Milk Thistle
23:9

Milk Thistle

Wendell L. Combest, Ph.D.
Associate Professor of Pharmacology, Department of Biopharmaceutical Sciences, Shenandoah University School of Pharmacy, Winchester, VA


Milk thistle (Silybum marianum) is a member of the Compositae family. It is found growing throughout Europe and was introduced to North America by European colonists. Now it grows abundantly throughout North and South America, particularly in southern locations with sunny exposures and well-drained soils. Milk thistle is also grown commercially in the United States. The plant has a long stem which branches upward and can reach a height of 5 feet. The leaves are broad and wavy with lance-shaped pointed tips. They are shiny green with numerous vein-like white markings. According to legend, the white veins carry the milk of the Virgin Mary, hence its other common name—Marian thistle. Indeed, the stem and leaves contain a milky white sap. Historically, wet nurses consumed the leaves, believing that this sap enhanced their milk production. The stem terminates in a spiney, spherical head bearing thick, reddish-purple flowers.

Silymarin has been successfully used as a supportive therapy for the liver after exposure to a variety of toxic chemicals and drugs.

The stems and leaves are palatable and are often prepared as a salad. The seeds and fruit contain the highest levels of medicinally active constituents.1 Extracts of various parts of the plant have been popular medicines since ancient Greece. Milk thistle has been used to treat a variety of ailments—from snake bites to liver diseases. Its use in treating liver disorders goes back to the late sixteenth century. A recent survey in a hepatology clinic in Oregon revealed that 30% of patients were using naturopathic remedies (mostly milk thistle) to treat their chronic liver disease.2 Today milk thistle extracts have become extremely popular throughout Europe, especially in Germany, where sales have reached $180 million annually.3

Chemical Composition and Active Constituents
The seeds and, to a lesser extent, the leaves and stems contain several isomeric flavonolignans collectively referred to as silymarin. Silymarin is composed primarily of silybin (also referred to as silibin or silibinin), accompanied by isosilybin, dehydrosilybin, silydianin and silychristin.4 Silymarin (C25H22O10; MW 482.5) is present at concentrations of 4%–6% in the seeds. These compounds are believed to be the biologically active constituents responsible for milk thistle’s antioxidant and hepatoprotective effects. Other compounds with as yet unknown functions are apigenin, silybonol, and a fixed oil that contains linoleic, oleic, myristic, palmitic, and stearic acids. Several polyacetylenes have been isolated from the roots.5 Other less prominent flavonolignans present are 3-deoxysilichristin, deoxysilydianin, siliandrin, silybinome, and silyermin.

Pharmacology and Therapeutic Uses
Mushroom Poisoning: One of the most well-documented uses of milk thistle is in the treatment of poisoning by the mushroom Amanita phalloides (death cap). Nausea, vomiting, abdominal cramps and severe diarrhea usually occur 8–12 hours after the patient has consumed the mushroom. Severe hepatic disease characterized by extensive necrosis results 1–2 days later. A 20%–30% mortality rate has been observed overall, while a rate as high as 50% has been seen in children under 10 years of age.6 In several clinical studies, silibin (intravenous 20–50 mg/kg/day) has been shown to protect patients against liver damage when administered within 48 hours of exposure to the mushroom.6,7 In a clinical series of 205 patients (with 46 fatalities), all patients receiving silibin survived.6

Alcohol-related hepatitis and cirrhosis of the liver have long been treated with milk thistle extracts with variable success.

Several animal studies support these clinical findings. In mice, liver damage can be prevented if silibin is administered within 30 minutes after ingestion of the mushroom. In dogs, silibin exhibits its antitoxic effect up to 24 hours after exposure.8 The exact mechanism for these protective effects is not fully understood, but appears to involve an alteration in the outer cell membrane of the hepatocytes. This alteration prevents the toxins from penetrating the liver cells. The toxin binding sites are therefore blocked and the uptake into the cells inhibited.

