Health Care Professional Information
Silybum marianum, Carduus marianum
Holy thistle, lady’s thistle, Mary thistle, Marian thistle
- Cancer prevention
- Drug-induced hepatotoxicity
- Food poisoning
- Liver disease
- Flavolignans: Silymarin, a mixture of silybinin, silidyanin, silychristin
- Tocopherol sterols: Cholesterol, capesterol, stigmasterol, and sitosterol
- Other constituents: Taxifolin, quercetin, dihydrokaempferol, kaempferol, apigenin, naringin, eriodyctiol, chrysoeriol, linoleic acid, palmitic acid
Mechanism of Action
Silymarin, a mixture of flavonoids derived from the seeds of milk thistle, is believed to be the active component responsible for the herb's hepatoprotective effects. Studies done in mice show that silymarin confers hepatoprotection, attributed to its down regulation of extracellular matrix proteins such as collagen, against thioacetamide-induced liver damage in mice (2). It may also be useful against liver carcinogenesis by negatively affecting the activity of mast cells, a source of matrix metalloproteins that are involved in invasion and angiogenesis (29). Silymarin reduced cisplatin-induced kidney damage in rats without diminishing its anti-tumor activity (7). It may play a role in preventing Alzheimer's disease: studies show that it suppressed formation of amyloid beta-protein and neurotoxicity in mice (30).
Silibinin, one of the flavonoids, demonstrated antioxidant and anti-inflammatory effects by inhibiting release of hydrogen peroxide and production of tumor necrosis factor alpha (31). Another study showed improvement in endothelial dysfunction in mice by silibinin via reduction in circulating and vascular asymmetric dimethylarginine (ADMA) levels. ADMA is an endogenous inhibitor of nitric oxide synthase (NOS) and is believed to play a role in endothelial dysfunction, associated with cardiovascular disease (32). Silibinin also inhibits the early phase of HepatitisC viral infection by affecting endosomal trafficking of virions (34).
Silybin and isosilybin were also shown to act as strong inhibitors of PXR-mediated CYP3A4 induction (35).
Other studies indicate the flavonoids in milk thistle exert anticancer effects by arresting G1 and S phases of the cell cycle (8). Silibinin suppressed the epidermal growth factor receptor (EGFR)-induced expression of CD44 (the transmembrane receptor for hyaluronan, implicated in tumor cell invasion and metastasis) by inhibiting EGFR activity in breast cancer cells (33).
Silybin was also shown to inhibit growth of hepatocellular carcinoma cells via the Notch signaling pathway (36).
Following oral administration, milk thistle is poorly absorbed from the gastrointestinal tract with a bioavailability of approximately 23-47%. Peak plasma concentrations occur within 2-4 hours (3). Milk thistle inhibits cytochrome p450 isoenzyme 3A4 and has an elimination half-life of approximately 4 hours. 30-40% of administered dose can be recovered from the bile as both glucuronide or sulfate conjugates and 2-5% is excreted in the urine (4).
Case report: A patient experienced intermittent episodes of sweating, nausea, vomiting, diarrhea, abdominal pain, weakness and collapse that resolved after discontinuation of milk thistle supplementation (5).
Case report: A 25-year-old man developed a severe case of epistaxis, which may have been due to his self medicating with aspirin, garlic, and milk thistle. His symptoms improved following treatment (22).
Clinical study: At high doses, silibinin can elevate bilirubin and liver enzymes (25).
- Cytochrome P-450 3A4 substrates: Milk thistle inhibits cytochrome P-450 3A4 (4) and can affect the intracellular concentration of drugs metabolized by this enzyme. However, conflicting data indicate no such effects (13) (14) (38).
According to another study, consumption of milk thistle did not reduce levels of indinavir, an AIDS drug (15).
- UGT (Uridine 5'-diphospho-glucuronosyltransferase) substrates: Milk thistle modulates UGT enzymes in vitro and can increase the side effects of drugs metabolized by them (26).
Literature Summary and Critique
Dosage (Inside MSKCC Only)
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- Bissett N, et al. Herbal Drugs and Phytopharmaceuticals. New York: Medpharm, CRC Press; 1994.
Chen IS, Chen YC, Chou CH, et al. Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis. J Sci Food Agric. 2012 May;92(7):1441-7.
- Schandalik R, Perucca E. Pharmacokinetics of silybin following oral administration of silipide in patients with extrahepatic biliary obstruction. Drugs Exp Clin Res. 1994;20:37-42.
- Venkataramanan R, et al. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucoronosyl transferase in human hepatocyte cultures. Drug Metab Dispos. 2000;28:1270-3.
- Adverse Drug Reactions Advisory Committee. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust. 1999;170:218-9.
