Milk Thistle

• How It Works

  Milk thistle and compounds derived from it are commonly used as herbal supplements for liver problems, but study results are mixed.

  Laboratory studies suggest that milk thistle or some of its compounds have protective effects on the liver, but other animal studies suggest negative effects when combined with chronic alcohol consumption.

  Studies in humans are mixed, and both a large survey and multicenter trial among patients with chronic hepatitis C did not find benefit on liver function tests with milk thistle. Other studies suggest milk thistle may reduce chemotherapy-induced hepatotoxicity in children with acute lymphoblastic leukemia and cisplatin-induced nephrotoxicity, as well as improve capecitabine-induced hand-foot syndrome and radiation therapy-induced mucositis.Topical administration of a silymarin gel was reported to reduce the severity of radiodermatitis and delay its occurrence.

• Purported Uses
  • To treat alcohol-induced liver damage or cirrhosis
    Some placebo-controlled trials suggest silymarin may be helpful in treating alcoholic liver disease or cirrhosis, but more study is needed.
  • To treat hepatitis
    A large survey and multicenter trial among patients with chronic hepatitis C did not find benefit on liver function tests with milk thistle. 
  • To prevent and treat drug-induced liver damage
    Laboratory, animal, and clinical trials suggest this use, although the effect varies by drug.
• Do Not Take If
  • You are taking cytochrome P450 3A4 substrate drugs: Milk thistle may increase the risk of side effects of these drugs.
  • You are taking UGT (Uridine 5’-diphospho-glucuronosyltransferase) substrate drugs: Milk thistle may increase the risk of side effects of these drugs.
  • You are taking sirolimus: Milk thistle may interfere with the clearance of this drug.
  • You are taking Haloperidol or Risperidone: 7 cases of pancreatitis were reported following concomitant use of milk thistle.
  • You are taking Aripiprazole: A case of hepatotoxicity was reported with combined use of milk thistle.
• Side Effects

  High doses of silibinin can elevate bilirubin and liver enzymes.

  Case reports
  GI symptoms: A patient experienced episodes of sweating, nausea, vomiting, diarrhea, abdominal pain, weakness, and collapse. Symptoms resolved after the patient discontinued use of milk thistle.
  Severe nosebleed: In a 25-year-old man, which may have been due to self-medication with aspirin, garlic, and milk thistle. His symptoms improved following treatment.

• Scientific Name

  Silybum marianum, Carduus marianum

• Clinical Summary

  Derived from the seed, pod, or fruit of milk thistle, the flavolignan silymarin is used primarily to manage various liver diseases. In vitro and animal studies suggest that flavonoids in milk thistle have antioxidant and anticancer effects ^{(7) (8) (12) (16) (17)}, and may protect against Alzheimer’s disease ^(23) (24).

  Clinical data suggest benefits of supplementation with milk thistle or silymarin for improving lipid profiles and glycemic indices in type 2 diabetic patients ^(18) (40). It may also be useful against alcoholic liver disease ⁽⁹⁾, cirrhosis ^(11) (19), and for improving fibrosis associated with nonalcoholic steatohepatitis ⁽³⁹⁾. However, in both a large survey and subsequent multicenter placebo-controlled trial among patients with chronic hepatitis C, silymarin did not significantly reduce serum ALT levels ^(41) (42). In addition, although silymarin was associated with reduced progression from fibrosis to cirrhosis, there was no impact on clinical outcomes was ⁽⁴³⁾. Milk thistle was also reported no more effective than placebo against trichotillomania in a study involving both adults and children ⁽⁴⁶⁾.

  Other studies suggest milk thistle may reduce chemotherapy-induced hepatotoxicity in children with acute lymphoblastic leukemia ⁽²⁰⁾, and cisplatin-induced nephrotoxicity ⁽²⁸⁾ as well as improve capecitabine-induced hand-foot syndrome ⁽⁶⁾ and radiation therapy-induced mucositis ⁽³⁾. Topical administration of a silymarin gel was reported to reduce the severity of radiodermatitis and delay its occurrence ⁽⁴⁷⁾.

  Both silymarin ⁽²⁷⁾ and silibinin ⁽⁴⁸⁾ have estrogenic effects with greater affinity for estrogen receptor (ER-beta), and activation of ER-beta results in suppression of cell growth.
  Silibinin can exacerbate the negative effects of chronic alcohol consumption on liver cancer ⁽¹⁰⁾.

• Purported Uses
  • Cancer prevention
  • Cirrhosis
  • Drug-induced hepatotoxicity
  • Hepatitis
  • Liver disease
• Mechanism of Action

  Animal models suggest that silymarin confers hepatoprotection via downregulation of extracellular matrix proteins such as collagen ⁽²⁾. It may also be useful against liver carcinogenesis by inhibiting mast cells, a source of matrix metalloproteins that are involved in invasion and angiogenesis ⁽²⁹⁾. In addition, silymarin reduced cisplatin-induced kidney damage in rats without diminishing the drug’s antitumor activity ⁽⁷⁾, and suppressed formation of amyloid beta-proteins 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 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 hepatitis C viral infection by affecting endosomal trafficking of virions ⁽³⁴⁾.

  Other studies indicate milk thistle flavonoids exert anticancer effects by arresting G1 and S phases of the cell cycle ⁽⁸⁾. Silybin inhibited hepatocellular carcinoma cell growth via the Notch signaling pathway ⁽³⁶⁾. 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⁾. Suggested mechanisms for reduced efficacy of silibinin in liver tumor-bearing animals that were co-administered ethanol include impaired hepatic processing of silibinin ⁽¹⁰⁾.

  Silybin and isosilybin were shown to strongly inhibit PXR-mediated CYP3A4 induction ⁽³⁵⁾.

