Last Modified: 01/13/2012
Human/Clinical Studies
Two published case reports describe the use of milk thistle as either a treatment or an adjunctive therapy in individuals with cancer. One case report describes the use of milk thistle in a 34-year-old woman with promyelocytic leukemia.[1] The investigators administered 800 mg of silymarin during the patient’s maintenance therapy, which consisted of treatment with methotrexate and 6-mercaptopurine. During the 4 months of treatment with silymarin, the patient who previously required intermittent breaks in therapy due to abnormal liver enzyme levels had normal liver enzyme levels with no further interruption of therapy. A second case report describes a 52-year-old man with hepatocellular carcinoma.[2] The patient began taking 450 mg of silymarin per day, and spontaneous regression of the tumor was reported in the absence of initiation of anticancer therapy.
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.[3] Four weeks following 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 to the placebo group; however, the difference was not significant. No adverse events were reported.
Most clinical trials of milk thistle have been conducted in patients with either hepatitis or cirrhosis. Other studies have investigated milk thistle in patients with hyperlipidemia, diabetes, and Amanita phalloides mushroom poisoning. Ten randomized trials [3-12] 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.[13] 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 B, one clinical trial found silymarin (140 mg daily for 3–4 weeks) resulting in lower levels of AST, ALT, and bilirubin by day 5, compared with a placebo group.[14] In another randomized, placebo-controlled study of patients with viral hepatitis B, silymarin (210 mg daily) had no effect on course of disease or enzyme levels.[7]
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 prior 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.[12] The aim was to reduce progression of chronic hepatitis C, particularly in the development of hepatocellular carcinoma. Among 1,145 study participants, 56% had never taken herbals, 21% admitted past use, and 23% were using herbals at enrollment. Silymarin constituted 72% of the 60 herbals used at enrollment. Users had significantly fewer symptoms and a better quality of life than nonusers.
Although there are many reports of the use of herbals for the treatment of chronic liver diseases, most treatment trials have suffered from poor scientific design, uncertainty of the required dosage of herbals, and an insufficient number of study participants. A recent review of complementary and alternative medications (CAM) to treat liver diseases focused on the classification, epidemiology, and the philosophy of CAM and reviewed the criteria needed to conduct a scientifically valid research study focusing on herbal products.[15]
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 are unable to 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.[16] 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 silibinin with and without PEG-interferon and ribavirin.[17] In the case series, 16 HCV nonresponder patients were administered intravenous silibinin in a dose of 10 mg/kg/day 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 the 10 mg/kg, 15 mg/kg, and 20 mg/kg doses of silybinin. Further declines were observed in HCV RNA with administration of PEG-interferon and ribavirin. Except for mild gastroenteritis, intravenous silibinin monotherapy was well tolerated.
In patients with chronic liver disease, a randomized, placebo-controlled study found normalization of serum AST, ALT, and bilirubin levels after 1 month of treatment with silymarin (140 mg 3 times a day) in comparison to treatment with a placebo.[18] In one of the largest observational studies involving 2,637 patients with chronic liver disease, 8-week treatment with 560 mg/day of silymarin 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.[19]
Another published report describes the use of silybinin as the only effective antidote in patients with liver damage from Amanita phalloides (Fr.) Link poisoning.[20] Patients were administered doses of 35 to 55 mg/kg body weight, with no reports of adverse events. A recent retrospective review of the treatment for Amanita phalloides poisoning suggests that silymarin continues to be a promising drug in the treatment of this rare mushroom poisoning.[21] The beneficial effect of silymarin on liver histology suggests it has a role in the prevention of hepatitis and/or hepatocellular carcinoma; however, no clinical trials in humans have investigated these uses of silymarin.
