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Milk Thistle

Botanical Name: Silybum marianum (L.) Gaertner.
Pharmacopoeial Name: Fructus silybi mariae.
Synonyms: Carduus marianus L., Cnicus marianus L., Cnicus benedictus L.
Common Names: Milk thistle, St. Mary’s thistle, holy thistle, wild artichoke.

Summary Table
Drug/Class Interaction TypeMechanism and SignificanceManagement
Platinum chemotherapy
Alkylating agents
Silymarin reduces drug-induced nephrotoxicity by countering lipid peroxidation and cell membrane destabilization.
Silymarin may additively increase anticancer effects of platinum compounds.
Coadminister during and after platinum chemotherapy.
May be restorative retroactively.
Anthracycline chemotherapy
Drug cardiotoxicity reduced by silymarin.
Possible chemosensitization of resistant cells to anthracyclines. Drug transporter inhibition may be involved.
Coadminister silymarin as adjunctive to support protocols during and after anthracycline chemotherapy.
Hepatotoxic substances; various agents and classes
General drug-induced hepatotoxicity countered by silymarin coadministration through multiple mechanisms, including free-radical scavenging, reduced lipid peroxidation, membrane stabilization, and cirrhosis/fibrosis inhibition. Demonstrated for numerous drugs and xenobiotic toxins.
Wide clinical significance probable.
Coadminister especially in hepatically compromised patients requiring drugs that stress liver function.

Silymarin normalizes glycemic control, maintains islet integrity, reduces insulin requirement.
May protect against diabetic sequelae, especially in cirrhotic patients.
Coadminister, long term.
Nitroimidazole antiprotozoals
/ /
Coadministration of herb with drug may reduce drug availability by induction of drug-metabolizing enzymes.Avoid coadministration.
Preexisting herb use may require higher drug dose for therapeutic efficacy.
herb description



Related species

Silybum eburneum Coss and Dur.

Habitat and Cultivation

Originally a Mediterranean native, milk thistle is now naturalized in many parts of Europe and North America, in drier sunny soils. Considered an invasive weed in some areas, it is widely cultivated for commercial use.

Parts Used

Fruit, typically described as milk thistle seed.

Common Forms

Powdered or whole dried hulled seed.

  • Tincture, Fluid Extract:   50% ethanol.

  • Standardized Extract:   Solid concentrate 70:1, standardized to 70% to 80% silymarin (as silibinin).

herb in clinical practice


Long known as a liver remedy in European and American botanical medicine, milk thistle is now well documented as a hepatoprotective herb and is used as an antidote to liver intoxication with chemical and biological toxins, including alcohol and a range of hepatotoxic drugs. After German researchers identified the flavolignan complex “silymarin” as the active component of the ripe seeds in the late 1960s, silymarin became available as a purified concentrate, and pharmacological research focused on the effects of silymarin on the liver. Silymarin was found to have antioxidant properties and was able to reverse glutathione depletion; it stabilized cell membranes and modulated efflux pumps such as P-glycoprotein (P-gp); it promoted hepatic ribosomal ribonucleic acid (rRNA) synthesis and liver regeneration; and it exerted anticirrhotic effects through inhibition of the transformation of stellate hepatocytes into fibroblasts. Several controlled clinical trials have found silymarin increases survival in alcohol-induced cirrhosis. It is widely prescribed for these indications, particularly in Germany.

The herb is well tolerated, with negligible toxicity and an excellent safety record. In the United States the herb typically ranks just under the “top 10” in retail sales. The German Commission E approved the whole herb for dyspeptic complaints and separately approved silymarin isolates for toxic liver damage and supportively for chronic inflammatory liver disease and hepatic cirrhosis. 1 The World Health Organization (WHO) monograph approves the herb for supportive treatment of acute and chronic hepatitis and cirrhosis induced by alcohol, drugs, or toxins. 2 A survey in 1998 showed that milk thistle was the most common hepatoprotectant used by outpatients in gastroenterological clinics. 3 A recent Cochrane systematic review of 13 trials of milk thistle extracts for alcoholic or hepatitis B/C virus–related liver disease found that liver-related mortality across all trials was significantly reduced. However, the methodological quality of the trials was poor, and the highest-quality data did not support the efficacy of the herb by criteria of overall mortality, liver histology, or liver-related complications. 4 Recent research has focused more on the anticancer effects of silymarin, but at present, despite promising basic science results with silymarin, clinical trial evidence in the oncological setting is lacking. 5

It is important to distinguish among milk thistle seed extracts (whole herb), the flavolignan complex or “silymarin” present in small quantities in the whole herb but available as a concentrated solid extract, and silybin (also called silibinin), the predominant component among the flavolignan constituents, used as a reference for standardization. Most preclinical and clinical trials have used silymarin concentrate (see Key Constituents).

