Milk Thistle (PDQ®): Integrative, alternative, and complementary therapies - Health Professional Information [NCI]

Overview

NOTE: There is either no new research on this topic or the recent published research is weak and not appropriate for inclusion in the summary. Therefore, the information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of milk thistle as a treatment and adjunct agent for people with cancer.

The summary includes a brief history of milk thistle, a review of the laboratory studies and clinical trials, and a description of adverse effects associated with milk thistle use.

This summary contains the following key information:

• Milk thistle is a plant whose fruit and seeds have been used for more than 2,000 years as a treatment for liver and biliary disorders.
• The active substance in milk thistle, silymarin, is a complex mixture of flavonolignans. Silymarin's primary constituents are the flavonolignan isomers silybins A and B, isosilybins A and B, silychristin (also known as silichristin), silydianin (also known as silidianin), and their flavonoid precursor, taxifolin. In the literature, the mixture of the silybins A and B is often referred to as silibinin.
• Laboratory studies demonstrate that silymarin stabilizes cellular membranes, stimulates detoxification pathways, stimulates regeneration of liver tissue, inhibits the growth of certain cancer cell lines, exerts direct cytotoxic activity toward certain cancer cell lines, and possibly increases the efficacy of certain chemotherapy agents.
• Human clinical trials have investigated milk thistle or silymarin primarily in individuals with hepatitis or cirrhosis, although small studies have been reported about individuals with acute lymphoblastic leukemia, prostate cancer, breast cancer, head and neck cancer, and hepatocellular carcinoma.
• Few adverse side effects have been reported for milk thistle, but little information about interactions with anticancer medications, radiation therapy, or other drugs is available.
• Milk thistle is available in the United States as a dietary supplement.

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

General Information

The botanical name for milk thistle is Silybum marianum (L.) Gaertn. Milk thistle is also referred to as the following:[1]

• Holy thistle.
• Marian thistle.
• Mary thistle.
• Our Lady's thistle.
• St. Mary thistle.
• Wild artichoke.
• Mariendistel (German).
• Chardon-Marie (French).

The plant is indigenous to Europe but can also be found in the United States and South America. Traditionally, the leaves have been used in salads, and the fruit of the flower has been roasted as a coffee substitute. The seed-like fruits (achenes) of milk thistle are the medicinal parts of the plant.[1] The active constituent of milk thistle is silymarin, which is a complex mixture of flavonoids and flavonoid derivatives, the flavonolignans. The major constituents of silymarin are the three diastereomeric pairs, silybins A and B (also called silibinin), isosilybins A and B, silychristin, isosilychristin, and silydianin.[2,3] Most supplements are standardized according to their silybin content. Special formulations of silymarin and/or the silybins have been developed to enhance their bioavailability by conjugation with phosphatidylcholine. Because of the lipophilic nature of its active constituents, milk thistle is usually administered as an extract in capsule or tablet form rather than as an herbal tea. In Europe, silybin is administered intravenously as the only effective antidote for Amanita phalloides (Fr.).[4] Humans exposed to this mushroom toxin develop serious liver failure that progresses to death.

Several companies distribute milk thistle as a dietary supplement. In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. Because dietary supplements are not formally reviewed for manufacturing consistency, ingredients may vary considerably from lot to lot and there is no guarantee that ingredients claimed on product labels are present (or are present in the specified amounts). The FDA has not approved the use of milk thistle as a treatment for cancer or any other medical condition.

Despite milk thistle's long history of being used to treat liver and biliary complaints, it was not until 1968 that silymarin was isolated from the seeds of the plant, and it was proposed that silymarin might be the active ingredient.[5] Researchers have investigated the role that silibinin may play in the treatment of hepatitis and cirrhosis. Most studies have investigated the isolated compound silymarin or its most active isomer silybin, rather than the herbal plant in its whole form.

Silymarin is most well known for its purported effects on the liver. In laboratory studies, silymarin has been found to stabilize cell membranes, thus preventing toxic chemicals from entering the cell.[4,6,7,8] Laboratory studies have also demonstrated that silymarin stimulates synthesis and activity of enzymes responsible for detoxification pathways.[7,8,9,10,11,12,13,14,15,16,17,18] Specifically, silymarin has been shown to stimulate the glutathione S-transferase pathway and alter the intracellular concentration of glutathione (a potent antioxidant). Silymarin has also been shown to neutralize a wide range of free radicals. Reports that associate the flavonolignans with potential estrogenic effect (e.g., via mediation of the estrogen receptor) are sparse and currently not supported by in vitro or in vivo experimental evidence.[19]

Laboratory experiments conducted using cancer cell lines have suggested that silibinin enhances the efficacy of cisplatin and doxorubicin against ovarian and breast cancer cells.[20] Silybin appears to have direct anticancer effects against prostate, breast, and ectocervical tumor cells.[21] Silybin may also affect the cell cycle in cancer cells by slowing down cell growth, as demonstrated with prostate cancer cell lines.[22] Laboratory studies using leukemia cell lines found that silybin did not stimulate growth of leukemia cells.[23]

Most clinical trials have investigated silymarin's effectiveness in the treatment of patients with hepatitis, cirrhosis, or biliary disorders.[24,25,26,27,28,29,30,31,32,33] These studies have employed a wide range of doses (120–560 mg /day) and have yielded conflicting results.[34,35] The most commonly reported adverse effects are a mild laxative effect and gastrointestinal upset.

