Scientific Name(s): Silybum marianum (L.) Gaertn. Family: Asteraceae (daisies)
Common Name(s): Blessed thistle , bull thistle , Carduus marianus , fructus cardui mariae , fructus silybi mariae , holy thistle , Lady's milk , Lady's thistle , Mariana mariana , marian thistle , mild marian thistle , milk thistle , pternix , Silberdistil , silibinin , silybe , silybon , silybum , silymarin , St. Mary's thistle , thistle , thistle of the Blessed Virgin
Adequate evidence from prospective clinical trial data for milk thistle is lacking. However, studies suggest potential clinical applications for silymarin, a flavonoid extract of milk thistle, in treating alcohol-related hepatitis, toxicity due to Amanita mushroom poisoning, diabetes, and cancer.
Consumption of the oral form of milk thistle (standardized to 70% to 80% silymarin) at 420 mg/day in divided doses is considered safe for up to 41 months, based on clinical trial data. High-dose milk thistle has been used within the confines of clinical trials.
Allergy to any plant in the Asteraceae family.
Information is limited. Use in pregnant and breast-feeding women has been reported in limited clinical studies without apparent ill-effect; however, until further data are available, avoid the use of milk thistle in pregnant or breast-feeding women.
Despite widespread usage of milk thistle, case reports of clinically important interactions are lacking. Exercise caution when using milk thistle at higher dosages or concomitantly with drugs of a narrow therapeutic index. Milk thistle decreases indinavir trough plasma concentrations.
In most clinical trials, the incidence of adverse reactions was approximately equal in milk thistle and placebo groups. No serious adverse events have been reported at recommended dosages. The most common effects occurring after oral ingestion included brief GI disturbances.
There are no milk thistle toxicities documented in humans, and toxicity appears to be low in laboratory animals.
Milk thistle is indigenous to Europe and Asia but has been naturalized in North and South America. The plant grows 1.5 to 3 m in height and has large, prickly leaves. When broken, the leaves and stems exude a milky sap. The reddish-purple flowers are ridged with sharp spines. The part used as the drug includes the shiny, mottled, black- or grey-toned fruits that often are referred to as seeds. These make up the thistle portion, along with its silvery pappus, which readily falls away and is not part of the extract preparation. 1 , 2
Milk thistle has been used medicinally since the 4th century BC. Its use in treating hepatobiliary diseases dates back to the 1700s, and its use as a liver protectant can be traced back to Greek references. Pliny the Elder, a 1st century Roman writer (AD 23 to 79), noted that the plant's juice was excellent for “carrying off bile.” The 17th century English herbalist Nicholas Culpepper wrote that milk thistle was beneficial in treating jaundice and for removing liver and spleen obstructions. The Eclectic medical system (19th to 20th century) used milk thistle to treat varicose veins, menstrual difficulty, and congestion in the liver, spleen, and kidneys. In homeopathy, a tincture of the seeds has been used to treat liver disorders, jaundice, gallstones, peritonitis, hemorrhage, bronchitis, and varicose veins. The fruit, stem, and seeds are all considered to have medicinal value.