• Adverse Reactions

  High doses of silibinin can elevate bilirubin and liver enzymes ⁽²⁵⁾.

  Case reports
  Intermittent GI symptoms: A patient experienced intermittent episodes of sweating, nausea, vomiting, diarrhea, abdominal pain, weakness, and collapse that resolved after discontinuation of milk thistle supplementation ⁽⁵⁾.
  Severe epistaxis: In a 25-year-old man, possibly due to self-medication with aspirin, garlic, and milk thistle. His symptoms improved following treatment  ⁽²²⁾.

• Herb-Drug Interactions
  • Cytochrome P450 3A4 substrates: Milk thistle inhibits cytochrome P450 3A4 ⁽⁴⁾ and can affect the intracellular concentration of drugs metabolized by this enzyme. However, conflicting data indicate no such effects ^{(13) (14) (38)}. In 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⁾.
  • Sirolimus: Milk thistle may decrease clearance. Monitor therapy especially when combined with nivolumab, which may interfere with the potential to help prevent rejection of donor kidney in transplant patients ^(44) (45).
  • Haloperidol or Risperidone: 7 cases of pancreatitis were reported following concomitant use of milk thistle ⁽⁴⁹⁾
  • Aripiprazole: A case of hepatotoxicity was reported with combined use of milk thistle ⁽⁴⁹⁾.
• References

  1. Bissett N, et al. Herbal Drugs and Phytopharmaceuticals. New York: Medpharm, CRC Press; 1994.

  2. 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.

  3. Elyasi S, Hosseini S, Niazi Moghadam MR et al. Aledavood SA, Karimi G. Effect of Oral Silymarin Administration on Prevention of Radiotherapy Induced Mucositis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phytother Res. 2016 Nov;30(11):1879-1885. doi: 10.1002/ptr.5704.

  4. 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.

  5. Adverse Drug Reactions Advisory Committee. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust. 1999;170:218-9.

  6. Elyasi S, Shojaee FSR, Allahyari A, et al. Topical Silymarin Administration for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phytother Res. 2017 Sep;31(9):1323-1329. doi: 10.1002/ptr.5857.

  7. 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.

  8. Tyagi A, et al. Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells. Prostate 2002 ;53:211-217.

  9. Feher J, et al. Liver-protective action of silymarin therapy in chronic alcoholic liver diseases. Orv Hetil. 1989;130:2723-7.

  10. Brandon-Warner E, Eheim AL, Foureau DM, et al. Silibinin (Milk Thistle) potentiates ethanol-dependent hepatocellular carcinoma progression in male mice. Cancer Lett. Dec 29 2012;326(1):88-95.

  11. Ferenci P, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol.1989;1:105-13.

  12. 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.

  13. 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.

  14. Fuhr U, Beckmann-Knopp S, Jetter A, et al. The effect of silymarin on oral nifedipine pharmacokinetics. Planta Med. 2007;73(14):1429-35.

  15. 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.

  16. Ramasamy K and Agarwal R. Multitargeted therapy of cancer by silymarin. Cancer Lett. 2008 Oct 8;269(2):352-62.

  17. 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.

  18. 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.

  19. 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.

  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.

  21. 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.

  22. 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.

  23. 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 Nov 23;74(11):2299-306.

  24. Yin F, Liu J, Ji X, et al. Silibinin: A novel inhibitor of Aβ aggregation. Neurochem Int. 2011 Feb;58(3):399-403.

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010 Oct;24(10):1423-32.

  38. 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.

  39. Wah Kheong C, Nik Mustapha NR, Mahadeva S. A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. Dec 2017;15(12):1940-1949.e1948.

  40. Ebrahimpour-Koujan S, Gargari BP, Mobasseri M, et al. Lower glycemic indices and lipid profile among type 2 diabetes mellitus patients who received novel dose of Silybum marianum (L.) Gaertn. (silymarin) extract supplement: A Triple-blinded randomized controlled clinical trial. Phytomedicine. May 15 2018;44:39-44.

  41. Seeff LB, Curto TM, Szabo G, et al. Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology. Feb 2008;47(2):605-612.

  42. Fried MW, Navarro VJ, Afdhal N, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA. Jul 18 2012;308(3):274-282.

  43. Freedman ND, Curto TM, Morishima C, et al. Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther. Jan 2011;33(1):127-137.

  44. Jiao Z, Shi XJ, Li ZD, et al. Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients. Br J Clin Pharmacol. Jul 2009;68(1):47-60.

  45. Barnett R, Barta VS, Jhaveri KD. Preserved Renal-Allograft Function and the PD-1 Pathway Inhibitor Nivolumab. N Engl J Med. Jan 12 2017;376(2):191-192.

  46. Grant JE, Redden SA, Chamberlain SR. Milk Thistle Treatment for Children and Adults with Trichotillomania: A Double-Blind, Placebo-Controlled, Crossover Negative Study. J Clin Psychopharmacol. 2019 Mar/Apr;39(2):129-134.

  47. Karbasforooshan H, Hosseini S, Elyasi S, Fani Pakdel A, Karimi G. Topical silymarin administration for prevention of acute radiodermatitis in breast cancer patients: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2019 Feb;33(2):379-386.

  48. Dupuis ML, Conti F, Maselli A, et al. The Natural Agonist of Estrogen Receptor β Silibinin Plays an Immunosuppressive Role Representing a Potential Therapeutic Tool in Rheumatoid Arthritis. Front Immunol. 2018 Aug 17;9:1903.

  49. Woroń J, Siwek M. Unwanted effects of psychotropic drug interactions with medicinal products and diet supplements containing plant extracts. Psychiatr Pol. 2018 Dec 29;52(6):983-996.