References:

1. PDR® for Herbal Medicines™. 2nd ed. Medical Economics, 2000.
2. Lee DY, Liu Y: Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, Isolated from Silybum marianum (milk thistle). J Nat Prod 66 (9): 1171-4, 2003.
3. Napolitano JG, Lankin DC, Graf TN, et al.: HiFSA fingerprinting applied to isomers with near-identical NMR spectra: the silybin/isosilybin case. J Org Chem 78 (7): 2827-39, 2013.
4. Hruby K, Csomos G, Fuhrmann M, et al.: Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2 (2): 183-95, 1983.
5. Wagner H, Hörhammer L, Münster R: [On the chemistry of silymarin (silybin), the active principle of the fruits from Silybum marianum (L.) Gaertn. (Carduus marianus L.)] Arzneimittelforschung 18 (6): 688-96, 1968.
6. Campos R, Garrido A, Guerra R, et al.: Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 55 (5): 417-9, 1989.
7. Farghali H, Kameniková L, Hynie S, et al.: Silymarin effects on intracellular calcuim and cytotoxicity: a study in perfused rat hepatocytes after oxidative stress injury. Pharmacol Res 41 (2): 231-7, 2000.
8. Lettéron P, Labbe G, Degott C, et al.: Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem Pharmacol 39 (12): 2027-34, 1990.
9. Zhao J, Agarwal R: Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 20 (11): 2101-8, 1999.
10. Valenzuela A, Guerra R, Videla LA: Antioxidant properties of the flavonoids silybin and (+)-cyanidanol-3: comparison with butylated hydroxyanisole and butylated hydroxytoluene. Planta Med (6): 438-40, 1986.
11. Valenzuela A, Guerra R, Garrido A: Silybin dihemisuccinate protects rat erythrocytes against phenylhydrazine-induced lipid peroxidation and hemolysis. Planta Med 53 (5): 402-5, 1987.
12. Valenzuela A, Aspillaga M, Vial S, et al.: Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Med 55 (5): 420-2, 1989.
13. Mira ML, Azevedo MS, Manso C: The neutralization of hydroxyl radical by silibin, sorbinil and bendazac. Free Radic Res Commun 4 (2): 125-9, 1987.
14. Mira L, Silva M, Manso CF: Scavenging of reactive oxygen species by silibinin dihemisuccinate. Biochem Pharmacol 48 (4): 753-9, 1994.
15. Koch HP, Löffler E: Influence of silymarin and some flavonoids on lipid peroxidation in human platelets. Methods Find Exp Clin Pharmacol 7 (1): 13-8, 1985.
16. Garrido A, Arancibia C, Campos R, et al.: Acetaminophen does not induce oxidative stress in isolated rat hepatocytes: its probable antioxidant effect is potentiated by the flavonoid silybin. Pharmacol Toxicol 69 (1): 9-12, 1991.
17. Bosisio E, Benelli C, Pirola O: Effect of the flavanolignans of Silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes. Pharmacol Res 25 (2): 147-54, 1992 Feb-Mar.
18. Altorjay I, Dalmi L, Sári B, et al.: The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. Acta Physiol Hung 80 (1-4): 375-80, 1992.
19. 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 17 (2): 116-25, 2010.
20. Scambia G, De Vincenzo R, Ranelletti FO, et al.: Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer 32A (5): 877-82, 1996.
21. Bhatia N, Zhao J, Wolf DM, et al.: Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 147 (1-2): 77-84, 1999.
22. Zi X, Agarwal R: Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 96 (13): 7490-5, 1999.
23. Duthie SJ, Johnson W, Dobson VL: The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimdines) and growth in human cells. Mutat Res 390 (1-2): 141-51, 1997.
24. Vailati A, Aristia L, Sozzé E, et al.: Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64 (3), 219-28, 1993.
25. Salmi HA, Sarna S: Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 17 (4): 517-21, 1982.
26. Parés A, Planas R, Torres M, et al.: Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 28 (4): 615-21, 1998.
27. Moscarella S, Giusti A, Marra F, et al.: Therapeutic and antilipoperoxidant effects of silybin-phosphatidylcholine complex in chronic liver disease: preliminary results. Current Therapeutic Research 53 (1): 98-102.
28. Marena C, Lampertico M: Preliminary clinical development of silipide: a new complex of silybin in toxic liver disorders. Planta Med 57 (Suppl 2): A124-5, 1991.
29. Marcelli R, Bizzoni P, Conte D, et al.: Randomized controlled study of the efficacy and tolerability of a short course of IdB 1016 in the treatment of chronic persistent hepatitis. European Bulletin of Drug Research 1 (3): 131-5, 1992.
30. Flisiak R, Prokopowicz D: Effect of misoprostol on the course of viral hepatitis B. Hepatogastroenterology 44 (17): 1419-25, 1997 Sep-Oct.
31. Ferenci P: [Therapy of chronic hepatitis C] Wien Med Wochenschr 150 (23-24): 481-5, 2000.
32. Buzzelli G, Moscarella S, Giusti A, et al.: Therapeutic effects of a new silybin complex in chronic active hepatitis (CAH). [Abstract] Hellenic Journal of Gastroenterology 5 (Suppl): A-151, 38, 1992.
33. Albrecht M, Frerick H, Kuhn U, et al.: Therapy of toxic liver pathologies with Legalon®. Z Klin Med 47: 87-92, 1992.
34. Rambaldi A, Jacobs BP, Gluud C: Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev (4): CD003620, 2007.
35. Yang Z, Zhuang L, Lu Y, et al.: Effects and tolerance of silymarin (milk thistle) in chronic hepatitis C virus infection patients: a meta-analysis of randomized controlled trials. Biomed Res Int 2014: 941085, 2014.

History

Milk thistle has been used for more than 2,000 years, primarily as a treatment for liver dysfunction. The oldest reported use of milk thistle was by Dioscorides (A.D. 40–90), who recommended the herb as a treatment for serpent bites.[1] Pliny the Elder (A.D. 23–79) reported that the juice of the plant mixed with honey is indicated for "carrying off bile."[1,2] In the Middle Ages, milk thistle was revered as an antidote for liver toxins.[1,2] The British herbalist Culpepper reported milk thistle to be effective for relieving obstructions of the liver.[1,2] In 1898, eclectic physicians Felter and Lloyd stated the herb was good for congestion of the liver, spleen, and kidney.[1,2] American Indian or Alaska Native people use milk thistle to treat boils and other skin diseases. Homeopathic practitioners use preparations from the seeds to treat jaundice, gallstones, peritonitis, hemorrhage, bronchitis, and varicose veins.[2] The German Commission E recommends milk thistle use for dyspeptic complaints, toxin-induced liver damage, hepatic cirrhosis, and as a supportive therapy for chronic inflammatory liver conditions.[3]

References:

1. Flora K, Hahn M, Rosen H, et al.: Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 93 (2): 139-43, 1998.
2. Foster S: Milk Thistle: Silybum marianum. Rev. ed. American Botanical Council, 1999.
3. Blumenthal M, Busse WR, et al., eds.: The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. American Botanical Council, 1998.