Clinical Studies Investigating Silymarin in the Treatment or Prevention of Liver Disease| Reference Citation | Type of Study | Type of Disease | No. of Patients: Enrolled; Treated; Controla | Strongest Benefit Reported |
| [5] | Double-blind, placebo-controlled, randomized clinical trial | Acute and subacute liver disease | 106b; 47; 50 | Decreased LFTs; improved histology |
| [9] | Double-blind, placebo-controlled, randomized clinical trial | Cirrhosis | 170; 87; 83 | Increased survival |
| [4] | Phase II randomized open trial | Viral or alcoholic hepatitis | 60c; 60; 0 | Reduction in ALT and gamma-glutamyl transpeptidase |
| [7] | Controlled, randomized trial | Viral hepatitis B | 52d; 20-silymarin, 20-misoprostol; 12 | No significant findings |
| [6] | Double-blind, placebo-controlled, randomized clinical trial | Alcohol-induced cirrhosis | 200e; 58; 67 | No significant findings |
| [10] | Double-blind, placebo-controlled, randomized clinical trial | Alcohol-induced cirrhosis | 60f; 24; 25 | Significant increases in erythrocyteglutathione and decreased platelet MDA values; no significant differences in liver function tests |
| [8] | Nonrandomized pilot study | Primary biliary cirrhosis | 27; 27; 0 | No significant findings |
| [17] | Nonrandomized, controlled trial | HCV nonresponder patients | 16; 16; 0 and 20; 20; 0 | Increased antiviral effect |
| [11] | Controlled, randomized trial | Diabetic patients with cirrhosis | 60; 30; 30 | Decrease in lipid peroxidation and insulin resistance |
| [12] | Randomized, controlled trial | Chronic hepatitis C | 1,145; 195; 772 | Decreased fatigue, nausea, liver pain, anorexia, and muscle and joint pain |
| [13] | Double-blind, placebo-controlled, randomized clinical trial | Patients treated with silymarin as a prophylaxis to psychotropic drug-induced hepatic damage | 60; 15-psychotropic drug+silymarin; 15-silymarin alone; 15-psychotropic drug+placebo; 15-placebo alone | Silymarin effective at reducing hepatotoxicity associated with psychotropic drug use |
| [3] | Double-blind, placebo-controlled, randomized clinical trial | Children with ALL experiencing elevated LFTs | 50; 24; 26 | Significant decrease in AST; trend towards reduction in ALT |
| ALL = acute lymphoblastic leukemia; ALT = alanine aminotransferase; HCV = hepatitis C virus; LFT = liver function test; No. = number. | ||||
| aNumber 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 studied AND for whom results were reported; historical control subjects are not included in number of patients enrolled. | ||||
| bNine patients were excluded from the final analysis (seven patients missed appointments, and two patients were missing data requirements). | ||||
| cStudy 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. | ||||
| dPatients were randomly assigned to the misoprostol and silymarin groups. Twelve nonrandomized patients served as controls. | ||||
| eFifteen patients were lost to follow-up, 18 patients were deceased, and 42 patients withdrew from the study (adverse events, noncompliance, and voluntary withdrawal). | ||||
| fEleven patients did not complete the trial (voluntary withdrawal, disease progression, and one adverse event). |
Current Clinical Trials
Check NCI’s list of cancer clinical trials for cancer CAM clinical trials on milk thistle 2 and silymarin 3 that are actively enrolling patients.
General information about clinical trials is also available from the NCI Web site 4.
References
- Invernizzi R, Bernuzzi S, Ciani D, et al.: Silymarine during maintenance therapy of acute promyelocytic leukemia. Haematologica 78 (5): 340-1, 1993 Sep-Oct. [PUBMED Abstract]
- Grossmann M, Hoermann R, Weiss M, et al.: Spontaneous regression of hepatocellular carcinoma. Am J Gastroenterol 90 (9): 1500-3, 1995. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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.
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Flisiak R, Prokopowicz D: Effect of misoprostol on the course of viral hepatitis B. Hepatogastroenterology 44 (17): 1419-25, 1997 Sep-Oct. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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.
- 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. [PUBMED Abstract]
- Azzam HS, Goertz C, Fritts M, et al.: Natural products and chronic hepatitis C virus. Liver Int 27 (1): 17-25, 2007. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- Trinchet JC, Beaugrand M, Callard P, et al.: Treatment of alcoholic hepatitis with colchicine. Results of a randomized double blind trial. Gastroenterol Clin Biol 13 (6-7): 551-5, 1989. [PUBMED Abstract]
- Albrecht M, Frerick H, Kuhn U, et al.: Therapy of toxic liver pathologies with Legalon®. Z Klin Med 47: 87-92, 1992.
- Hruby K, Csomos G, Fuhrmann M, et al.: Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2 (2): 183-95, 1983. [PUBMED Abstract]
- 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. [PUBMED Abstract]