INDEX

Milk Thistle (Silybum marianum 2)

Indications

Liver disease including cirrhosis, cancer prevention, supporting liver function and metabolism of glucose (e.g., diabetes, metabolic syndrome, hyperglycemia, and insulin resistance), lipids (hyperlipidemia) and hormones, hepatitis and viral-induced inflammation, and protection from exogenous chemicals and toxins1 (parenteral preparations have become established as a viable treatment to save the liver after acute ingestion of hepatotoxins such as poison mushrooms2,3).

Mechanism of Action

Nearly all of the research on Silybum has focused on the silymarin complex, a mixture of flavonolignans obtained from the seeds. Silymarin includes the individual flavonolignans silybin A and silybin B (two isomers, together referred to as silibinin4), isosilybin A and isosilybin B (two isomers), silydianin, and silychristin. Silymarin also contains fatty acids5 and a flavonone dihydroquercetin (taxifolin),6 also credited with medicinal effects. Silybin is sometimes mixed with phosphatidylcholine to treat liver disease.7

At an adequate dose, Silybum metabolites can be detected in the urine, peaking in 2 hours and continuing to be excreted for 48 hours, mostly in the form of monoglucuronides, followed by sulfate-glucuronides and diglucuronides, respectively, indicating a strong affinity for hepatic phase II enzymes.8

Silybum flavonolignans have significant antioxidant and membrane-stabilizing effects on hepatocytes.9 They improve hepatic regulation of plasma lipoproteins,10 increase protein synthesis in hepatocytes by stimulating RNA polymerase I activity,11 and significantly improve liver enzymes in various liver diseases.12 Specific investigations on antioxidant actions are numerous and include an ability to protect from a wide variety of hepatotoxins (listed below) and promote superoxide dismutase, leading to regeneration of glutathione within liver cells.13

As a group the silymarin flavonolignans show numerous anti-inflammatory and immune-modulating actions including inhibition of hepatitis C virus (HCV) cell culture infection, NS5B polymerase activity, tumor necrosis factor (TNF)-α–induced nuclear factor-κB transcription, virus-induced oxidative stress, and T-cell proliferation.14 Silymarin enhances hepatic glutathione generation by elevating cysteine availability, increasing cysteine synthesis, and inhibiting its catabolism to taurine. Animal studies suggest that silymarin increases sulfur distribution and activity, up-regulating trans-sulfuration of homocysteine or S-adenosyl methionine into cystathionine, cysteine, and glutathione, all of which are significant in liver detoxification.15

Silibinin is considered one of the most active hepatoprotective constituents of Silybum seeds. It is one of the agents believed to protect mitochondrial function, and it has been shown to increase hepatocellular ATP when studied in isolation.16 Oil from Silybum seeds also attenuates oxidative damage and liver mitochondrial dysfunction in aging mice.5

Evidence-Based Research

Much of the clinical and animal research on the use of Silybum in various liver diseases shows antifibrotic17,18,19 anti-cirrhotic, and hepatoprotective effects via reduction of oxidative and inflammatory stress and support of hepatocyte function. For several decades now, Silybum has been shown to have broad hepatoprotective and metabolic effects including antioxidant and anti-inflammatory activities, cell permeability regulation and membrane stabilization, stimulation of liver regeneration, and inhibition of deposition in collagen, which may contribute to cirrhosis.20

A 2014 review of phase III Silybum clinical trials reports silymarin to be the best available medication for nonalcoholic fatty liver disease.21 A subcategory of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), is a progressive liver disease related to metabolic syndrome, obesity, and diabetes and has no effective pharmaceutical therapies to date, other than correcting the underlying metabolic disorders. NASH is characterized by accumulation of fat in the liver (steatosis), accompanied by inflammatory infiltration and hepatocellular damage. Animal models of NASH have shown Silybum to decrease the severity of the disease as evidenced by reduced steatosis and histological improvement, significantly decrease liver weight and the liver-to-body weight ratio,22 dramatically reduce TNF-α and transforming growth factor-β mRNA and malondialdehyde and increase liver glutathione.23 Isolated Silibinin at a dose of 200 mg/kg is shown to produce similar results in animal models of NASH.24

Silybum has been shown to offer hepatoprotection, and in a few cases protection of other tissues, against the toxic effect of acute cocaine-induced toxicity,25 aflatoxin,26 hydrogen sulfide gas,27 iron overload,28 high lipid load,12,13 ethanol,11 acetaminophen,11 manganese,29 chemotherapy drugs,30 methotrexate,31 doxorubicin,32 vincristine,33 statin drugs,34 carbon tetrachloride,35 and Schistosoma infections and schistosomiasis drugs.18 Parenteral Silybum preparations have become established as a viable treatment to save the liver after acute ingestion of hepatotoxic mushrooms.2,3