Laboratory / Animal / Preclinical Studies

Research studies conducted in the laboratory have investigated the properties of silymarin or its isomer silybin using cell lines and animal models. Other substances in milk thistle have not been extensively studied.

Several research studies have investigated the effects of silymarin or silybin in a noncancer context. These studies have tested silymarin or silybin:

• In healthy animal liver and kidney cells.
• As a prophylaxis against toxic chemicals.
• In stimulating detoxification pathways (enzyme concentrations and activity).

Silymarin or silybin has also been investigated in cancer models. The effects of silymarin and/or silybin have been investigated in the following cell lines:

• Prostate (DU 145, LNCaP, PC-3).[1,2,3,4,5,6]
• Breast (MDA-MB 468, MCF-7).[7,8,9]
• Hepatic (HepG2).[10,11]
• Epidermoid (A431).[11]
• Colon (Caco-2).[12]
• Ovarian (OVCA 433, A2780).[13]
• Histiocytic lymphoma (U-937).[14]
• Leukemia (HL-60).[15,16]

In animal tumor models, tongue cancer,[17] skin cancer,[18,19,20,21,22,23]bladder cancer,[24] and adenocarcinoma of the colon [25,26] and small intestine [26] have been investigated. These studies have tested the ability of silymarin or silibinin to:

• Mitigate the toxicity associated with chemotherapy agents.
• Enhance the efficacy of chemotherapy agents.
• Inhibit the growth of cancer cell lines and inhibit tumor initiation or tumor promotion.

Laboratory data suggest that silymarin and silybin protect the liver from damage induced by toxic chemicals. Animal studies have found that liver cells treated with silybin and then exposed to toxins do not incur cell damage or death at the same rate as liver cells that are not treated with silybin. This finding suggests that silybin can prevent toxins from entering the cell or effectively exports toxins out of the cell before damage ensues.[11,27,28,29,30,31] Alternatively, this may be related to the effect of silymarin on detoxification systems. In vitro data have shown silybin to stimulate and/or inhibit phase I detoxification pathways in silybin-treated human liver cells. However, this effect was found to be dose-dependent, and these levels are not physiologically attainable with the current manufacturer dose recommendations.[32,33]

Silymarin and silybin have also been found to accelerate cell regeneration in the liver through stimulation of precursors to DNA synthesis and enhancement of production of the cellular enzymes required for DNA synthesis.[34,35,36,37,38,39] Silymarin has been shown to mitigate oxidative stress in cells treated with pro-oxidant compounds.[40]

While some reports exist about the estrogenic effects assigned to silybin and silybin-containing materials,[41] the observed effects are moderate, and the molecular mechanisms are not yet understood. Some evidence exists about the positive impact of these milk thistle compounds on bone density in rats and mice that have undergone ovariectomy.[42]

Silibinin inhibits prostate cancer cell–induced osteoclastogenesis, suggesting that silibinin may be useful clinically for the treatment of bone metastases. Silibinin targets prostate cancer cell–induced osteoclast differentiation and activity of murine macrophage cells.[43]

Although many of these studies have produced encouraging results, none of the findings have been replicated in human clinical trials.

Table 1. Inhibit the Growth of Cancer Cell Lines and Inhibit Tumor Initiation

Study Type/Reference	Cancer Type	Outcome
In vitro[7]	Prostate, breast, cervical	Cancer chemopreventive andanticarcinogeniceffects of silymarin were reported
In vitro[15]	Leukemia	Silybinin stimulated HL-60cell differentiationalong the monocytic pathway
In vitro[44]	Epidermal	Silymarin inhibited cell growth by inducing G1 and G2-M arrest in cell cycle progression
In vitro[45]	Epidermal	Silymarin inhibitedcell proliferationand induced cell growth arrest
In vitro[46]	Colon	Silibinin suppressedcolorectal cancercell growth and progression, possibly through itsanti-inflammatoryactivity, by interfering withnuclear factor-kappa B(NF-kappa B) activation; In human colorectal cancer SW480, LoVo, and HT29 cells, silibinin treatment strongly inhibitedtumor necrosis factoralpha–induced NF-kappa B activation and decreased nuclear levels of both p65 and p50 subunits
In vivo[2];[19];[24];[47];[48];[49]	Various	Inhibitedtumor volume; reduced tumorincidence; exerted protective and preventive effects against tumor promotion

Several in vitro studies have explored anticancer effects of milk thistle extracts. Silybinin has been shown to inhibit cell proliferation by inducing cell cycle arrest at the G1 and G2-M transition in epidermal,[7,44,45] prostate,[7] breast,[7] and cervical [7] cancer cell lines. One study also demonstrated that growth of colon cancer cell lines was inhibited by silibinin, apparently through suppression of NF-kappa B.[46] Finally, silymarin has also been shown to induce differentiation in a human leukemia cell line.[15]

Table 2. Enhance the Efficacy of Chemotherapy Agents (In VitroStudies)

Reference	Cancer Type	Outcome
[50]	Glioma	Silibinin potentiated the effect ofetoposidebut notirinotecanin LN229 cells
[13]	Ovarian, breast	Silybin potentiated the cytotoxic effect ofcisplatinand doxorubicin in MCF-7 and A2780 cells
[51]	Ovarian	Silybin potentiated the cytotoxic effect of cisplatin in A2780 cells
[52]	Prostate	Silybin potentiated the cytotoxic effect of DU145 cells

Other in vitro studies have demonstrated that components of milk thistle extract can enhance the effects of certain cytotoxic agents against various cancer types (i.e., etoposide against LN229 glioma cells,[50] cisplatin against A2780 ovarian cancer cells [13,51] and MCF-7 breast cancer cells,[13] and tumor necrosis factor alpha against DU145 prostate cancer cells [52]).