Historical/Ethnomedicine Precedent

Dioscorides mentions milk thistle use for snakebite, and the herb and seeds were used in Europe in the Middle Ages for liver conditions. The leaves have been used as a food, according to Culpeper, especially as a cleansing spring vegetable when well cooked, and were also considered to enhance milk production in nursing mothers. The ethanolic seed extract, which included the husks, was first promoted in the United States by Rademacher in 1841. The homeopathic physicians in the U.S. were enthusiastic about the remedy, which was included in the U.S. Homeopathic Pharmacopeia in 1878, where it is indicated for melancholy as well as varicose ulcers, among other uses. The Eclectic physician Ellingwood used the extract for hepatic indications closer to contemporary use, although other Eclectics viewed the seeds extracts as an “alterative.” Brinker 6 provides a comprehensive historical review of the migration of the herb into American botanical medicine.

Known or Potential Therapeutic Uses

Amanita mushroom poisoning, amenorrhea, chemotherapy adjunctive, cholestasis, cirrhosis, constipation, diabetic complications, dyspepsia, fatty liver, gallstones, hepatitis (drug, alcohol, or chemical induced), hepatoprotection, protective against skin cancer (phototherapy, ultraviolet B, or radiation induced), right-upper-quadrant pain (associated with jaundice, hepatomegaly, or gallstones), uterine hemorrhage, varicose veins, venous congestion/stasis.

Key Constituents

1.5% to 3.0% silymarin, a flavolignan complex of silybin and isosilybin (its stereoisomer), silychristin, and silydianin. Silybin is also called silibinin. Other flavolignans are present, but silibinin is the primary compound.

  • Flavonoids:   Quercetin, taxifolin, and dehydrokaempferol.

  • Lipids:   20% to 30% of the fruit is a lipid fraction, including linoleic acid and beta-sitosterol. Silymarin concentrates do not incorporate the broad spectrum of ingredient compounds, including the lipid fraction.

Therapeutic Dosing Range

  • Dried seed by infusion or decoction:   Up to 15 g per day.

  • Tincture/Fluid Extract:   Up to 8.5 mL 1:1 per day.

  • Standardized Extract:   Concentrated 200 to 800 mg 70% to 80% silymarin per day. Clinical trial doses have typically been 420 mg/day in divided dose. The most common proprietary form is a 140 mg per dose 36:1 to 44:1 extract (from an ethyl acetate extraction), known as Thisilyn in the United States or Legalon in Europe, standardized to approximately 80% silymarin as silibinin. Bioavailability of oral silymarin is very low, and preparations complexed with lipids such as phosphatidylcholine have been developed.

interactions review

Strategic Considerations

Therapeutic monographs for milk thistle are notable for an absence of established interactions with drugs. Herbalists regard the seeds as among the more benign, neutral, nontoxic foodlike botanicals in the materia medica; this is supported by the clinical trial data, which report negligible adverse effects, other than minimal incidence of mild gastric discomfort. 4 Toxicity studies corroborate this, with median lethal dose (LD50) tests failing to produce mortality at oral doses of 20 g/kg in rodents.

In practice, the herb is used to ameliorate the adverse effects of xenobiotics, including pharmaceuticals, particularly on the liver. These beneficial effects of milk thistle were first discovered through its ability to antidote to Amanita mushroom intoxication. 7 Subsequently, similar hepatoprotective effects were established for a wide range of industrial chemicals and poisons, including carbon tetrachloride (CCl4), tyramine beta-hydroxylase (TBH), and heavy metals. 8-15The mechanisms underlying these effects are multifactorial; they include antioxidant activity through free-radical scavenging, prevention of glutathione depletion and enhancement of superoxide dismutase (SOD) activity, prevention of lipid peroxidation, stabilization of hepatocyte cell membranes, stimulation of liver regeneration, promotion of hepatocyte protein and glycoprotein synthesis, and antifibrotic effects from prevention of collagen formation by stellate hepatocytes. Silymarin also chelates metals such as lead and thallium, exhibits anti-inflammatory effects (by lipoxygenase inhibition and other mechanisms), and has chemopreventive influences through its inhibition of intestinal beta-glucuronidase, modulation of carcinogen-metabolizing enzymes, and signal transduction effects (notably epidermal growth factor receptor [EGFR] inhibition) and kinase inhibition. Recent research on the pharmacology of silymarin has been reviewed. 16-22

The multiple mechanisms underlying the hepatoprotective properties of milk thistle seed connect a number of documented beneficial interactions between silymarin and hepatotoxic drugs. These are considered here as thematically related and are described later.

