 420 mg/day
in 3 divided doses significantly reduced serum lev-
els of AST and bilirubin compared with placebo.
However, there were no significant between-group
differences with respect to serum levels of GGT,
ALT, alkaline phosphatase and cholinesterase, or
PT compared with placebo over a treatment period
of between 21 and 28 days (table V). Silymarin also
had no effect on serum markers for hepatitis B (e.g.
hepatitis B surface antigen).[71]
Furthermore, there were no between-group dif-
ferences in liver function parameters (actual data
not reported) in 3 randomised, double-blind trials
involving 187 patients with acute viral hepatitis (n
= 151, viral type not reported)[73] or chronic hepa-
titis (n = 24[72] and 12[72]) who were given sily-
marin 420 mg/day in 3 divided doses or placebo for
between 5 weeks[73] and 1 year.[72]
Similarly, while silymarin 420 mg/day signifi-
cantly improved some liver function parameters
compared with baseline values (table V), only se-
rum ALT levels in patients with chronic active hep-
atitis were significantly decreased with silymarin
compared with placebo in a randomised, double-
blind study involving 180 patients with chronic
persistent hepatitis, chronic active hepatitis or he-
patic cirrhosis. Hepatitis B serology was not re-
ported.[74]
However, in a noncomparative study reported as
an abstract,[79] serum levels of AST, ALT and GGT
were significantly reduced compared with baseline
values during treatment with silymarin 400 mg/day
in combination with ursodeoxycholic acid 500
mg/day for 8 months. 26 patients with chronic viral
hepatitis who did not respond to interferon- treat-
ment were included in the study. Serum levels of
AST were reduced from baseline by 22%, ALT by
30% and GGT by 40% (p < 0.04 for all 3 tests).
Adis International Limited. All rights reserved.
Wellington & Jarvis
4.5 Other Studies
Silymarin had no significant effect on tacrine-
induced elevated serum levels of ALT or AST in a
12-week, randomised, double-blind, placebo-con-
trolled trial among patients with Alzheimers dis-
ease.[76] 110 patients were given silymarin 420
mg/day (initiated 1 week before tacrine therapy)
and tacrine 40 mg/day for 6 weeks followed by a
dosage increase to 80 mg/day for a further 6 weeks;
112 patients received placebo and tacrine. Serum
levels of ALT or AST were similar in both groups
throughout the study. However, 83.9% of patients
were receiving undisclosed concomitant medica-
tions for comorbid conditions. These medications
may have had some effect on serum ALT and AST
levels.[76]
Among 49 patients who had haematological dis-
orders due to being exposed to toxic levels of tol-
uene and/or xylene, silymarin 420 mg/day signifi-
cantly improved platelet count (p < 0.05), serum
levels of AST (p < 0.01), ALT (p < 0.01) and GGT
(p < 0.05) but not leucocytosis or relative lympho-
cytosis in 30 patients compared with the 19 un-
treated patients.[75] Patients were divided into treat-
ment and nontreatment groups on the basis of sex,
physical status and lifestyle habits. Alcoholic pa-
tients were excluded from the study.[75]
5. Tolerability
In 2 trials involving 295 patients with liver
cirrhosis, 9 patients (4 of whom withdrew from treat-
ment) receiving silymarin 420 or 450 mg/day com-
plained of adverse events compared with 6 receiving
placebo. Adverse events included nausea, epigas-
tric discomfort, arthralgia, pruritus, headache and
urticaria.[80,81] In other trials,[59,71,73,74,82-84,89] no
adverse events were reported. However, assessment
of the tolerability of silymarin was often not in-
cluded in the trial designs.