References:

1. Zi X, Agarwal R: Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 96 (13): 7490-5, 1999.
2. Singh RP, Dhanalakshmi S, Tyagi AK, et al.: Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Res 62 (11): 3063-9, 2002.
3. Zi X, Zhang J, Agarwal R, et al.: Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Res 60 (20): 5617-20, 2000.
4. Zi X, Grasso AW, Kung HJ, et al.: A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res 58 (9): 1920-9, 1998.
5. Sharma Y, Agarwal C, Singh AK, et al.: Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells. Mol Carcinog 30 (4): 224-36, 2001.
6. Flaig TW, Glodé M, Gustafson D, et al.: A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer. Prostate 70 (8): 848-55, 2010.
7. Bhatia N, Zhao J, Wolf DM, et al.: Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 147 (1-2): 77-84, 1999.
8. Jiang C, Agarwal R, Lü J: Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochem Biophys Res Commun 276 (1): 371-8, 2000.
9. Zi X, Feyes DK, Agarwal R: Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins. Clin Cancer Res 4 (4): 1055-64, 1998.
10. Saliou C, Rihn B, Cillard J, et al.: Selective inhibition of NF-kappaB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence for different activating pathways. FEBS Lett 440 (1-2): 8-12, 1998.
11. Shear NH, Malkiewicz IM, Klein D, et al.: Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacol 8 (6): 279-91, 1995.
12. Duthie SJ, Johnson W, Dobson VL: The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimdines) and growth in human cells. Mutat Res 390 (1-2): 141-51, 1997.
13. Scambia G, De Vincenzo R, Ranelletti FO, et al.: Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer 32A (5): 877-82, 1996.
14. Manna SK, Mukhopadhyay A, Van NT, et al.: Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol 163 (12): 6800-9, 1999.
15. Kang SN, Lee MH, Kim KM, et al.: Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C. Biochem Pharmacol 61 (12): 1487-95, 2001.
16. Clinton SK: The dietary antioxidant network and prostate carcinoma. Cancer 86 (9): 1629-31, 1999.
17. Yanaida Y, Kohno H, Yoshida K, et al.: Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis 23 (5): 787-94, 2002.
18. Agarwal R, Katiyar SK, Lundgren DW, et al.: Inhibitory effect of silymarin, an anti-hepatotoxic flavonoid, on 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and mRNA in SENCAR mice. Carcinogenesis 15 (6): 1099-103, 1994.
19. Katiyar SK, Korman NJ, Mukhtar H, et al.: Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 89 (8): 556-66, 1997.
20. Lahiri-Chatterjee M, Katiyar SK, Mohan RR, et al.: A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model. Cancer Res 59 (3): 622-32, 1999.
21. Singh RP, Tyagi AK, Zhao J, et al.: Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. Carcinogenesis 23 (3): 499-510, 2002.
22. Zhao J, Sharma Y, Agarwal R: Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion. Mol Carcinog 26 (4): 321-33, 1999.
23. Zhao J, Lahiri-Chatterjee M, Sharma Y, et al.: Inhibitory effect of a flavonoid antioxidant silymarin on benzoyl peroxide-induced tumor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis 21 (4): 811-6, 2000.
24. Vinh PQ, Sugie S, Tanaka T, et al.: Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice. Jpn J Cancer Res 93 (1): 42-9, 2002.
25. Kohno H, Tanaka T, Kawabata K, et al.: Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer 101 (5): 461-8, 2002.
26. Gershbein LL: Action of dietary trypsin, pressed coffee oil, silymarin and iron salt on 1,2-dimethylhydrazine tumorigenesis by gavage. Anticancer Res 14 (3A): 1113-6, 1994 May-Jun.
27. Campos R, Garrido A, Guerra R, et al.: Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 55 (5): 417-9, 1989.
28. Farghali H, Kameniková L, Hynie S, et al.: Silymarin effects on intracellular calcuim and cytotoxicity: a study in perfused rat hepatocytes after oxidative stress injury. Pharmacol Res 41 (2): 231-7, 2000.
29. Lettéron P, Labbe G, Degott C, et al.: Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem Pharmacol 39 (12): 2027-34, 1990.
30. Valenzuela A, Guerra R, Garrido A: Silybin dihemisuccinate protects rat erythrocytes against phenylhydrazine-induced lipid peroxidation and hemolysis. Planta Med 53 (5): 402-5, 1987.
31. Campos R, Garrido A, Guerra R, et al.: Acetaminophen hepatotoxicity in rats is attenuated by silybin dihemisuccinate. Prog Clin Biol Res 280: 375-8, 1988.
32. Zuber R, Modrianský M, Dvorák Z, et al.: Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 16 (7): 632-8, 2002.
33. Venkataramanan R, Ramachandran V, Komoroski BJ, et al.: Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 28 (11): 1270-3, 2000.
34. Sonnenbichler J, Mattersberger J, Rosen H: [Stimulation of RNA synthesis in rat liver and isolated hepatocytes by silybin, an antihepatotoxic agent from Silybum marianum L. Gaertn (author's transl)] Hoppe Seylers Z Physiol Chem 357 (8): 1171-80, 1976.
35. Sonnenbichler J, Zetl I: [Mechanism of action of silibinin. V. Effect of silibinin on the synthesis of ribosomal RNA, mRNA and tRNA in rat liver in vivo] Hoppe Seylers Z Physiol Chem 365 (5): 555-66, 1984.
36. Sonnenbichler J, Zetl I: Biochemical effects of the flavonolignane silibinin on RNA, protein and DNA synthesis in rat livers. Prog Clin Biol Res 213: 319-31, 1986.
37. Sonnenbichler J, Goldberg M, Hane L, 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 Pharmacol 35 (3): 538-41, 1986.
38. Machicao F, Sonnenbichler J: Mechanism of the stimulation of RNA synthesis in rat liver nuclei by silybin. Hoppe Seylers Z Physiol Chem 358 (2): 141-7, 1977.
39. Dehmlow C, Erhard J, de Groot H: Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology 23 (4): 749-54, 1996.
40. Malekinejad H, Rahmani F, Valivande-Azar S, et al.: Long-term administration of Silymarin augments proinflammatory mediators in the hippocampus of rats: evidence for antioxidant and pro-oxidant effects. Hum Exp Toxicol 31 (9): 921-30, 2012.
41. 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 17 (2): 116-25, 2010.
42. Kim JL, Kim YH, Kang MK, et al.: Antiosteoclastic activity of milk thistle extract after ovariectomy to suppress estrogen deficiency-induced osteoporosis. Biomed Res Int 2013: 919374, 2013.
43. Kavitha CV, Deep G, Gangar SC, et al.: Silibinin inhibits prostate cancer cells- and RANKL-induced osteoclastogenesis by targeting NFATc1, NF-κB, and AP-1 activation in RAW264.7 cells. Mol Carcinog 53 (3): 169-80, 2014.
44. Zi X, Agarwal R: Modulation of mitogen-activated protein kinase activation and cell cycle regulators by the potent skin cancer preventive agent silymarin. Biochem Biophys Res Commun 263 (2): 528-36, 1999.
45. Ahmad N, Gali H, Javed S, et al.: Skin cancer chemopreventive effects of a flavonoid antioxidant silymarin are mediated via impairment of receptor tyrosine kinase signaling and perturbation in cell cycle progression. Biochem Biophys Res Commun 247 (2): 294-301, 1998.
46. Raina K, Agarwal C, Agarwal R: Effect of silibinin in human colorectal cancer cells: targeting the activation of NF-κB signaling. Mol Carcinog 52 (3): 195-206, 2013.
47. Zi X, Mukhtar H, Agarwal R: Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: inhibition of mRNA expression of an endogenous tumor promoter TNF alpha. Biochem Biophys Res Commun 239 (1): 334-9, 1997.
48. Lee MH, Huang Z, Kim DJ, et al.: Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth. Cancer Prev Res (Phila) 6 (5): 455-65, 2013.
49. Velmurugan B, Gangar SC, Kaur M, et al.: Silibinin exerts sustained growth suppressive effect against human colon carcinoma SW480 xenograft by targeting multiple signaling molecules. Pharm Res 27 (10): 2085-97, 2010.
50. Elhag R, Mazzio EA, Soliman KF: The effect of silibinin in enhancing toxicity of temozolomide and etoposide in p53 and PTEN-mutated resistant glioma cell lines. Anticancer Res 35 (3): 1263-9, 2015.
51. Giacomelli S, Gallo D, Apollonio P, et al.: Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin. Life Sci 70 (12): 1447-59, 2002.
52. Dhanalakshmi S, Singh RP, Agarwal C, et al.: Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-induced apoptosis. Oncogene 21 (11): 1759-67, 2002.