Environmental Toxins and Drugs: Silymarin has been successfully used as a supportive therapy for the liver following exposure to a variety of toxic chemicals and drugs. Szilard et al. treated 30 patients who had been exposed to toxic levels of the solvents toluene and xylene, resulting in elevated liver enzymes (AST and ALT). These liver enzyme levels decreased when the patients were treated with silymarin.9 In another study, involving rats, an acute dose of CCl4 was administered, resulting in enhanced lipid peroxidation and alterations in membrane lipid composition in the liver.10 Silymarin was found to protect against these toxic effects through its potent antioxidant properties and by modifying the plasma membrane phospholipid content.

Iron exposure can lead to hepatic fibrosis and cirrhosis, perhaps by inducing lipid peroxidation of biological membranes. Oral administration of silibin was found to protect against this iron-induced hepatic damage in rats.11 This beneficial effect was thought to be most likely due to the antioxidant properties of silibin.

Silymarin significantly reduced hepatic necrosis in rats caused by toxic doses of acetamin-ophen.12 With treatment, lipid peroxidation and elevated serum liver enzymes (diagnostic signs of liver damage) fell to normal levels, even during chronic exposure to acetaminophen. Again, investigators attributed this protective effect to the free-radical scavenging properties
of silymarin.

Two clinical trials have been published documenting the effectiveness of silymarin in improving or preventing liver damage caused by long-term treatment with certain psychotropic medications (phenothiazines or butyrophenones). One trial included 60 patients, half of whom received 800 mg/day of silymarin.13 Silymarin therapy resulted in improved liver function tests. The other clinical study involved 19 patients treated with the same psychotropic drugs for 6 months.14 Again, liver function tests revealed that silymarin was effective in protecting the liver against drug-induced damage.
Alcohol Abuse: The damage to the liver (hepatitis and cirrhosis) associated with alcohol abuse has long been treated with milk thistle extracts, with variable success. In a 6-month, double-blind trial involving 17 patients with documented alcohol-related hepatitis, silymarin (140 mg twice a day) treatment resulted in the normalization of liver function tests.15 Improvements were also noted in liver histology and extent of membrane lipid peroxidation. In another study, 97 patients with abnormal liver function tests due to chronic alcohol abuse were withdrawn from alcohol for one month and treated for four months with either silymarin or placebo.16 Results showed that liver function improved in those patients receiving silymarin. A double-blind, randomized, placebo-controlled trial targeted 66 patients meeting the histological criteria for alcoholic hepatitis. The patients were divided into two groups, and one group received silymarin treatment.17 Liver function tests normalized sooner in the treatment group (13 days vs. 24 days). Likewise, the results of one long-term (41 months), double-blind clinical trial involving 170 alcohol-related cirrhosis patients showed that silymarin was an effective treatment for this condition.18

All available data indicate that milk thistle extracts are safe, especially if administered in daily doses of 200–400 mg.

In contrast, two studies concluded that silymarin was ineffective in protecting the liver in patients with alcohol-related hepatitis. One of these studies involved 116 patients. The treatment group received 420 mg/day of silymarin,19 and no improvement was seen in any of these patients. Another negative result was obtained in a controlled trial of 72 alcoholic patients. These patients were treated with 280 mg/day of silymarin.20 The lack of success in these two studies could be due to differences in the treatment protocols or in the severity of the liver disease treated.

Other forms of chronic liver disease (hepatitis/cirrhosis) unrelated to alcohol abuse have also been treated with silymarin. A total of 2,637 patients with chronic liver disease were treated with silymarin (560 mg/day) for 8 weeks.21 Subjective symptoms were reduced in 63% of the patients. Liver enzymes decreased by 34%–46% and there was also a decrease in palpable hepatomegaly by examination. In contrast, a 12-month, double-blind clinical trial in 60 patients with persistent or aggressive hepatitis with or without cirrhosis showed little benefit from silymarin therapy.22 However, there was a trend toward improvement in portal inflammation and parenchymal alterations in this study.