Other adverse events possibly related to treat-
ment with silymarin have been reported in uncon-
trolled studies or case reports. Silymarin was re-
ported to cause a mild laxative effect in 4 of 24
patients who were being treated for exposure to
organophosphates. Patients received silymarin 420
mg/day for 30 days.[90]
BioDrugs 2001; 15 (7)
Silymarin: A Review
A 57-year-old woman experienced intermittent
episodes of sweating, nausea, colicky abdominal
pain, fluid diarrhoea, vomiting, weakness and col-
lapse after taking silymarin capsules (dosage not
reported).[91] This was confirmed on rechallenge
with silymarin. The patient was also taking ethinyl-
estradiol and amitriptyline. However, the investi-
gators were unable to confirm that silybin was re-
sponsible for the reactions and suggested that they
could have been caused by some other substance
contained in the capsules.[91] The Adverse Drug
Reactions Advisory Committee also reported 2
other isolated incidents: an 83-year-old man devel-
oped thrombocytopenia while receiving silymarin
(although whether silymarin was the cause was never
established) and another patient developed abdom-
inal pains, nausea, listlessness and insomnia.[91]
6. Dosage and Administration
Silymarin can be administered either as capsules
or tablets (usually 70 or 140mg) or as an infusion
of milk thistle fruits.[6,92,93] The German Commis-
sion E recommends a daily dosage of 12 to 15g of
crude herb or 200 to 400mg of silymarin calculated
as silybin.[6]
An infusion of crude silymarin extract can be
prepared by first crushing the seeds of Silybum
marianum to release the oils and flavonolignans.
However, because of the variable and low concen-
trations of silybin present in such an extraction,
infusions are recommended only for the treatment
of dyspepsia.[92]
6.1 Indications
The German Commission E indications for
silymarin are for the treatment of acute mushroom
poisoning (caused by Amanita spp.), adjunctive
treatment of hepatic cirrhosis with or without a his-
tory of ethanol abuse or concurrent chronic hepa-
titis C infection, adjunctive treatment of acute viral
hepatitis due to hepatitis A or B infection, and as a
nutritional supplement to promote healthy liver
function.[6,92]
Because silymarin is promoted as a food supple-
ment, rather than a drug, it is not subject to the
approval processes of the US Food and Drug Ad-
Adis International Limited. All rights reserved.
483
ministration (FDA). As such, the indications for
silymarin therapy are not FDA approved indica-
tions. Rigid quality control standards are not re-
quired for such herbal products, and some varia-
tion can occur in both the potency and purity of the
commercial preparations.[92]
6.1.1 Adjunctive Treatment of Hepatic Cirrhosis
Adult patients with hepatic cirrhosis, regardless
of prior history of ethanol abuse or concurrent hep-
atitis C infection, may receive silymarin 420 mg/
day (as capsules to be administered in 3 divided
doses) before meals. Patients should also abstain
from any alcohol consumption.[92] The duration of
treatment in clinical trials has been up to 4 years
(section 4.1).
6.1.2 Acute Mushroom Poisoning Caused
by Amanita spp.
A reliable history of the time course, symptoms
and description or specimens of the ingested mush-
room should be obtained, if possible, from adult
and paediatric patients with suspected mushroom
poisoning, as the treatment of the toxic ingestion
is specific to the species of mushroom.[92] How-
ever, if there is even a mere suspicion of deathcap
mushroom (Amanita phalloides) poisoning, spe-
cific antidote treatment should be started. Silybin
dihemisuccinate, a derivative of silybin (the main
active component of silymarin), is the most often
used treatment for acute Amanita poisoning. The
initial dosage should consist of silybin dihemi-
succinate 5 mg/kg by intravenous infusion over 1
hour followed by 20 mg/kg/day by continuous in-
fusion for 6 days.[94] Treatment should be discon-
tinued if the patient shows no sign of hepatic tox-
icity by the fourth day after ingestion of the fungi.
In Europe, silybin therapy is combined with
standard treatment such as aggressive fluid resus-
citation, activated charcoal, catharsis, intravenous
aqueous penicillin C, and occasionally haemo-
dialysis/haemoperfusion.[92]
6.2 Contraindications
There are insufficient data concerning the use
of silymarin during pregnancy and, therefore, it
should be used only when the benefits to the
BioDrugs 2001; 15 (7)
484
mother outweigh the risks to the fetus.[5,92] Further-
more, it is unknown if silymarin is excreted in
breast milk and a decision should be made whether
to discontinue breast feeding when taking sily-
marin.[92]
Silymarin should not be administered to chil-
dren under 12 years of age, unless the benefits out-
weigh the risks, because of a lack of adequate clin-
ical investigations.[5]
7. Place of Silymarin in the
Management of Hepatic Disorders
Silymarin is promoted as a herbal extract that
has liver regeneration properties, and is among the
most popular over-the-counter herbal preparations
in Europe.[1,5] Furthermore, approximately 30% of
US patients with chronic hepatic diseases take
silymarin in addition to their prescribed medica-
tions.[92]
Pharmacological studies in patients with liver
cirrhosis have demonstrated the ability of sily-
marin to increase SOD activity and expression in
erythrocytes and lymphocytes as well as increase
levels of glutathione and glutathione peroxidase
(section 2.2.1). Both SOD and the glutathione sys-
tem are associated with the physiological defence
against free radicals. Therefore, the ability of
silymarin to increase these parameters is indicative
of its antioxidant properties. This is also apparent
in studies that have demonstrated the ability of
silymarin to decrease serum levels of malon-
dialdehyde, an end-product of lipid peroxidation.