Human / Clinical Studies

Several small studies have investigated silymarin for its direct treatment of cancer or for its effects on treatment-related toxicity.

A phase I study was designed to determine the maximum tolerated dose per day of silybin phosphatidylcholine (Siliphos) in patients with advanced hepatocellular carcinoma (HCC) and hepatic dysfunction.[1] Three patients were enrolled in this single-institution trial. All patients who were enrolled consumed 2 g /d of the study agent in divided doses. Serum concentrations of silibinin and silibinin glucuronide increased within 1 to 3 weeks. In all three patients, liver function abnormalities and tumor marker alpha-fetoprotein progressed, but after day 56, the third patient showed some improvement in liver function abnormalities and inflammatory biomarkers. All three patients died within 23 to 69 days of enrolling in the trial, likely from hepatic failure, but it could not be ruled out that deaths were possibly caused by the study drug. This patient population may have been too ill to benefit from an intervention designed to improve liver function tests.

In a double-blind, placebo-controlled trial, 50 children who were undergoing treatment for acute lymphoblastic leukemia, and who had chemotherapy -related hepatotoxicity, were randomly assigned to receive silymarin or placebo for a 4-week period.[2] Four weeks after completion of the intervention, the silymarin group had a significantly lower aspartate aminotransferase (AST) (P = .05) and a trend towards a significantly lower alanine aminotransferase (ALT) (P = .07). Fewer chemotherapy dose reductions were observed in the silymarin group compared with the placebo group; however, the difference was not significant. No adverse events were reported.

A randomized placebo-controlled study of 37 men, who had a status of post–radical prostatectomy, investigated whether a 6-month daily administration of a silymarin and selenium combination would alter basic clinical chemistry, oxidative stress markers, and improve the quality-of-life (QOL) score in men after radical prostatectomy.[3] The 6-month daily administration of silymarin and selenium improved the QOL score, decreased low-density lipoproteins and total cholesterol, and increased serum selenium levels. The combination had no effect on blood antioxidant status and no influence on testosterone level. No adverse events were recorded. No improvement was found in the placebo group.

Another randomized placebo-controlled study of 30 patients with head and neck cancer investigated a 6-week course of silymarin for the prevention of radiation therapy –associated mucositis. Mucositis scores (World Health Organization, National Cancer Institute Common Toxicity Criteria) were significantly lower in the silymarin group.[4] Delay in progression to mucositis was also observed.

In a nonrandomized observational trial of 101 women with breast cancer who had undergone breast-conserving surgery followed by radiation therapy with 50.4 Gy plus a boost of 9 Gy to 16 Gy, a silymarin-based cream (Leviaderm) was tested in 51 women compared with panthenol-containing cream, the standard of care (SOC), which was given interventionally if local skin lesions occurred and administered to 50 women.[5] The acute skin reactions were classified according to the Radiation Therapy Oncology Group and visual analog scale scores. The median time to toxicity was prolonged significantly with the silymarin-based cream (45 vs. 29 days [SOC], P < .0001). Only 9.8% of patients using the silymarin-based cream showed grade 2 toxicity in week 5 of radiation therapy, compared with 52% in the SOC group. At the end of radiation therapy, 23.5% of the women in the silymarin-based study group developed no skin reactions compared with 2% of the women in the SOC group, while grade 3 toxicity occurred in only 2% of women in the silymarin-based group and in 28% of women in the SOC group.

Hepatitis

Most clinical trials of milk thistle have been conducted in patients with either hepatitis or cirrhosis. Other studies have investigated the use of milk thistle in patients with hyperlipidemia, diabetes, and Amanita phalloides (Fr.) mushroom poisoning. Ten randomized trials [2,6,7,8,9,10,11,12,13,14] have been reported in patients with hepatitis or cirrhosis, and one randomized trial has reported the use of silymarin as a prophylaxis to iatrogenic hepatic toxicity.[15]Endpoints for these trials have included serum levels of bilirubin and/or the liver enzymes AST and ALT, as higher levels are an indicator of liver inflammation, damage, or disease. The lowering of these serum levels is a sign of an improving condition. In patients with hepatitis A and hepatitis B, one clinical trial found silymarin (140 mg daily for 3–4 wk) resulting in lower levels of AST, ALT, and bilirubin by day 5, compared with a placebo group.[16] In another randomized, placebo-controlled study of patients with viral hepatitis B, silymarin (210 mg/d) had no effect on course of disease or enzyme levels.[9]