Most of the successful studies mentioned above postulated that the hepatoprotective effect of silymarin was due to its free-radical scavenging properties. Silymarin has been shown to be a potent antioxidant in many studies, confirming this conclusion. Ethanol is the best known and most common hepatotoxic agent. Its mechanism of action is not completely understood. However, several products of ethanol, such as acetaldehyde and various free-radical intermediates, have been shown to bind to and damage proteins, nucleic acids, and lipids in cellular membranes. In isolated rat hepatocytes, silibin caused a dose-dependent inhibition of lipid peroxidation induced by several pro-oxidant agents, one being alcohol.23 Silibin was a strong scavenger of highly reactive HOCl radicals in human granulocytes. Silymarin has been shown to increase the intracellular levels of glutathione, which is necessary in combating the excess oxidative reactions in the liver.24 In addition to protecting against lipid peroxidation, silymarin may have a general membrane-stabilizing effect.25

A stimulatory effect on liver protein synthesis has also been demonstrated in animal studies and could contribute to the overall hepatoprotective effect. Several studies have shown that silibin increases ribosomal RNA in rat liver, hepatocyte cultures, and in isolated liver nuclei via activation of DNA dependent-RNA polymerase I.26 This activation leads to the formation of liver ribosomes, with a resulting increase in protein synthesis. In addition, DNA replication is enhanced by 23%–35% in hepatectimized rats.27 Silibin’s inhibition of the 5-lipoxygenase pathway in rat livers leading to a selective inhibition of leukotriene formation may be another possible component of silymarin’s hepatoprotective effect.28 Leukotrienes contribute to liver damage most likely by acting as chemotactic agents for leukocytes. These leukocytes accumulate in the liver and further the inflammatory process.

Milk thistle is marketed in the U.S. most often as a capsule containing 200 mg of concentrated seed extract (140 mg of silymarin).

Gastrointestinal/Renal/Neuronal Effects: Limited studies have indicated that milk thistle may have protective effects on tissues in other areas of the body as well. Two studies in rats have demonstrated an anti-ulcer effect of silymarin. In the first study, rats were immobilized and subjected to 3°–5°C temperatures for three hours. Orally administered silymarin prevented gastric ulceration induced by this cold-restraint stress.29 It also significantly reduced the number and severity of ulcers without reducing the volume or acidity of gastric secretions. Investigators stated that silymarin’s oxygen free-radical scavenging effect as well as its blockade of the lipoxygenase pathway in the arachidonate cascade was responsible for these experimental results. In the other study, pretreatment with silymarin prevented stomach mucosal injury in a rat gastric injury model.30

Cisplatin is a cytotoxic agent commonly used in chemotherapy of testicular cancer. However, its use is associated with significant kidney damage. The agent is proposed to generate oxygen free radicals, which have the potential to damage renal tubular cells. Silibin could therefore act to prevent this oxidative injury. In a rat model, silibin coadministered with cisplatin resulted in a significant decrease in renal toxicity.31

In patients with diabetic neuropathy, cellular protein mono-ADP-ribosylation in the retina as well as in several other peripheral nerve tissues is excessive. Silibin was found to be a potent mono-ADP-ribosyltransferase inhibitor, acting to normalize protein ADP-ribosylation in a rat model of diabetes.32 Silibin prevented many of the biochemical changes known to occur in these diabetic animals.

Anti-allergic and Anti-inflammatory Effects: Silibin markedly inhibited in vitro antigen-induced histamine release from human basophils.33 The likely mechanism involves stabilization of basophil plasma membrane as well as blockade of calcium entry. Silymarin had anti-inflammatory activity in an acute inflammation experimental animal model.34 Silymarin given orally inhibited carrageenan-induced paw edema in rats in a concentration-related manner. Xylene-induced mouse ear inflammation was significantly inhibited by silymarin in the same study. Silymarin also inhibited leukocyte accumulation in the inflammed tissue. The above studies indicate a potential for utilizing silymarin in the treatment of certain allergic or inflammatory conditions.