However, there have been no studies which clearly
link these effects to important health outcomes in
patients with liver disease.
7.1 Alcoholic Cirrhosis
In the US, 24% of liver cirrhosis cases are
caused by chronic alcohol consumption, while a
further 14% are attributable to chronic hepatitis C
in addition to alcoholism.[95] However, a study in
Germany reported that alcohol-related cirrhosis
was the third highest cause of death in men aged
between 25 and 60 years and that 60 to 70% of all
cases of cirrhosis were caused by alcohol.[4] Heavy
consumption of alcohol results in a number of liver
Adis International Limited. All rights reserved.
Wellington & Jarvis
abnormalities ranging from simple fatty liver
(steatosis) to steatohepatitis, cirrhosis and hepato-
cellular carcinoma.[96] Even when the liver disease
has advanced to cirrhosis, the best course of thera-
peutic action is abstinence from alcohol consump-
tion.[95] However, only a minority of patients can
achieve long term sobriety.
To date, no effective treatment has been found
for alcoholic cirrhosis. Although there have been
studies that have shown drugs such as colchicine,[97]
propylthiouracil,[98] malotiate,[99] S-adenosylme-
thionine,[100,101] insulin and glucagon[102] and cia-
nidol[103] may have some beneficial effect on the
clinical course of cirrhosis, unequivocal results
have not been forthcoming. As liver histology and
biochemical parameters can be measured quantita-
tively, these are useful measures of clinical pro-
gression. However, death (including liver-related
death) is the best measure of clinical progression.
Primary efficacy data from 3 trials[80-82] which
examined the therapeutic potential of silymarin in
patients with cirrhosis, and included patient sur-
vival as an end-point, demonstrated that silymarin
had no significant beneficial effect on patient sur-
vival (section 4.1). However, subanalyses indi-
cated benefit in 1 of the 3 studies,[80] thus indicat-
ing a need for a further large study in a well-defined
patient population.
In 1 of the trials, silymarin was more signifi-
cantly effective than placebo in patients with alco-
holic cirrhosis than in patients with nonalcoholic
cirrhosis, implying that the effect of silymarin may
be via the prevention of metabolic or toxic effect
of alcohol on the liver (60% of the patients with
alcoholic cirrhosis continued to consume alco-
hol).[80]
Silymarin was effective in reducing lipid per-
oxidation of liver cell membranes and decreasing
the endogenous production of insulin and the need
for exogenous insulin in patients with type 2 dia-
betes mellitus and alcoholic liver cirrhosis (section
4.2).[59]
Among the clinical trials that measured serum
indices of liver function in patients with hepatic
disorders,[71-74,77,81-84] 4 reported a significant im-
provement in biochemical parameters (section
BioDrugs 2001; 15 (7)
Silymarin: A Review
4.1.1, 4.1.2 and 4.3; table V), thereby strengthen-
ing the theory that silymarin exerts a hepatoprotec-
tive and regenerative effect upon liver cells. How-
ever, liver cells have an intrinsic regenerative
capacity and, therefore, a well designed study is
required to clearly demonstrate such an effect.