A randomized, controlled trial supported by the National Institute of Diabetes and Digestive and Kidney Diseases examined patients with chronic hepatitis C who had failed previous antiviral therapy. All patients had advanced chronic liver disease consisting of histologic evidence of either marked fibrosis or cirrhosis. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial used a half dose of pegylated interferon versus no treatment; the treatment was to be administered for 3.5 years.[14] The aim was to reduce progression of chronic hepatitis C, particularly in the development of HCC. Among 1,145 study participants, 56% had never taken herbal products, 21% admitted past use, and 23% were using herbal products at enrollment. Silymarin constituted 72% of the 60 herbal products used at enrollment. Users had significantly fewer symptoms and a better QOL than did nonusers. In follow-up, silymarin use was associated with reduced progression of fibrosis to cirrhosis but without an impact on clinical outcome.[17]

Although there are many reports on the use of herbals for the treatment of chronic liver diseases, most treatment trials have suffered because of the following:

• Poor scientific design.
• Uncertainty about the required dosage of herbals.
• An insufficient number of study participants.

A review of complementary and alternative medications (CAM) to treat liver diseases focused on classification, epidemiology, and the philosophy of CAM and reviewed the criteria needed to conduct a scientifically valid research study focusing on herbal products.[18]

There has been skepticism regarding the evidence that silymarin has a direct impact on the hepatitis C virus (HCV)—some studies suggest that it does, but most studies cannot confirm these reports. However, at least two articles in major journals have suggested that silymarin or its congeners may inhibit HCV. In one report, investigators found that a standardized silymarin extract inhibited tumor necrosis factor -alpha in anti-CD3–stimulated human peripheral blood mononuclear cells and nuclear factor-kappa B –dependent transcription in human hepatoma Huh-7 cells.[19] Silymarin also displayed prophylactic and therapeutic effects against HCV infection, and when combined with interferon-alpha, was more inhibitory of HCV replication than was interferon alone. This indicates that silymarin has anti-inflammatory and antiviral effects in patients with chronic hepatitis C.

In a case series /phase I study, patients with HCV were treated with intravenous (IV) silibinin with and without PEG-interferon and ribavirin.[20] In the case series, 16 HCV nonresponder patients were administered IV silibinin in a dose of 10 mg/kg/d for 7 days. Subjects then began treatment with oral silibinin in combination with PEG-interferon and ribavirin for 12 weeks. At the end of the study period, all patients were positive for HCV RNA, but 5 of 13 completed patients had reductions in HCV RNA. Significance was not reported. In the same study, the authors presented results of a phase I study in which 20 patients were administered 5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg of silibinin for 14 days in combination with PEG-interferon and ribavirin (initiated on day 8). A significant drop in HCV RNA was observed on day 7 in patients administered silibinin doses of 10 mg/kg, 15 mg/kg, and 20 mg/kg. Further declines were observed in HCV RNA with administration of PEG-interferon and ribavirin. Except for mild gastroenteritis, IV silibinin monotherapy was well tolerated.

Patients in a phase I pharmacokinetics study for the evaluation of absorption characteristics and determination of effective doses received increasing oral doses of silymarin.[21] A subsequent multicenter, double-blind, placebo-controlled trial, involving 154 patients with chronic HCV infection who had previously failed interferon-based treatment and had raised ALT levels, was performed.[22] Patients were randomly assigned to receive 420 mg of silymarin, 700 mg of silymarin, or a matching placebo orally 3 times per day for 24 weeks, with the aim of reducing ALT levels to less than 40 U/L or less than 65 U/L if this was at least a 50% decline from the baseline level. In this study, silymarin given orally in higher-than-usual doses failed to significantly reduce serum ALT levels. No significant adverse effects were associated with silymarin. In one of the largest observational studies involving 2,637 patients with chronic liver disease, 8 weeks of treatment with 560 mg of silymarin per day resulted in reductions of serum AST, ALT, and gamma-glutamyltranspeptidase (GGT, a marker of bile duct disease), and a decrease in the frequency of palpable hepatomegaly.[23]

Mushroom Poisoning

Another published report describes the use of silibinin as the only effective antidote in patients with liver damage from Amanita phalloides (Fr.) poisoning.[24] Patients were administered doses of 35 to 55 mg/kg of body weight, with no reports of adverse events. A retrospective review of the treatment for Amanita phalloides (Fr.) poisoning suggests that silymarin has been shown to be an effective drug in the treatment of this mushroom poisoning.[25] The beneficial effect of silymarin on liver histology suggests it has a role in the prevention of hepatitis and/or HCC; however, no clinical trials in humans have investigated these uses of silymarin.

Iron Chelation

Silymarin was found to be beneficial as an adjunct to the iron chelator desferrioxamine in patients with transfusion -dependent beta-thalassemia major.[26] In a study of 97 patients, significant decreases in markers of iron overload (serum ferritin, serum iron, hepcidin, and soluble transferring receptor) were observed in the patients who received silymarin as compared with those who received a placebo.