Silybum has shown less efficacy for HCV-induced hepatitis than NASH, but it still shows promise and continues to be investigated. HCV has significant morbidity and mortality as cirrhotic changes progress to liver failure or as the virus induces hepatocellular carcinoma with a poor survival rate. The main therapies are interferon and the antiviral ribavirin, but the regimen is not highly successful, offering improvement to roughly 50% of users,36 and it has numerous adverse effects. One multicenter randomized controlled trial on hepatitis C patients who had not responded to conventional antiviral therapy were treated with either Silybum or a placebo, with encouraging findings warranting more rigorous studies.37 The investigators point out that the results of their study were on HCV patients who did not respond to antivirals; therefore, the results may not apply to all HCV patients. One pilot study assessed the efficacy and safety of silymarin at 650 mg/day for 6 months in patients with HCV, and Silybum improved the serum HCV-RNA titer, serum aminotransferases (alanine transaminase [ALT], aspartate transaminase [AST]), hepatic fibrosis, and patient’s quality of life, thus warranting larger trials.38 In several separate studies with HCV patients having previously failed interferon therapy, doses up to 700 mg of silymarin did not significantly reduce serum ALT levels more than placebo39,40; however, the dosage duration was quite short (7 days) in one trial and longer studies are warranted given the difficulty of the condition. Chronic hepatitis B and C infections are associated with the pathophysiology of hepatocellular carcinoma, which emerges out of a milieu of oxidative stress and inflammation, and Silybum therapy may still offer chemoprevention for those with chronic hepatitis.41

A small cohort study followed a group of patients with noncirrhotic liver disease (either NAFLD or HCV) and compared the uptake and distribution of silymarin versus placebo on before and after blood markers. After 7 days on 280 or 560 mg of silymarin or placebo, individual components of silymarin, silybin A and B, were higher in NAFLD patients compared with HCV patients because of higher flavonolignan plasma concentrations and more extensive enterohepatic cycling in this pathology.42

Patients with thalassemia treated with chronic blood transfusions frequently develop iron toxicity. Silymarin is shown to improve the efficacy of the iron chelator desferrioxamine, compared with desferrioxamine plus placebo.28 In fact, the desferrioxamine plus placebo was not effective in lowering serum iron and total iron-binding capacity, whereas silymarin showed significant improvements, suggesting Silybum may be better than the present standard therapy.

Safety in Pregnancy and Breastfeeding

Because of its long-standing history as a wild food–the leaves, the roots, and the seeds—Silybum is assumed safe during pregnancy. Silybum is considered safe in lactation and, in fact, is a folkloric galactogogue,43 with modern clinical trials showing efficacy in promoting lactation in preterm mothers with infants in the neonatal intensive care unit.44 Another study compared 429 mg of silymarin per day to placebo in nursing women with hypogalactia and reported clear galactogogue effects calculated to be an 85.94% increase in breast milk production from Silybum without side effects or difficulties in tolerance.45

General Safety

Silybum is considered to be safe in both short- and long-term applications. Because of its extensive use as a modern natural medicine, Silybum has been the beneficiary of extensive studies by the National Institute of Environmental Health Sciences. The animal investigations found no significant toxicities, no interference with reproductive functions, and no carcinogenic effects.46 Animals with long-term Silybum exposure displayed a significantly lower incidence of bile duct hyperplasia, lower mean body weights, significantly decreased incidences of hepatocellular adenoma and hepatocellular carcinoma, and decreased incidences of mammary gland neoplasms occurred in exposed groups of female rats.47
A 2-year toxicity study dosing Silybum to rats and mice found no significant toxicity and a reduction in background tumors.48

No adverse effects or toxicities were noted in any of the human trials cited. A 2007 review of clinical trials reported Silybum extracts to be safe and well tolerated and toxic or adverse effects to be minimal.49 The main side effects of silymarin seem to be rare gastrointestinal disturbances and allergic skin rashes.50 Oral doses of silymarin up to 2.1 g/day have been shown to be well tolerated and not associated with side effects in human HCV patients.40

Silybum, and particularly isolated silybin, are potent inhibitors of cytochrome P2C951 and cytochrome P3A52 groups of enzymes; however, isolated silybin was not shown to have significant interactions with other drugs and at doses 46 No antagonistic interactions are noted between Silybum and vincristine, and a modest synergistic effect has been demonstrated.53 No drug-related adverse events were reported.40

Dosage

Silybum is generally considered safe at doses up to 700 mg/day. Because Silybum has been so widely studied, medicinal products and clinical studies are often standardized to approximately 80% silymarin content. Dosages may range from 50 to 200 mg or more of Silybum taken two or three times daily to support liver function, reduce cholesterol, and improve glycemic control.

Nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.40 Pharmacokinetic studies in human HCV patients have shown a nonlinear dose–blood level curve where doses of 140, 280, and 560 mg result in similar blood levels that suddenly jump at dose of 700 mg.40

Traditional Uses

Silybum marianum is a medicinal plant used for its hepatoprotective properties in chronic liver disease since the 4th century BC. It has also been used to treat gallbladder and biliary disease, jaundice, peritonitis, malarial fevers, bronchitis, insufficient lactation, varicose veins, and reduce insulin resistance. The roots of Silybum have been prepared as a medicinal food, and the spines can be cut from leaves and used a salad greens and pot herbs. Silybum seeds have been roasted brewed into teas and coffee substitutes. Recent research is also showing the Silybum can be useful for renal disease and inflammation and may have efficacy against hormonal cancers including breast, cervical, and prostate.

References

1 J Sci Food Agric. 2012;92(7):1441–7. Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis. Chen IS, Chen YC, Chou CH, Chuang RF, Sheen LY, Chiu CH.

2 Przegl Lek. 2012;69(8):541–3. Silibinin and its hepatoprotective action from the perspective of a toxicologist. Kostek H, Szponar J, Tchórz M, Majewska M, Lewandowska-Stanek H.

3 Curr Pharm Biotechnol. 2012;13(10):1964–70. Legalon® SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Mengs U, Pohl RT, Mitchell T.

4 Chem Biol Interact. 2012;195(2):119–32. Metabolic effects of silibinin in the rat liver. Colturato CP, Constantin RP, Maeda AS Jr, Constantin RP, Yamamoto NS, Bracht A, Ishii-Iwamoto EL, Constantin J.

5 Pharmacogn Mag. 2014;10(Suppl 1):S92–9. Silybum marianum oil attenuates oxidative stress and ameliorates mitochondrial dysfunction in mice treated with D-galactose. Zhu SY, Dong Y, Tu J, Zhou Y, Zhou XH, Xu B.

6 Eur J Pharmacol. 2012;684(1–3):19–26. Dihydroquercetin: More than just an impurity? Weidmann AE.

7 Integr Cancer Ther. 2014;13(1):46–53. A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma. Siegel AB, Narayan R, Rodriguez R, Goyal A, Jacobson JS, Kelly K, Ladas E, Lunghofer PJ, Hansen RJ, Gustafson DL, Flaig TW, Tsai WY, Wu DP.

8 Phytomedicine. 2012;20(1):40–6. Absorption and metabolism of milk thistle flavanolignans in humans. Calani L, Brighenti F, Bruni R, Del Rio D.

9 Food Chem Toxicol. 2010;48(3):803–6. Silymarin, the antioxidant component and Silybum marianum extracts prevent liver damage. Shaker E, Mahmoud H, Mnaa S.

10 Physiol Res. 1998;47(1):1–7. Silymarin as a potential hypocholesterolaemic drug. Skottová N, Krecman V.

11 World J Hepatol. 2014;6(3):144–9. Hepatoprotective effect of silymarin. Vargas-Mendoza N, Madrigal-Santillán E, Morales-González A, Esquivel-Soto J, Esquivel-Chirino C, García-Luna Y González-Rubio M, Gayosso-de-Lucio JA, Morales-González JA.

12 World J Hepatol. 2013;5(3):109–13. Silymarin in non-alcoholic fatty liver disease. Cacciapuoti F, Scognamiglio A, Palumbo R, Forte R, Cacciapuoti F.

13 Pharmacol Res. 2004;50(2):123–30. Phenolics-rich extracts from Silybum marianum and Prunella vulgaris reduce a high-sucrose diet induced oxidative stress in hereditary hypertriglyceridemic rats. Skottová N, Kazdová L, Oliyarnyk O, Vecera R, Sobolová L, Ulrichová J.

14 Proc Natl Acad Sci USA. 2010;107(13):5995–9. Identification of hepatoprotective flavonolignans from silymarin. Polyak SJ, Morishima C, Lohmann V, Pal S, Lee DY, Liu Y, Graf TN, Oberlies NH.