Anti-Cancer Activity: Antioxidants protect against tumor promotion by inhibiting oxidative stress induced by tumor promoters. In this regard, silymarin has proven effective in inhibiting the promotion and growth of certain cancerous cells. Silymarin inhibits the transformation of rat tracheal epithelial cells by exposure to benzo[a]pyrene.35 Silymarin also inhibits 7,12 dimethylbenz[a]anthracene-
initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted mammary lesion formation in organ culture.36 Topical application of silymarin to the skin of mice prevented the induction by TPA of the enzyme ornithine decarboxylase, a well-known biochemical marker of tumor promotion.37 An additional study demonstrated a similar protective effect of silymarin on UV radiation-induced nonmelanoma skin cancer in mice.38 Silymarin treatment reduced tumor incidence from 100% to 60% and tumor volume per mouse by 90%.

Side Effects and Toxicity
Toxicity studies in rats and mice have shown that silymarin, even at daily doses as high as 2,500–5,000 mg/kg, produced no adverse toxic effects. In a 12-month study in rats and dogs given up to 2,500 mg/day, no signs of toxicity were seen.39 Most of the human trials performed with silymarin have reported no noticeable side effects. GI disturbances and mild allergic reactions were only rarely reported. Mild laxative effects have also occasionally been reported.40 All available data indicate that milk thistle extracts are safe, especially if administered in daily doses of 200–400 mg.

Available Formulations and Dosage Recommendations
Capsules, tablets, or ethanol extracts are available containing dried or extracted seeds standardized to 70% silymarin. An intravenous formulation is available in Europe and has been utilized in many clinical trials. The German Commission E currently approves milk thistle as a supportive therapy for chronic inflammatory liver conditions and cirrhosis. The average daily recommended dose is 12–15 g (equivalent to 200–400 mg of silymarin). Milk thistle is marketed in the U.S. most often in a capsule form containing 200 mg of a concentrated seed extract, which in turn contains 140 mg of silymarin.41 Pharmacokinetic studies have shown oral doses of silibin are rapidly absorbed from the intestine. Plasma concentrations reach a peak after 2 hours and elimination half-life is 6 hours. Much of the silibin (20%–40%) is recovered in the bile as a glucuronide or as sulfate conjugates.42 Silibin is often combined with phosphatidylcholine to increase its normally poor absorption (20%–50%) from the intestine. Silymarin has a very low water solubility; therefore, milk thistle would be essentially ineffective as a tea.