Early colonists introduced milk thistle to North America. The plant was grown in Europe and the de-spined leaves were used in salads and eaten as a vegetable; the stalks and root parts also were consumed. The flower portion was eaten “artichoke-style.” The roasted seeds were used as a coffee substitute. 2 , 3 , 4
Milk thistle extract is composed of 65% to 80% silymarin. The remainder consists of polyphenolics and fatty acids, such as linoleic acid. Silymarin is a complex of at least 7 flavolignans, including silibinin, silychristin (silichristin), and silidianin (silidianin) and the flavonoid taxifolin. Silybin A and B, diastereoisomers of silibinin, are considered the most biologically active components, although isosilibinin may be more potent. Other flavonolignans have been described, and various methods for chemical constituent identification have been detailed. 2 , 5 , 6 , 7 , 8 , 9 , 10
Uses and Pharmacology
Most studies evaluating the mechanism of action of milk thistle have used silymarin and silibinin. Antioxidant properties have been demonstrated in various models using human cells, such as platelets. A reduction in drug-induced hepatotoxic ischemic damage and iron-overload oxidative stress has also been shown. Silymarin stabilized hepatocyte and other cell membranes, as well as stimulated macromolecular and protein synthesis. Additionally, anti-inflammatory action was demonstrated with inhibition of neutrophil-mediated histamine release, lipoxygenase and prostaglandin synthetase, and leukotriene synthesis. 2 , 11 , 12 , 13
The US National Institutes of Health clinical trials database lists a number of clinical trials currently in process, or preparing to recruit participants, to evaluate the efficacy of milk thistle extracts. 14Cancer
In vitro experiments and limited animal studies investigated the potential of silymarin and silibinin in a variety of cancer cell lines, including bladder, breast, cervical, hepatocellular, and prostate cancer. A variety of molecular mechanisms have been proposed, including antioxidant, anti-angiogenic action, apoptosis via cell cycle arrest, inhibition of transcription factors, and modulation of hormone receptors and cell signaling. 7 , 15 , 16 , 17 , 18 , 19 , 20Clinical trials
Clinical trials are lacking, and use of milk thistle preparations in cancer is not recommended outside of the trial setting. 18 A small phase 1 trial evaluating the tolerability of silibinin (commercial preparation Siliphos ) in prostate cancer patients has been completed, and phase 2 trials are being planned. 14 , 21 Additionally, silibinin was administered to patients with colorectal adenocarcinoma over 7 days to evaluate the tissue concentrations of silibinin in the colorectal mucosa. 18 A clinical trial included silymarin combined with soy, isoflavones, lycopene, and antioxidants in patients with prostate cancer; therefore, outcomes cannot be attributed to any single ingredient alone. 22 Use as an adjunct to chemotherapy to prevent drug-related hepatotoxicity has also been studied in limited trials, including 1 in which children with acute lymphoblastic leukemia administered silibinin (as Siliphos ) for 28 days achieved greater reduction in total bilirubin at day 28 compared with placebo. 14 , 23Diabetes
In vitro and animal experiments
Limited clinical trials have been conducted in type 2 diabetes, insulin-dependent diabetes, and diabetes with comorbid conditions, such as alcoholic liver disease. 14 , 23 , 26 , 27 Most trials record decreases in fasting and postprandial serum glucose, and coincidentally note improvements in the lipid profile; however, because the trials are of varying quality (unblinded and small numbers of participants), no conclusions can be made.Hepatitis
A number of clinical trials in hepatitis have been undertaken, making the findings from animal experiments largely irrelevant.Clinical trials
A number of meta-analyses have been conducted on the efficacy of milk thistle in alcohol-induced and viral hepatitis. 28 , 29 , 30 , 31 , 32 , 33 No effect on all-cause mortality has been found, and no effect on complications of liver disease or on liver histology could be established. 28 , 29 Although a decrease in liver-related mortality could be demonstrated, when only high-quality trials were included, no effect on mortality was found (relative risk, 0.57; 95% confidence interval, 0.28 to 1.19). 28 , 30 In some trials, a reduction in serum transaminases was demonstrated, but with no effect on liver histology or clinical progression. 30 , 34 , 35 A quicker resolution of those symptoms related to biliary retention has been shown in 1 subsequent trial, but with no effect on quality of life measures. 36 One small, open-label study in viral hepatitis demonstrated a reduction in viral load with high-dose intravenous administration of silibinin. 35
Considering the low-toxicity profile of milk thistle, clinical reviewers suggest use of milk thistle preparations in treating alcoholic-related cirrhosis 29 , 30 ; however, its use in viral hepatitis outside of clinical trials is not supported by current data. 28 , 30 , 33 , 37 , 38 The use of silymarin in the treatment of toxicity due to Amanita mushroom poisoning is also supported, based on retrospective analysis of data. Prospective clinical trial data are not available. 11 , 14 , 30 , 39Other pharmacological effects
Silybin and silymarin have been studied in the treatment of aging skin and rosacea, and in skin cancer prevention. 40 , 41 , 42 In older studies, silybin has been evaluated in patients with cholestasis. 43 , 44 , 45 Silybin possesses antibacterial activity against gram-positive bacteria but shows no activity against gram-negative bacteria or fungi. 46 Milk thistle extract demonstrates neuroprotective effects in animal studies. 11 , 47 , 48 , 49
Consumption of the oral form of milk thistle (standardized to 70% to 80% silymarin) at 420 mg/day in divided doses is considered safe for up to 41 months based on clinical trial data. 50
Information is limited. Use in pregnant women has been reported in few clinical studies, without apparent ill-effect. 20 , 23 A study evaluated the efficacy and safety of silymarin to promote milk production in 50 women who had elected to stop breast-feeding because their infants did not consume the milk. Milk production was enhanced, and no change to the chemical composition of the milk was found. 51 Until further data are available, avoid the use of milk thistle in pregnant or breast-feeding women.