15 Planta Med. 2013;79(12):997–1002. Alterations in sulfur amino acid metabolism in mice treated with silymarin: a novel mechanism of its action involved in enhancement of the antioxidant defense in liver. Kwon do Y, Jung YS, Kim SJ, Kim YS, Choi DW, Kim YC.

16 J Ethnopharmacol. 2008;115(3):507–14. Antioxidant and mitochondrial protective effects of silibinin in cold preservation-warm reperfusion liver injury. Ligeret H, Brault A, Vallerand D, Haddad Y, Haddad PS.

17 Chin J Nat Med. 2013;11(6):645–52. Reversing effects of silybin on TAA-induced hepatic CYP3A dysfunction through PXR regulation. Xie Y, Hao HP, Wang H, Wang ZX, Wang GJ.

18 Parasit Vectors. 2012;5:9. Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis. El-Lakkany NM, Hammam OA,
El-Maadawy WH, Badawy AA, Ain-Shoka AA, Ebeid FA.

19 Hepat Mon. 2011;11(6):464–8. The effects of milk thistle on hepatic fibrosis due to methotrexate in rat. Ghaffari AR, Noshad H, Ostadi A, Ghojazadeh M, Asadi P.

20 J Evid Based Complementary Altern Med. 2015. Silybum marianum: Beyond hepatoprotection. Bahmani M, Shirzad H, Rafieian S, Rafieian-Kopaei M.

21 Rev Recent Clin Trials. 2014;9(3):195–203. Phytotherapy and NAFLD – from goals and challenges to clinical practice. Milosevic N, Milanovic M, Abenavoli L, Milic N.

22 Drugs R D. 2014;14(4):291–9. In vivo efficacy study of milk thistle extract (ETHIS-094™) in STAM™ model of nonalcoholic steatohepatitis. Pais P, D’Amato M.

23 Exp Toxicol Pathol. 2011;63(6):569–74. Anti-apoptotic and anti-inflammatory effects of Silybum marianum in treatment of experimental steatohepatitis. Aghazadeh S, Amini R, Yazdanparast R, Ghaffari SH.

24 Evid Based Complement Alternat Med. 2011;2011:nep164. Antioxidant and hepatoprotective effects of silibinin in a rat model of nonalcoholic steatohepatitis. Haddad Y, Vallerand D, Brault A, Haddad PS.

25 Mol Med Rep. 2014;10(5):2287–92. Milk thistle seed extract protects rat C6 astroglial cells from acute cocaine toxicity. Badisa RB, Fitch-Pye CA, Agharahimi M, Palm DE, Latinwo LM, Goodman CB.

26 J Res Med Sci. 2013;18(9):786–90. Effects of milk thistle seed against aflatoxin B1 in broiler model. Amiridumari H, Sarir H, Afzali N, Fanimakki O.

27 Daru. 2013;21(1):28. Hepatoprotective effect of silyamarin in individuals chronically exposed to hydrogen sulfide; modulating influence of TNF-α cytokine genetic polymorphism. Mandegary A, Saeedi A, Eftekhari A, Montazeri V, Sharif E.

28 Eur J Haematol. 2013;90(3):202–9. A randomized double-blind, placebo-controlled study of therapeutic effects of silymarin in β-thalassemia major patients receiving desferrioxamine. Moayedi B, Gharagozloo M, Esmaeil N, Maracy MR, Hoorfar H, Jalaeikar M.

29 Hum Exp Toxicol. 2013;32(1):70–81. Therapeutic efficacy of silymarin from milk thistle in reducing manganese-induced hepatic damage and apoptosis in rats. Chtourou Y, Garoui E, Boudawara T, Zeghal N.

30 J Oncol Pharm Pract. 2012;18(3):360–5. Silybum marianum (milk thistle) in the management and prevention of hepatotoxicity in a patient undergoing reinduction therapy for acute myelogenous leukemia. McBride A, Augustin KM, Nobbe J, Westervelt P.

31 Ren Fail. 2015;37(4):1–6. Effects of silymarin on methotrexate-induced nephrotoxicity in rats. Dabak DO, Kocaman N.

32 Molecules. 2011;16(10):8601–13. The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. Rašković A, Stilinović N, Kolarović J, Vasović V, Vukmirović S, Mikov M.

33 Cancer. 2010;116(2):506–13. A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL). Ladas EJ, Kroll DJ, Oberlies NH, Cheng B, Ndao DH, Rheingold SR, Kelly KM.