- Brinker F. Herb Contraindications and Drug Interactions, 2nd ed. Sandy (OR): Eclectic Med; 1998.
- Kohno H, et al. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer. 2002;101:461-8.
- Tyagi A, et al. Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells. Prostate 2002 ;53:211-217.
- Feher J, et al. Liver-protective action of silymarin therapy in chronic alcoholic liver diseases. Orv Hetil. 1989;130:2723-7.
- Salmi HA, et al.Effect of Silymarin on chemical, functional, and morphological alterations of the liver: a double blind study. Scand J Gastroenterol. 1982;17:517-21.
- Ferenci P, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol.1989;1:105-13.
- Thelen P, Wuttke W, Jarry H, Grzmil M, Ringert RH. Inhibition of telomerase activity and secretion of prostate specific antigen by silibinin in prostate cancer cells. J Urol. 2004 May;171(5):1934-8.
- Gurley B, Hubbard MA, Williams KD, et al. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J Clin Pharmacol. 2006 ;46(2):201-13.
- Fuhr U, Beckmann-Knopp S, Jetter A, et al. The effect of silymarin on oral nifedipine pharmacokinetics. Planta Med. 2007;73(14):1429-35.
- Mills E, Wilson K, Clarke M, et al. Milk thistle and indinavir: a randomized controlled pharmacokinetics study and meta-analysis. Eur J Clin Pharmacol. 2005;61(1):1-7.
- Ramasamy K and Agarwal R. Multitargeted therapy of cancer by silymarin. Cancer Lett. 2008 May 8.
- Verschoyle RD, Greaves P, Patel K, et al. Evaluation of the cancer chemopreventive efficacy of silibinin in genetic mouse models of prostate and intestinal carcinogenesis: relationship with silibinin levels. Eur J Cancer. 2008 ;44(6):898-906.
- Huseini HF, Larijani B, Heshmat R, et al. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Phytother Res. 2006;20(12):1036-9.
- Saller R, Brignoli R, Melzer J, Meier R. An updated systematic review with meta-analysis for the clinical evidence of silymarin.Forsch Komplementmed 2008;15(1):9-20.
- Ladas EJ, Kroll DJ, Oberlies NH, et al. A Randomized, Controlled, Double-Blind, Pilot Study of Milk Thistle for the Treatment of Hepatotoxicity in Childhood Acute Lymphoblastic Leukemia (ALL).Cancer. 2010;116(2):506-13.
- Payer BA, Reiberger T, Rutter K, et al. Successful HCV eradication and inhibition of HIV replication by intravenous silibinin in an HIV-HCV coinfected patient. J Clin Virol. 2010 Oct;49(2):131-3.
- Shakeel M, Trinidade A, McCluney N, Clive B. Complementary and alternative medicine in epistaxis: a point worth considering during the patient's history. Eur J Emerg Med. 2010 Feb;17(1):17-9.
- Murata N, Murakami K, Ozawa Y, et al. Silymarin attenuated the amyloid â plaque burden and improved behavioral abnormalities in an Alzheimer's disease mouse model. Biosci Biotechnol Biochem. 2010 Nov 23;74(11):2299-306.
- Yin F, Liu J, Ji X, et al. Silibinin: A novel inhibitor of Aâ aggregation. Neurochem Int. 2011 Feb;58(3):399-403.
- Flaig TW, Gustafson DL, Su LJ, et al. A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest New Drugs. 2007 Apr;25(2):139-46.
- Mohamed ME, Frye RF. Effects of herbal supplements on drug glucuronidation. Review of clinical, animal, and in vitro studies. Planta Med. 2011 Mar;77(4):311-21.
- El-Shitany NA, Hegazy S, El-Desoky K. Evidences for antiosteoporotic and selective estrogen receptor modulator activity of silymarin compared with ethinylestradiol in ovariectomized rats. Phytomedicine. 2010 Feb;17(2):116-25.
- Ninsontia C, Pongjit K, Chaotham C, Chanvorachote P. Silymarin selectively protects human renal cells from cisplatin-induced cell death. Pharm Biol. 2011 Oct;49(10):1082-90.
Ramakrishnan G, Jagan S, Kamaraj S, Anandakumar P, Devaki T. Silymarin attenuated mast cell recruitment thereby decreased the expressions of matrix metalloproteinases-2 and 9 in rat liver carcinogenesis. Invest New Drugs. 2009 Jun;27(3):233-40.
- Murata N, Murakami K, Ozawa Y, et al. Silymarin attenuated the amyloid β plaque burden and improved behavioral abnormalities in an Alzheimer's disease mouse model. Biosci Biotechnol Biochem. 2010;74(11):2299-306.