7.2 -Amanitin Poisoning
The clinical progress of poisoning by Amanita
phalloides (deathcap mushroom) and related species
(A. verna and A. virosa) often results in fatality,
even after therapeutic intervention.[104] -Amanitin,
the toxin relevant to human toxicology, can be fatal
at doses of 0.1 mg/kg. 100g of fresh deathcap
mushrooms contains about 8mg of -amanitin and
about 5.5mg of - and -amanitin.[105] Therefore, a
single deathcap mushroom (which weighs approx-
imately 50g freshly picked) could contain a lethal
dose for an adult of average size. Symptoms usu-
ally occur between 8 and 12 hours after ingestion
and include nausea, vomiting, abdominal cramps
and severe diarrhoea.[106] After 3 to 5 days, severe
hepatic disease with extensive necrosis of hepatic
cells leads to aggravation of the patients condi-
tion. During this phase, serum levels of ALT, AST,
bilirubin and alkaline phosphatase increase mark-
edly, and impaired synthesis of clotting factors
(which causes a blood coagulation deficiency) also
occurs.[106] Hepatic coma may follow and renal
failure may also occur.[105] Patients typically die
within 10 days of ingestion of the mushroom, de-
pending on the quantity they ingested (the ingested
dose is usually not reported). The overall mortality
rate based on 493 case studies compiled between
1919 and 1980 is between 22 and 30%.[106,107]
However, children under the age of 10 have ap-
proximately a 51% chance of death compared with
patients >10 years of age who have a mortality rate
of about 16.5%.[107] This is presumably because
children eat about the same amount of mushrooms
as an adult and therefore absorb a larger dose of
toxins per kilogram of bodyweight.[106]
Traditional therapy of Amanita poisoning in-
cludes penicillin, benzylpenicillin, other antibiot-
ics (e.g. sulfamethoxazole, chloramphenicol and
rifampicin), thioctic acid, haemoperfusion, blood
Adis International Limited. All rights reserved.
485
purification and general support, none of which,
apart from perhaps benzylpenicillin, provides a
high survival rate.[85] In cases of severe poisoning,
liver transplantation is a viable option.[108]
In a retrospective study involving 205 case reports
of Amanita poisoning, administration of benzyl-
penicillin and hyperbaric oxygenation was signif-
icantly more often associated with patient survival
than thioctic acid, sulfamethoxazole, exchange
transfusion, haemodialysis and treatment of the
haemorrhagic diathesis.[107]
Silymarin and/or silybin, in the 175 case reports
examined in this review, has shown some efficacy
in the treatment of Amanita poisoning (section
4.3). Of the 175 patients treated with silymarin,
only 8.6% died. However, 131 of the patients were
also receiving benzylpenicillin treatment. Of the
remaining 44 patients who received silymarin
alone, only 1 patient died and that was because of
a suicidal intake of mushroom. However, it is un-
certain how effective silymarin and/or silybin is in
patients with severe liver damage. The mean inter-
val between mushroom ingestion and the com-
mencement of silybin treatment was found to
correlate significantly with the severity of liver
damage. As such, patients who were treated with
silymarin <48 hours after mushroom ingestion
were less likely to experience severe liver damage.
Although the number of cases is relatively small
and the studies are noncomparative, silymarin ap-
pears to represent a viable option as a clinical an-
tidote to deathcap mushroom poisoning. Further
studies detailing the amount of ingested mushroom
and time elapsed before administration of sily-
marin in patients with severe poisoning are needed
to clarify its role in this indication.
7.3 Exposure to Toxic Substances
There have been numerous publications detail-
ing the protective abilities of silymarin, in vitro and
in animals, against a range of toxic substances in-
cluding paracetamol, iron, thallium, phenylhydra-
zine, cisplatin, CCl4 and ethanol (section 2.2.2, ta-
bles I and II). However, reports detailing the use of
silymarin in human patients with long term expo-
sure to toxic substances are relatively scarce.
BioDrugs 2001; 15 (7)
486
Silymarin significantly improved serum indices
of liver function in 44 patients who had been ex-
posed to toxic levels of toluene, xylene or organo-
phosphates, but not in patients exposed to tacrine
for 12 weeks (section 4.5). However, the patient
numbers are too small to make any conclusion re-
garding the efficacy of silymarin in the treatment
of patients who have been exposed to such toxins.
7.4 Viral Hepatitis
Silymarin was largely ineffective in the treat-
ment of patients with viral hepatitis (2 of the 5
randomised, double-blind trials showed an in-
crease in some liver function indices). The clinical
progression of the disease was not improved in any
of the studies (section 4.4).
7.5 Conclusions
The antioxidant properties of silymarin (a mix-
ture 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 an-
imal and human studies. However, studies evaluat-
ing 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 toler-
ability, in the treatment of alcoholic cirrhosis.
Moreover, silybin 20 to 48 mg/kg/day has shown
promise as an antidote for acute mushroom poison-
ing by Amanita phalloides; however, further stud-
ies 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 regener-
ation properties that silymarin is promoted as pos-
sessing.
References
1. Schuppan D, Jia J-D, Brinkhaus B, et al. Herbal products for
liver diseases: a therapeutic challenge for the new millen-
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ited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
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E-mail: demail@adis.co.nz
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