Table 3. Clinical Studies Investigating Silymarin or Its Components

ALL = acute lymphoblastic leukemia; ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCV = hepatitis C virus; IV = intravenous; LFT = liver function test; No. = number; QOL = quality of life; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamate pyruvate transaminase.
a Number of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studiedAND for whom results were reported;historical control subjectsare not included in number of patients enrolled.
b Nine patients were excluded from the final analysis (seven patients missed appointments, and two patients were missing data requirements).
c Study investigated dose-response relationships. Patients were randomly assigned to receive 80 mg 2 times a day (n = 20), 120 mg 2 times a day (n = 20), or 120 mg 3 times a day (n = 20). The effective dose was 120 mg 2 times a day and 120 mg 3 times a day.
d Patients were randomly assigned to the misoprostol and silymarin groups. Twelve nonrandomized patients served as controls.
e Fifteen patients were lost to follow-up, 18 patients weredeceased, and 42 patients withdrew from the study (adverse events, noncompliance, and voluntary withdrawal).
f Eleven patients did not complete the trial (voluntary withdrawal,disease progression, and one adverse event).
g For information about levels of evidence analysis and scores, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.
Prevention or Treatment of Liver Disease/Dysfunction
Reference	Condition or Cancer Type	Trial Design	Route of Administration and Dose	Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)a	Results	Level of Evidence Score g
[7]	Acute and subacute liver disease	Double-blind, placebo-controlled, randomized clinical trial	Silymarin; 420 mg/d; oral (tablets)	106b; 47; 50	Decreased LFTs; improved histology	1iDiii
[1]	Advanced hepatocellular carcinoma and hepatic dysfunction	Phase I, open-label, dose-escalation trial	Silybin phosphatidylcholine; 3 g/d in 3 divided doses; oral (powder mixed in applesauce)	3; 3; none	Nodose-limitingtoxicity was identified	2D
[9]	Viral hepatitis B	Controlled, randomized trial	Silymarin; 210 mg/d; oral	52d; 20-silymarin, 20-misoprostol; 12	Silymarin did not have an effect on the course of disease, but misoprostol reduced the degree ofhepatocytedamage during the course of the disease	1iiDiii
[6]	Viral oralcoholichepatitis	Phase II, randomized, open trial	Silybin and phosphatidylcholine; 80 mg twice/d, 120 mg twice/d, or 120 mg 3 times/d; oral	60c; 60; 0	Reduction in ALT and gamma-glutamyl transpeptidase	1iiDiii
[14]	Chronic hepatitis C	Randomized, controlled trial	Silymarin; no dose listed; oral	1145; 195; 772	Decreasedfatigue,nausea, liver pain,anorexia, and muscle andjointpain	1iiC
[20]	HCV nonresponder patients	Nonrandomized, controlled trial	Silibinin; 10 mg/kg/d; IV	16; 16; 0 (protocol1) and 20; 20; 0 (protocol 2)	Increased antiviral effect with silibinin when antiviral therapy began after silibinin was started	2D
[11]	Cirrhosis	Double-blind, placebo-controlled, randomized clinical trial	Silymarin; 140 mg/d; oral	170; 87; 83	Decrease in SGOT and SGPT in silymarin-treated group	1iB
[13]	Diabetic patients with cirrhosis	Controlled, randomized trial	Silymarin; 600 mg (200 mg 3 times/d); oral	60; 30; 30	Decrease in SGOT and SGPT in silymarin-treated group	1iiDiii
[12]	Alcohol-induced cirrhosis	Double-blind, placebo-controlled, randomized clinical trial	Silymarin; 450 mg (150 mg 3 times/d); oral	60f; 24; 25	No significant differences in liver function tests	1iDiii
[8]	Alcohol-induced cirrhosis	Double-blind, placebo-controlled, randomized clinical trial	Silymarin; 450 mg (150 mg 3 times/d); oral	200e; 58; 67	No significant differences in liver function tests	1iB
[10]	Primarybiliary cirrhosis	Nonrandomized, pilot clinical trial	Silymarin; 420 mg (140 mg 3 times/d); oral	27; 27; 0	No significant differences in liver function tests	2C
[15]	Prevention of drug-induced hepatic damage	Double-blind, placebo-controlled, randomized clinical trial	Silymarin; 800 mg (divided in 2 doses); oral	60; 15 psychotropic drug + silymarin; 15 silymarin alone; 15 psychotropic drug + placebo; 15 placebo alone	Silymarin effective at reducing ALT and AST levels when psychotropic drug use was suspended	1iC
[2]	Children with ALL experiencing elevated LFTs	Double-blind, placebo-controlled, randomized clinical trial	Silibinin and soy phosphatidylcholine; dose ranges: 15–20 kg = 80 mg/d; 21–40 kg = 160 mg/d; 41–60 kg = 240 mg/d; 61–70 kg = 320 mg/d; oral	50; 24; 26	Significant decrease in AST; trend towards reduction in ALT	1iDiii
Prevention or Treatment of Non-Liver Disease
Reference	Condition or Cancer Type	Trial Design	Route of Administration and Dose	Treatment Groups (Enrolled; Treated; Placebo or No Treatment Control)a	Results	Level of Evidence Score g
[4]	Radiation therapy–associated mucositis	Double-blind, placebo-controlled, randomized clinical trial	Silymarin; 420 mg (140 mg 3 times/d); oral	30; 13; 14	Lower mucositis scores	1iC
[3]	Prostate cancer	Double-blind, placebo-controlled, randomized clinical trial	Silymarin; 570 mg (190 mg 3 times/d); oral	37; 19; 18	Increased QOL, decreased low-density lipoproteins, decreased total cholesterol, and increased selenium levels	1iC
[5]	Breast cancer	Nonrandomized, observational clinical trial	Silymarin (Silybum marianum, content 0.25%); topical	101; 51; 50	Decreased dermatitis	2C

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Siegel AB, Narayan R, Rodriguez R, et al.: A phase I dose-finding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma. Integr Cancer Ther 13 (1): 46-53, 2014.
2. 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 116 (2): 506-13, 2010.
3. Vidlar A, Vostalova J, Ulrichova J, et al.: The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy - a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154 (3): 239-44, 2010.
4. Elyasi S, Hosseini S, Niazi Moghadam MR, et al.: Effect of Oral Silymarin Administration on Prevention of Radiotherapy Induced Mucositis: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. Phytother Res 30 (11): 1879-1885, 2016.
5. Becker-Schiebe M, Mengs U, Schaefer M, et al.: Topical use of a silymarin-based preparation to prevent radiodermatitis : results of a prospective study in breast cancer patients. Strahlenther Onkol 187 (8): 485-91, 2011.
6. Vailati A, Aristia L, Sozzé E, et al.: Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64 (3), 219-28, 1993.
7. Salmi HA, Sarna S: Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 17 (4): 517-21, 1982.
8. Parés A, Planas R, Torres M, et al.: Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 28 (4): 615-21, 1998.
9. Flisiak R, Prokopowicz D: Effect of misoprostol on the course of viral hepatitis B. Hepatogastroenterology 44 (17): 1419-25, 1997 Sep-Oct.
10. Angulo P, Patel T, Jorgensen RA, et al.: Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 32 (5): 897-900, 2000.
11. Ferenci P, Dragosics B, Dittrich H, et al.: Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 9 (1): 105-13, 1989.
12. Lucena MI, Andrade RJ, de la Cruz JP, et al.: Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. Int J Clin Pharmacol Ther 40 (1): 2-8, 2002.
13. Velussi M, Cernigoi AM, De Monte A, et al.: Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 26 (4): 871-9, 1997.
14. 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 47 (2): 605-12, 2008.
15. Palasciano G, Portincasa P, Palmieri V, et al.: The effect of silymarin on plasma levels of malon-dialdehyde in patients receiving long-term treatment with psychotropic drugs. Current Therapeutic Research 55 (5): 537-45.
16. Magliulo E, Gagliardi B, Fiori GP: [Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres (author's transl)] Med Klin 73 (28-29): 1060-5, 1978.
17. 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 33 (1): 127-37, 2011.
18. Azzam HS, Goertz C, Fritts M, et al.: Natural products and chronic hepatitis C virus. Liver Int 27 (1): 17-25, 2007.
19. Polyak SJ, Morishima C, Shuhart MC, et al.: Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Gastroenterology 132 (5): 1925-36, 2007.
20. 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 135 (5): 1561-7, 2008.
21. Hawke RL, Schrieber SJ, Soule TA, et al.: Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol 50 (4): 434-49, 2010.
22. 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 308 (3): 274-82, 2012.
23. Albrecht M, Frerick H, Kuhn U, et al.: Therapy of toxic liver pathologies with Legalon®. Z Klin Med 47: 87-92, 1992.
24. Hruby K, Csomos G, Fuhrmann M, et al.: Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2 (2): 183-95, 1983.
25. Enjalbert F, Rapior S, Nouguier-Soulé J, et al.: Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 40 (6): 715-57, 2002.
26. Moayedi B, Gharagozloo M, Esmaeil N, et al.: A randomized double-blind, placebo-controlled study of therapeutic effects of silymarin in β-thalassemia major patients receiving desferrioxamine. Eur J Haematol 90 (3): 202-9, 2013.