34 Planta Med. 1998;64(2):138–42. Silymarin inhibits the development of diet-induced hypercholesterolemia in rats. Krecman V, Skottová N, Walterová D, Ulrichová J, Simánek V.

35 Life Sci. 2014;117(1):13–8. Milk thistle impedes the development of carbontetrachloride-induced liver damage in rats through suppression of bcl-2 and regulating caspase pathway. Aslan A, Can Mİ.

36 Virol J. 2011;8:153. Inhibition of HCV 3a core gene through Silymarin and its fractions. Ashfaq UA, Javed T, Rehman S, Nawaz Z, Riazuddin S.

37 Clin Trials. 2012;9(1):102–12. Rationale, challenges, and participants in a Phase II trial of a botanical product for chronic hepatitis C. Reddy KR, Belle SH, Fried MW, Afdhal N, Navarro VJ, Hawke RL, Wahed AS, Doo E, Meyers CM.

38 J Res Med Sci. 2011;16(3):287–90. Effects of silybum marianum on patients with chronic hepatitis C. Kalantari H, Shahshahan Z, Hejazi SM, Ghafghazi T, Sebghatolahi V.

39 JAMA. 2012;308(3):274–82. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. Fried MW, Navarro VJ, Afdhal N, Belle SH, Wahed AS, Hawke RL, Doo E, Meyers CM, Reddy KR.

40 J Clin Pharmacol. 2010;50(4):434–49. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH, Afdhal NH, Navarro VJ, Berman J, Liu QY, Doo E, Fried MW; SyNCH Trial.

41 Anticancer Drugs. 2015;26(5):475–86. Silymarin and hepatocellular carcinoma: a systematic, comprehensive, and critical review. Mastron JK, Siveen KS, Sethi G, Bishayee A.

42 Drug Metab Dispos. 2011;39(12):2182–90. Differences in the disposition of silymarin between patients with nonalcoholic fatty liver disease and chronic hepatitis C. Schrieber SJ, Hawke RL, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH, Afdhal NH, Navarro VJ, Meyers CM, Doo E, Fried MW.

43 Ann Pharmacother. 2012;46(10):1392–404. The use of galactogogues in the breastfeeding mother. Forinash AB, Yancey AM, Barnes KN, Myles TD.

44 Minerva Pediatr. 2014;66(5):375–80. Silymarin/galega administration in term and preterm mothers to sustain breast feeding: an observational study. Castoldi F, Pivetti V, Moiraghi L, Marangione P, Lista G.

45 Acta Biomed. 2008;79(3):205–10. Clinical efficacy, safety and tolerability of BIO-C (micronized Silymarin) as a galactagogue. Di Pierro F, Callegari A, Carotenuto D, Tapia MM.

46 World J Gastroenterol. 2011;17(18):2288–301. Silybin and the liver: from basic research to clinical practice. Loguercio C, Festi D.

47 Natl Toxicol Program Tech Rep Ser. 2011;(565):1–177. Toxicology and carcinogenesis studies of milk thistle extract (CAS No. 84604-20-6) in F344/N rats and B6C3F1 mice (Feed Studies). National Toxicology Program. Collaborators (45).

48 Toxicol Pathol. 2011;39(2):398–409. Investigating the potential for toxicity from long-term use of the herbal products, goldenseal and milk thistle. Dunnick JK, Singh B, Nyska A, Peckham J, Kissling GE, Sanders JM.

49 Integr Cancer Ther. 2007;6(2):146–57. Review of clinical trials evaluating safety and efficacy of milk thistle (Silybum marianum [L.] Gaertn.). Tamayo C, Diamond S.

50 Drugs. 2001;61(14):2035–63. The use of silymarin in the treatment of liver diseases. Saller R, Meier R, Brignoli R.

51 J Pharm Pharmacol. 2014;66(9):1339–46. The in-vitro effect of complementary and alternative medicines on cytochrome P450 2C9 activity. Mooiman KD, Goey AK, Huijbregts TJ, Maas-Bakker RF, Beijnen JH, Schellens JH, Meijerman I.

52 Drug Metab Dispos. 2013;41(9):1662–70. A systematic approach to evaluate herb-drug interaction mechanisms: investigation of milk thistle extracts and eight isolated constituents as CYP3A inhibitors. Brantley SJ, Graf TN, Oberlies NH, Paine MF.

53 Cancer. 2010;116(2):506–13. A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL). Ladas EJ, Kroll DJ, Oberlies NH, Cheng B, Ndao DH, Rheingold SR, Kelly KM.