Botanical Substances: Milk Thistle (Silybum Marianum)

MILK THISTLE (SILYBUM MARIANUM)

Chemistry

The fruit and seeds of the milk thistle plant contain a lipophilic mixture of flavonolignans known as silymarin. Silymarin com-prises 2–3% of the dried herb and is composed of three primary isomers, silybin (also known as silybinin or silibinin), silychristin (silichristin), and silydianin (silidianin). Silybin is the most preva-lent and potent of the three isomers and accounts for about 50% of the silymarin complex. Products should be standardized to contain 70–80% silymarin.

Pharmacologic Effects

A. Liver Disease

In animal models, milk thistle purportedly limits hepatic injury associated with a variety of toxins, including Amanita mushrooms, galactosamine, carbon tetrachloride, acetaminophen, radiation, cold ischemia, and ethanol. In vitro studies and some in vivo stud-ies demonstrate that silymarin reduces lipid peroxidation, scav-enges free radicals, and enhances glutathione and superoxide dismutase levels. This may contribute to membrane stabilization and reduce toxin entry.

Milk thistle appears to have anti-inflammatory properties. In vitro, silybin strongly and noncompetitively inhibits lipoxygenase activity and reduces leukotriene formation. Inhibition of leuko-cyte migration has been observed in vivo and may be a factor when acute inflammation is present. Silymarin also inhibits tumor necrosis factor-α-mediated activation of nuclear factor kappa B (NF-κB), which promotes inflammatory responses. One of the most unusual mechanisms claimed for milk thistle involves an increase in RNA polymerase I activity in nonmalignant hepato-cytes but not in hepatoma or other malignant cell lines. By increasing this enzyme’s activity, enhanced protein synthesis and cellular regeneration may occur in healthy but not malignant cells.In an animal model of cirrhosis, it reduced collagen accumulation, and in an in vitro model it reduced expression of the fibrogenic cytokine transforming growth factor-β. If confirmed, milk thistle may have a role in the treatment of hepatic fibrosis.

In animal models, silymarin has a dose-dependent stimulatory effect on bile flow that could be beneficial in cases of cholestasis. To date, however, there is insufficient evidence to warrant the use of milk thistle for these indications.

B. Chemotherapeutic Effects

Preliminary in vitro and animal studies of the effects of silymarin and silybinin have been carried out with several cancer cell lines. In murine models of skin cancer, silybinin and silymarin were said to reduce tumor initiation and promotion. Induction of apoptosis has also been reported using silymarin in a variety of malignant human cell lines (eg, melanoma, prostate, leukemia cells, bladder transitional-cell papilloma cells, and hepatoma cells). Inhibition of cell growth and proliferation by inducing a G₁ cell cycle arrest has also been claimed in cultured human breast and prostate cancer cell lines. The use of milk thistle in the clinical treatment of cancer has not yet been adequately studied but preliminary trials are under way.

C. Lactation

Historically, milk thistle has been used by herbalists and midwives to induce lactation in pregnant or postpartum women. In female rats, milk thistle increases prolactin production. As such, it is possible that it could have an effect on human breast milk production. Clinical trial data are lacking, however, for this indication, as are safety data on nursing mothers and infants. Until further data become available, milk thistle should not be used for this indication.

Clinical Trials

Milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. A systematic review of 13 randomized trials involving 915 patients with alcoholic liver disease or hepatitis B or C found no significant reductions in all-cause mortality, liver histopathology, or complications of liver disease with 6 months of use. A significant reduction in liver-related mortality was claimed using the data from all the surveyed trials, but not when the data were limited to trials of better design and controls. It was concluded that the effects of milk thistle in improving liver function or mortality from liver disease are currently poorly substantiated. Until additional well-designed clinical trials (possibly exploring higher doses) can be performed, a clinical effect can be neither supported nor ruled out.

Although milk thistle has not been confirmed as an antidote following acute exposure to liver toxins in humans, parenteral silybin is nevertheless marketed and used in Europe as an antidote in Amanita phalloides mushroom poisoning. This use is based on favorable outcomes reported in case-control studies.

Adverse Effects

Milk thistle has rarely been reported to cause adverse effects when used at recommended doses. In clinical trials, the incidence of

adverse effects (eg, gastrointestinal upset, dermatologic, headaches) was comparable to that of placebo. At high doses (> 1500 mg), it can have a laxative effect caused by stimulation of bile flow and secretion.