Effects on Drug Metabolism and Bioavailability

In vitro, silymarin has been shown to have some modulating effects on phase I and phase II drug-metabolizing enzymes, but the relevance of the limited available data is unclear. The few in vivo studies that have been performed suggest that clinically significant modulation of drug availability by silymarin on cytochrome P450 (CYP450) is unlikely . For example, the disposition of indinavir (a well-known substrate of both CYP3A4 and P-gp) is unaffected by milk thistle coadministration in healthy volunteers despite in vitro evidence of CYP3A4 and P-gp inhibition by silymarin. 23,24Effects on phase II drug conjugation through induction of glutathione- S-transferase and inhibition of beta-glucuronidase (affecting conjugated drug–glucuronides subject to enterohepatic recycling) are also possible. 25,26Effects on phase III (transporter proteins) may be significant, although at present this is extrapolated from in vitro data.

A universal problem, discussed throughout this text, is the issue of validity of such extrapolations, especially from nonphysiological concentrations used in vitro to in vivo clinical practice. This is particularly acute with silymarin, which has very low bioavailability and may only attain nanogram levels in the plasma after oral administration. 27 Weyhenmeyer et al. 28 found that at high oral doses (1270 mg silymarin per day, or approximately two to three times the normal therapeutic dose), peak plasma concentration of silibinin isomers in healthy volunteers was only 2.0 µg/mL. Preparations that complex silymarin with phosphatidylcholine (or lecithin) have superior bioavailability. 29-31

In vitro CYP450 modulation data can be summarized as follows: Beckmann-Knopp et al. 32 found no significant effect on 2E1, 2C19, 1A2, or 2A6 but significant inhibition of 3A4 and 2C9 (at IC50of 29-45 micromolar [µM]) with human liver microsomes and silibinin. Budzinski et al. 33 used dilutions of milk thistle whole-seed extract and found no significant effect on 3A4 using fluorometric assays with recombinant human enzymes. Venkataramanan et al. 34 used human hepatocytes and determined that 0.25 millimolar (a very high concentration) silymarin effected 100% inhibition of 3A4 and uridine glucuronosyltransferase (UGT1A). Zuber et al. 35 found that all three flavolignan components of silymarin exhibited dose-dependent competitive inhibition of 2D6, 2E1, and 3A4; however, doses were in excess of physiological levels in vivo, and interactions caused by enzyme inhibition were unlikely. Raucy 36 found that silymarin caused no significant changes in CYP3A4 messenger ribonucleic acid (mRNA) levels of human hepatocytes, suggesting that silymarin did not induce 3A4. Patel et al. 37 found a similar lack of effect on CYP3A4 mRNA and MDR1 mRNA in a CaCo-2 cell-line model. Sridar et al. 38 used recombinant enzymes and established that purified silibinin could effect a dose-dependent inhibition in vitro of 3A4 and 2C9. The potassium iodide (KI) values for 3A4 (166 µM) were not comparable to in vivo levels, although the lower value of 5.0 µM for 2C9 may be more clinically significant. Another rodent model was used to examine the effects of silymarin on drug-induced increases in 2E1 following chronic exposure to three 2E1 inducers. When the drugs were coadministered (for 12 weeks) with 50 mg/kg silymarin orally, 2E1 levels were not elevated. 39

Extrapolation from data that employ different milk thistle preparations or compounds (silibinin, silymarin, whole-seed extract) in a range of experimental models at widely varying concentrations is problematic. The significance of the lack of effect on in vivo indinavir pharmacokinetics has already been noted. 23,24This suggests that CYP3A4 is not inhibited in vivo despite the in vitro inhibition data. In fact, a small clinical trial by Rajnarayana et al. 40 suggested that silymarin pretreatment for 9 days at 140 mg/day significantly increased the clearance of 3A4/2C9 cosubstrate metronidazole, suggesting an in vivo induction effect. In a clinical study, Gurley et al. 41 examined the effects of herbal compounds on CYP450 in healthy volunteers by means of probe cocktails administered after 28 days of pretreatment with each botanical. Milk thistle was administered at 175 mg, standardized to 80% silymarin, twice daily. No significant changes were found in 1A2, 2D6, 2E1, or 3A4. The authors concluded that pharmacokinetic interactions with prescription pharmaceuticals were unlikely. Van Erp et al. 42 examined the effects milk thistle on the pharmacokinetics of irinotecan in six cancer patients. Irinotecan is a known substrate of CYP3A4 and UGT1A1. The administration of milk thistle (for 4 or 12 days) did not produce any significant change in irinotecan disposition.