Silibinin inhibits phase 1 and 2 enzymes and inactivates cytochromes P450 3A4 and 2C9, potentially via an irreversible mechanism. 5 , 52 , 53 Despite widespread usage of milk thistle, case reports of clinically significant interactions are lacking. 39 Studies conducted largely among healthy volunteers evaluated the effect of milk thistle on prescription drugs. These drugs included antiretrovirals (especially indinavir), digoxin, ranitidine, losartan, and metronidazole, with most studies finding some effect on the area under the curve, but no clinical effect. 52 , 53 , 54 , 55 , 56 Milk thistle has been reported to decrease indinavir trough plasma concentrations; however, it is unlikely that milk thistle will interfere with therapy. 57 , 58 , 59
Exercise caution when using milk thistle, especially at higher dosages or concomitantly with drugs of a narrow therapeutic index. 5
In most clinical trials, the incidence of adverse reactions was approximately equal in milk thistle and control (placebo) groups. 28 The Agency for Healthcare Research and Quality and German Commission E report no serious adverse events when taken within the recommended dosage range. 12 , 39 Consumption of the oral form of milk thistle (standardized to 70% to 80% silymarin) at 420 mg/day is considered safe for up to 41 months, based on clinical trial data. 50
Tolerability of silymarin is good; the most common effects after oral ingestion include brief GI disturbances (eg, abdominal bloating, abdominal fullness or pain, anorexia, changes in bowel habits, diarrhea, dyspepsia, flatulence, nausea). Other reported adverse reactions include headache, impotence, and skin reactions (eg, eczema, pruritus, rash, urticaria). 50 A tea made from crude milk thistle resulted in a case report of anaphylaxis. 2 High dosages in cancer trials have been associated with asymptomatic hyperbilirubinemia and increases in ALT enzymes. 50
Acute oral toxicity of silymarin in rats, dogs, and monkeys has been estimated to be greater than 5 g/kg. Subacute toxicity studies suggest no toxicity in rats and monkeys for dosages of up to 2 g/kg for 13 weeks, and up to 1 g/kg in rats and dogs for up to 26 weeks. Investigations, including urine analysis and postmortem studies, showed no evidence of toxicity. No evidence of effect on reproduction in rats has been found, and silymarin was not mutagenic in several tests. 2 , 60
Bibliography1. Silybum marianum . USDA, NRCS. 2010. The PLANTS Database ( http://plants.usda.gov , February 2010). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Fructus Silybi Mariae. In: WHO Monographs on Selected Medicinal Plants . Vol 1. Geneva, Switzerland: World Health Organization; 1999:300-316.
3. Foster S. Milk thistle- Silybum marianum . No. 305. Austin, TX: American Botanical Council; 1991:3-7.
4. Schauenberg P, Paris F. Guide to Medicinal Plants . New Canaan, CT: Keats Publishing; 1990.
5. Kroll DJ, Shaw HS, Oberlies NH. Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies. Integr Cancer Ther . 2007;6(2):110-119.
6. Kren V, Walterová D. Silybin and silymarin—new effects and applications. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub . 2005;149(1):29-41.
7. Gazák R, Walterová D, Kren V. Silybin and silymarin—new and emerging applications in medicine. Curr Med Chem . 2007;14(3):315-338.
8. Halbach G, Görler K. Separation of flavonoids from the fruits of St Mary's distel ( Silybum marianum ) [in German]. Planta Med . 1971;19(4):293-298.