1. Hobbs C. Milk Thistle: the liver herb. Capitola, CA: Botanical Press. 1992. 2. Flora K, Rosen H, et al. The use of naturopathic remedies for chronic liver disease. Am J Gastroenterol. 1996;91:2654-2655. 3. Brevoort P. The U.S. botanical market-an overview. Herbalgram. 1996;36:49-57. 4. The Review of Natural Products. Facts and Comparisons. Jan 1997. Milk Thistle. 5. Schulte K, et al. Arch Pharm. 1970;303(Jan):7-17. 6. Floersheim G. Treatment of human Amatoxin mushroom poisoning: myths and advances in therapy. Medical Tox. 1987;2:1-9. 7. Hruby K, Csomos G. et al. Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Human Toxicology. 1983;2:183-195. 8. Vigel G, Tuchweber B. Protection by silibinin against Amanita phalloides intoxication in beagles. Tox and Appl Pharm. 1984;73:355-362. 9. Szilard S, Szentgyorgyi D, et al. Protective effect of legalon in workers exposed to organic solvents. Acta Med Hung. 1988;45:249-256. 10. Muriel P, Mourelle M. Prevention by silymarin of membrane alterations in acute CCl4 liver damage. J Applied Tox. 1990;10(4):275-279. 11. Pietrangelo A, Borella F. Antioxidant activity of silybin in vivo during long-term iron overload in rats. Gastroenterology. 1995;109:1941-1949. 12. Muriel P, Garciapina T, et al. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Applied Tox. 1992;12(b):439-442. 13. Palasciano G, Portinacasa P, et al. The effect of silymarin on plasma levels of malondialdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Ther Res. 1994;55:537-545. 14. Saba P, Galeone F, et al. Effetti terapeutici della silimarina nelle epatopatie croniche indotte da psicofarmaci. Gaz Med It. 1976;135:236-251. 15. Feher J, Peak G, et al. Hepatoprotective activity of silymarin (legalon) therapy in patients with chronic liver disease. Orvosi Hetilap. 1989;130;2723-2727. 16. Salmi H, Sarna S. Effect of silymarin on chemical functional and morphological alterations of the liver: a double-blind study. Scand J Gastroenterol. 1982;17;517-521. 17. Fintelmann V, Nachweis A. Nachweis der therapeutischen wirksamkeit von Legalon bei toxischen leberkran kungen im duppleblindversuch. Therapiewoche. 1980;30:5589-5594. 18. Ferenci P, Dragosics B, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatology. 1989;9:105-113. 19. Trinchet J, et al. Int J Clin Pharmacol Ther Toxicol. 1993;31(9):456-460. 20. Bunout D, et al. Rev Med Chil. 1992;120(17):1370-1375. 21. Albrecht M, Freric H, et al. Therapy of toxic liver pathologies with legalon. Z Klin Med. 1992;47:87-92. 22. Kiesewetter E, Leodolter I, et al. Ergebnisse zweir doppelblindstudien zur wirksamkeit von silymarin bei chronischer hepatitis. Leber Magen Darm. 1977;7:318-323. 23. Carini R, Comoglio A. Lipid peroxidation and irreversible damage in the rat hepatocyte model. Biochemical Pharm. 1992;43(10):2111-2115. 24. Dehmlow C, Murawski N. Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. Life Sciences. 1996;58(18):1591-1600. 25. Valenzuela A, et al. Biological Research. 1994 ;27(2):105-112. 26. Sonnenbichler J, Zetl I. Hoppe Seyler’s Z Physiol Chem. 1984;365;555. 27. Sonnenbichler J , Goldberg M, et al. Stimulatory effect of silibinin on the DNA synthesis in partially hepatectomized rat livers: non-response in hepatoma and other malign cell lines. Biochem Pharm. 1986;35(3):538-541. 28. Dehmlow C, Erhard J. Inhibition of kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology. 1996;23(4):749-754. 29. Lastra C, Marhuenda M. Gastric anti-ulcer activity of silymarin, a lipoxygenase inhibitor, in rats. J Pharm Pharmacol. 1992;44:929-931. 30. Lastra C, Martin M. gastroprotection induced by silymarin, the hepatoprotective principle of Silybum marianum in ischemia-reperfusion mucosal injury: role of Neutrophils. Planta Med. 1995;61:116-119. 31. Bokemeyer C, Fels L, et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumor activity. British J Cancer. 1996;74:2036-2041. 32. Gorio A, Donadoni M, et al. Endogenous Mono-ADP-ribosylation in Retina and Peripheral Nervous System. ADP-ribosylation in animal tissue. Editors Haag and Koch-Nolte. 1997, Plenum Press, New York, NY. 33. Miadonna A, Tedeschi A, et al. Effects of silybin on histamine release from human basophil leukocytes. Br J Clin Pharm. 1987;24:747-752. 34. Puerta R, Martinez E, et al. Effect of silymarin on different acute inflammation models and on leukocyte migration. 1996;48:968-970. 35. Steele V, Kelloff G, et al. Inhibition of transformation in cultured rat tracheal epithelial cells by potential chemopreventive agents. Cancer Res. 1990;50:2068-2074. 36. Mehta R, Moon R. Characterization of effective chemopreventive agents in mammary gland in vitro using an initiation-promotion protocol. Anticancer Res. 1991;11:593-596. 37. Agarwal R, Katiyar S. Inhibitory effect of silymarin, an anti-hepatotoxic flavonoid, on 12-O-tetradecnoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and mRNA in SENCAR mice. Carcinogenesis. 1994 ;15(6):1099-1103. 38. Katiyar S, Korman N, et al. Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J National Cancer Institute. 1997;89(8):556-566. 39. Legalon Booklet. Madaus AG D-5000 Koln, West Germany. 1989;91:3-42. 40. Brown D. Drug Store News for the Pharmacist. 1994;4:58-60. 41. Leung A, et al. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. John Wiley and Sons Inc. New York, NY. 1996;366-368. 42. Tyler V. Herbs of Choice: the therapeutic use of phytomedicinals. Pharmaceutical Products Press, New York, NY. 1994;64-65.