The principal drug-metabolizing enzymes of phase II drug transformation are the uridine-5′-diphosphate glucuronosyltransferases (UGTs). This family of enzymes is primarily hepatic but is also distributed intestinally; it plays a key part in first-pass metabolism of drugs. Glucuronide conjugates are eliminated in the bile and, when hydrolyzed by beta-glucuronidase, undergo enterohepatic recirculation while the glucuronic acid recycles for use in further conjugation. There is in vitro evidence for silymarin-induced inhibition of UGT enzyme inhibition in a recombinant human enzyme model. 34,38However, a study with rodent hepatocyte model and in vivo liver models showed that UGT inhibition induced by galactosamine might be reversed by silymarin. 43 Some inhibitory effects have also been found on the glutathione- S-transferases (GSTs), also involved with phase II metabolism, in the rodent hepatocyte model. 44 These GST inhibition effects have not been identified in vivo, where the main action of silymarin is on the prevention of thiol depletion and promotion of thiol replenishment, particularly in conjunction with cysteine donors. 45 On balance, induction of GST seems probable, and enzyme increase has been demonstrated in rodent liver, lung, stomach, skin, and small bowel after systemic administration of silibinin at 50 mg/kg orally. 26 These authors suggest that phase II enzyme induction may underlie the chemopreventive properties of silymarin, as demonstrated especially with skin cancers. 18,46,47

Several herbal agents are now known to modulate drug transporters (phase III) at transcriptional and posttranscriptional levels. 48 Experimental data suggest that milk thistle flavolignans inhibit P-gp. This has been shown using the standard Caco-2 model in vitro, with drugs that are substrates of P-gp, such as digoxin, doxorubicin, vinblastine, and ritonavir. 37,49,50Nguyen et al. 51 used a pancreatic cell-line (Panc-1) that overexpresses the MRP-1 transporter protein to examine the effects of flavonoids on the accumulation of transporter substrates daunorubicin and vinblastine. Silymarin significantly inhibited transport of these drugs. Because of the interest in potential modulators of drug resiance in cancer therapy, structure/function studies have examined the effects of different compounds on transporter proteins. Semisynthetic derivatives of silibinin have been tested to be even more effective P-gp inhibitors than the natural parent compound. 52-54Combinations of flavonoid molecules in a “cocktail” from different botanicals, including silymarin sources, appear to have additive effects on inhibition of resistance to mitoxantrone in an MCF-7 in vitro model. 55 Once again, in vitro and in vivo data appear to be in conflict. For example, Gurley et al. 56 found that milk thistle supplementation for 2 weeks in healthy volunteers had no significant effect on any pharmacokinetic parameters of digoxin compared with rifampin and clarithromycin, used as positive controls for P-gp induction and inhibition, respectively.

In summary, in vivo pharmacokinetic interactions caused by milk thistle seem improbable, despite suggestions from in vitro studies. The case of metronidazole is a possible exception, as discussed later.

herb-drug interactions
Cisplatin and Related Platinum-Based Chemotherapy
Doxorubicin and Related Anthracycline Chemotherapy
Hepatotoxic Substances, Including Acetaminophen, Acetylsalicylic Acid, Antitubercular Agents, Butyrophenone and Phenothiazine Neuroleptics, Ethyl Alcohol, Halothane, Methandienone, Methotrexate, Nortriptyline, and Phenytoin
Metronidazole and Related Nitroimidazole Antiprotozoals
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Oral Contraceptives and Related Estrogen-Containing and Synthetic Estrogen and Progesterone Analog Medications
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  • 39.Tasduq S, Peerzada K, Koul S et al. Biochemical manifestations of anti-tuberculosis drugs induced hepatotoxicity and the effect of silymarin. Hepatol Res 2005;31:132-135.View Abstract
  • 40.Rajnarayana K, Reddy MS, Vidyasagar J, Krishna DR. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. Arzneimittelforschung 2004;54:109-113.View Abstract
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  • 42. Van Erp NPH, Baker SD, Zhao M et al. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 2005;11:7800-7806.
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  • 46.Zi X, Agarwal R. Modulation of mitogen-activated protein kinase activation and cell cycle regulators by the potent skin cancer preventive agent silymarin. Biochem Biophys Res Commun 1999;263:528-536.View Abstract
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  • 57.Bokemeyer C, Fels LM, Dunn T et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 1996;74:2036-2041.
  • 58.Gaedeke J, Fels LM, Bokemeyer C et al. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996;11:55-62.View Abstract
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