9. Khafagy SM, Salam NA, Hamid RA. Constituents of Silybum marianum (L.) Gaertn. (Compositae). Sci Pharm . 1981;49:157-161.
10. Varma PN, Talwar SK, Garg GP. Chemical investigation of Silybum marianum . Planta Med . 1980;38(4):377-378.
11. Pradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res . 2006;124(5):491-504.
12. Post-White J, Ladas EJ, Kelly KM. Advances in the use of milk thistle ( Silybum marianum ). Integr Cancer Ther . 2007;6(2):104-109.
13. Gharagozloo M, Moayedi B, Zakerinia M, et al. Combined therapy of silymarin and desferrioxamine in patients with beta-thalassemia major: a randomized double-blind clinical trial. Fundam Clin Pharmacol . 2009;23(3):359-365.
14. U.S. National Institutes of Health (NIH). Clinical Trials Database. Available from URL: http://clinicaltrials.gov/ct2/home .
15. Agarwal R, Agarwal C, Ichikawa H, Singh RP, Aggarwal BB. Anticancer potential of silymarin: from bench to bed side. Anticancer Res . 2006;26(6B):4457-4498.
16. Meeran SM, Katiyar SK. Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front Biosci . 2008;13:2191-2202.
17. Sagar SM. Future directions for research on Silybum marianum for cancer patients. Integr Cancer Ther . 2007;6(2):166-173.
18. Ramasamy K, Agarwal R. Multitargeted therapy of cancer by silymarin. Cancer Lett . 2008;269(2):352-362.
19. Comelli MC, Mengs U, Schneider C, Prosdocimi M. Toward the definition of the mechanism of action of silymarin: activities related to cellular protection from toxic damage induced by chemotherapy. Integr Cancer Ther . 2007;6(2):120-129.
20. Deep G, Agarwal R. Chemopreventive efficacy of silymarin in skin and prostate cancer. Integr Cancer Ther . 2007;6(2):130-145.
21. 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;25(2):139-146.
22. Schröder FH, Roobol MJ, Boevé ER, et al. Randomized, double-blind, placebo-controlled crossover study in men with prostate cancer and rising PSA: effectiveness of a dietary supplement. Eur Urol . 2005;48(6):922-930.
23. Greenlee H, Abascal K, Yarnell E, Ladas E. Clinical applications of Silybum marianum in oncology. Integr Cancer Ther . 2007;6(2):158-165.
24. McCarty M. Potential utility of natural polyphenols for reversing fat-induced insulin resistance. Med Hypotheses . 2005;64(3):628-635.
25. Zhang JQ, Mao XM, Zhou YP. Effects of silybin on red blood cell sorbitol and nerve conduction velocity in diabetic patients [in Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi . 1993;13(12):725-726, 708.
26. Hussain SA. Silymarin as an adjunct to glibenclamide therapy improves long-term and postprandial glycemic control and body mass index in type 2 diabetes. J Med Food . 2007;10(3):543-547.
27. 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):1036-1039.
28. Rambaldi A, Jacobs BP, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev . 2007;(4):CD003620.
29. Liu J, Manheimer E, Tsutani K, Gluud C. Medicinal herbs for hepatitis C virus infection: a Cochrane hepatobiliary systematic review of randomized trials. Am J Gastroenterol . 2003;98(3):538-544.
30. 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.
31. Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C liver diseases—a systematic cochrane hepato-biliary group review with meta-analyses of randomized clinical trials. Am J Gastroenterol . 2005;100(11):2583-2591.
32. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs . 2001;61(14):2035-2063.
33. Verma S, Thuluvath PJ. Complementary and alternative medicine in hepatology: review of the evidence of efficacy. Clin Gastroenterol Hepatol . 2007;5(4):408-416.
34. Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepat . 2005;12(6):559-567.
35. Ferenci P, Scherzer TM, Kerschner H, et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology . 2008;135(5):1561-1567.
36. El-Kamary SS, Shardell MD, Abdel-Hamid M, et al. A randomized controlled trial to assess the safety and efficacy of silymarin on symptoms, signs and biomarkers of acute hepatitis. Phytomedicine . 2009;16(5):391-400.