- Bannwart CF, Peraçoli JC, Nakaira-Takahagi E, Peraçoli MT. Inhibitory effect of silibinin on tumour necrosis factor-alpha and hydrogen peroxide production by human monocytes. Nat Prod Res. 2010 Nov;24(18):1747-57.
- Li Volti G, Salomone S, Sorrenti V, et al. Effect of silibinin on endothelial dysfunction and ADMA levels in obese diabetic mice. Cardiovasc Diabetol. 2011 Jul 14;10:62.
- Kim S, Han J, Kim JS, et al. Silibinin suppresses EGFR ligand-induced CD44 expression through inhibition of EGFR activity in breast cancer cells. Anticancer Res. 2011 Nov;31(11):3767-73.
- Blaising J, Lévy PL, Gondeau C, et al. Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking. Cell Microbiol. Cell Microbiol. 2013 Nov;15(11):1866-82.
- Mooiman KD, Maas-Bakker RF, Moret EE, et al. Milk Thistle's Active Components Silybin and Isosilybin: Novel Inhibitors of PXR-mediated CYP3A4 Induction. Drug Metab Dispos. 2013 Aug;41(8):1494-504.
- Zhang S, Yang Y, Liang Z, et al. Silybin-mediated inhibition of notch signaling exerts antitumor activity in human hepatocellular carcinoma cells. PLoS One. 2013 Dec 27;8(12):e83699.
- Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010 Oct;24(10):1423-32.
- Kawaguchi-Suzuki M, Frye RF, Zhu HJ, et al. The Effects of Milk Thistle (Silybum marianum) on Human Cytochrome P450 Activity. Drug Metab Dispos. 2014 Oct;42(10):1611-6.
How It Works
Bottom Line: Milk thistle protects against alcohol-induced liver damage, and even reverses its effects in some cases. Whether it can treat other liver diseases is not clear.
Laboratory studies support milk thistle's liver protective effects. For example, when rats fed milk thistle are given toxins and drugs that are known to be toxic to the liver, they are protected from liver damage compared to rats not given milk thistle. Scientists think that silymarin, a compound in milk thistle, alters and stabilizes the structure of the liver cells so that toxins cannot enter them as easily. In addition, it stimulates the synthesis of proteins, which is an important part of cell growth and regeneration after damage.
Studies also show that milk thistle may protect against Alzheimer's disease and has anticancer activity against colon and prostate cancer cells. Silymarin was shown to have estrogenic effects in rats. It is not known if these effects occur in the human body.
- To prevent and treat alcohol-induced liver damage
Laboratory data and several clinical trials support this use.
- As an antidote to poisonous mushrooms (such as Amanita phalloides)
No scientific evidence supports this use.
- To prevent and treat drug-induced liver damage
Laboratory, animal, and clinical trials support this use, although the effect varies by drug.
- To treat dyspepsia (gastrointestinal upset)
Some clinical trials support this use.
- To treat cirrhosis of the liver
Clinical trials support this use, specifically for patients with alcohol-induced cirrhosis.
- To treat hepatitis
Laboratory studies show that milk thistle protects and promotes regeneration of the liver.
- As supportive therapy for chronic inflammatory liver disease
Laboratory studies show that milk thistle protects and promotes regeneration of the liver.
Fifty children with acute lymphoblastic leukemia (ALL) and liver toxicity were randomized to receive milk thistle (240 mg capsule containing 80 mg of silibinin) or placebo orally for 28 days. Supplementation began the day after the children received intravenous chemotherapy. Liver function tests were conducted through the study period. Researchers observed significant reductions in the levels of aspartate amino transferase (AST) and amino alanine transferase (ALT) in patients on milk thistle compared to those who took placebo. Further, milk thistle did not interfere with the chemotherapy. Larger studies are needed to establish the efficacy of milk thistle as a supportive agent.
Do Not Take If
- You are taking drugs that are substrates of Cytochrome P450 3A4 (milk thistle may increase the risk of side effects of these drugs).
- You are taking drugs that are substrates of UGT (Uridine 5'-diphospho-glucuronosyltransferase) enzymes (Milk thistle may increase the risk of side effects of these drugs).
- Case report: A patient experienced episodes of sweating, nausea, vomiting, diarrhea, abdominal pain, weakness, and collapse after taking milk thistle. These symptoms resolved after the patient discontinued use of milk thistle.
- Case report: A 25-year-old man developed a severe case of epistaxis (nosebleed), which may have been due to his self medication with aspirin, garlic, and milk thistle. His symptoms improved following treatment.
- Clinical study: At high dosage, silibinin can elevate bilirubin and liver enzymes.
Last updated: September 3, 2014