Adverse Effects

Human studies of silymarin have shown minimal adverse effects in multiple large, blinded, placebo-controlled, randomized studies. Silymarin is well tolerated, with only rare reports of a mild laxative effect. Mild allergic reactions have been seen at high doses (>1,500 mg /day), although the details of these allergic reactions were not reported.[1] A case report from Australia described a reaction to a milk thistle extract that included intermittent episodes of sweating, abdominal cramping, nausea, vomiting, diarrhea, and weakness.[2] All symptoms resolved when the silymarin was discontinued. The authors suggested that the capsules were contaminated; the type of contamination was unknown.

According to the German Commission E, there are no reported side effects with milk thistle when the recommended doses are used. Rare cases of milk thistle producing a laxative effect have been reported. Human studies have reported stomach upset, heartburn, and transient headaches; however, none of these symptoms were attributed to supplementation with milk thistle, and supplementation was not discontinued.[3] One human dosing study reported nausea, heartburn, and dyspepsia in patients treated with 160 mg/day, dyspepsia in patients treated with 240 mg/day, and postprandial nausea and meteorism in patients treated with 360 mg/day. None of these side effects were dose related.

Silymarin has been well tolerated in high doses. Silymarin has been used in pregnant women with intrahepatic cholestasis at doses of 560 mg/day for 16 days, with no toxicity to the patient or the fetus.[4] The published data on silymarin use in children focuses on intravenous doses of 20 to 50 mg/kg of body weight for mushroom poisoning.[5] Silymarin has also proved nontoxic in rats and mice when administered in doses as high as 5,000 mg/kg of body weight. Rats and dogs have received silymarin at doses of 50 to 2,500 mg/kg of body weight for a 12-month period. Investigations, including postmortem analyses, showed no evidence of toxicity.

It is not known whether milk thistle may reduce, enhance, or have no impact on the effectiveness of chemotherapy. In vitro studies show that silymarin decreases the components of the cytochrome P450 enzyme system, which is involved in the clearance of certain chemotherapy drugs.[6] However, the dose at which inhibition is observed is high and not achieved with oral intake of silymarin.[7] One study investigated the effects of silymarin on the pharmacokinetics of irinotecan. Oral administration of milk thistle (200 mg, a clinically relevant dose, 3 times per day) had no significant effects on the pharmacokinetics of irinotecan. The authors concluded that the recommended doses of milk thistle are too low to affect activity of CYP3A4 or UGT1A1 enzyme pathways.[8]

Theoretically, milk thistle may also interact adversely with chemotherapy drugs that exert their cytotoxic effects through the generation of free radicals. Silymarin and its metabolite inhibit p-glycoprotein–mediated cellular efflux, leading to the potentiation of doxorubicin cytotoxicity.[9] No trials have been performed to support or negate these theoretical considerations. No effects on indinavir and alcohol pharmacokinetics have been observed. Enhancement of the antiarrhythmic effects of amiodarone in rats has been observed.[9]

References:

1. PDR® for Herbal Medicines™. 2nd ed. Medical Economics, 2000.
2. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Adverse Drug Reactions Advisory Committee. Med J Aust 170 (5): 218-9, 1999.
3. Vailati A, Aristia L, Sozzé E, et al.: Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia 64 (3), 219-28, 1993.
4. Hernández R, Nazar E: [Effect of silymarin in intrahepatic cholestasis of pregnancy (preliminary communication)] Rev Chil Obstet Ginecol 47 (1): 22-9, 1982.
5. Hruby K, Csomos G, Fuhrmann M, et al.: Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2 (2): 183-95, 1983.
6. Venkataramanan R, Ramachandran V, Komoroski BJ, et al.: Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 28 (11): 1270-3, 2000.
7. Zuber R, Modrianský M, Dvorák Z, et al.: Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 16 (7): 632-8, 2002.
8. van Erp NP, Baker SD, Zhao M, et al.: Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res 11 (21): 7800-6, 2005.
9. Hu Z, Yang X, Ho PC, et al.: Herb-drug interactions: a literature review. Drugs 65 (9): 1239-82, 2005.

Summary of the Evidence for Milk Thistle

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

• Be published in a peer-reviewed scientific journal.
• Report on therapeutic outcome or outcomes, such as tumor response, improvement in survival, or measured improvement in quality of life.
• Describe clinical findings in sufficient detail for a meaningful evaluation to be made.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For an explanation of the scores and additional information about levels of evidence analysis of CAM treatments for cancer, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Given the limited amount of human data, the use of milk thistle/silymarin as a treatment for cancer patients cannot be recommended outside the context of well-designed clinical trials.

Latest Updates to This Summary (02 / 17 / 2022)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of milk thistle in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Milk Thistle. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/milk-thistle-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389223]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2022-02-17