37. Gordon A, Hobbs DA, Bowden DS, et al. Effects of Silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well-being in patients with chronic hepatitis C. J Gastroenterol Hepatol . 2006;21(1, pt 2):275-280.
38. Tanamly MD, Tadros F, Labeeb S, et al. Randomised double-blinded trial evaluating silymarin for chronic hepatitis C in an Egyptian village: study description and 12-month results. Dig Liver Dis . 2004;36(11):752-759.
39. Rainone F. Milk thistle. Am Fam Physician . 2005;72(7):1285-1288.
40. Berardesca E, Cameli N, Cavallotti C, Levy JL, Piérard GE, de Paoli Ambrosi G. Combined effects of silymarin and methylsulfonylmethane in the management of rosacea: clinical and instrumental evaluation. J Cosmet Dermatol . 2008;7(1):8-14.
41. Singh RP, Agarwal R. Cosmeceuticals and silibinin. Clin Dermatol . 2009;27(5):479-484.
42. Singh RP, Agarwal R. Mechanisms and preclinical efficacy of silibinin in preventing skin cancer. Eur J Cancer . 2005;41(13):1969-1979.
43. Schandalik R, Gatti G, Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschung . 1992;42(7):964-968.
44. Schandalik R, Perucca E. Pharmacokinetics of silybin following oral administration of silipide in patients with extrahepatic biliary obstruction. Drugs Exp Clin Res . 1994;20(1):37-42.
45. Rumyantseva ZN. The pharmacodynamics of hepatoprotectants derived from blessed milk thistle ( Silybum marianum ). Vrach Delo . 1991;5:15-19.
46. Lee DG, Kim HK, Park Y, et al. Gram-positive bacteria specific properties of silybin derived from Silybum marianum . Arch Pharm Res . 2003;26(8):597-600.
47. Wang MJ, Lin WW, Chen HL, et al. Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation. Eur J Neurosci . 2002;16(11):2103-2112.
48. Kittur S, Wilasrusmee S, Pedersen WA, et al. Neurotrophic and neuroprotective effects of milk thistle ( Silybum marianum ) on neurons in culture. J Mol Neurosci . 2002;18(3):265-269.
49. Katiyar SK. Silymarin and skin cancer prevention: anti-inflammatory, antioxidant and immunomodulatory effects (Review). Int J Oncol . 2005;26(1):169-176.
50. Tamayo C, Diamond S. Review of clinical trials evaluating safety and efficacy of milk thistle ( Silybum marianum [L.] Gaertn.). Integr Cancer Ther . 2007;6(2):146-157.
51. Di Pierro F, Callegari A, Carotenuto D, Tapia MM. Clinical efficacy, safety and tolerability of BIO-C (micronized Silymarin) as a galactagogue. Acta Biomed . 2008;79(3):205-210.
52. Wu JW, Lin LC, Tsai TH. Drug-drug interactions of silymarin on the perspective of pharmacokinetics. J Ethnopharmacol . 2009;121(2):185-193.
53. van den Bout-van den Beukel CJ, Koopmans PP, van der Ven AJ, De Smet PA, Burger DM. Possible drug-metabolism interactions of medicinal herbs with antiretroviral agents. Drug Metab Rev . 2006;38(3):477-514.
54. 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.
55. Han Y, Guo D, Chen Y, Chen Y, Tan ZR, Zhou HH. Effect of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 in healthy Chinese volunteers. Eur J Clin Pharmacol . 2009;65(6):585-591.
56. Hu Z, Yang X, Ho PC, et al. Herb-drug interactions: a literature review. Drugs . 2005;65(9):1239-1282.
57. Piscitelli SC, Formentini E, Burstein AH, Alfaro R, Jagannatha S, Falloon J. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy . 2002;22(5):551-556.
58. DiCenzo R, Shelton M, Jordan K, et al. Coadministration of milk thistle and indinavir in healthy subjects. Pharmacotherapy . 2003;23(7):866-870.
59. 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.
60. Kidd P, Head K. A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex ( Siliphos ). Altern Med Rev . 2005;10(3):193-203.
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