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Milk thistle (silybum marianum) is a plant that has been used to treat liver diseases and promote liver health for centuries. It is presently one of the most commonly used medicinal plants worldwide [1]. The extract of the active components of milk thistle, consisting of various flavonolignans and the isoflavanoid taxifolin, is known as silymarin. The flavanolignans in silymarin include silybinin (also spelled silibinin), isosilybinin, silydianin, silychristin, and dehydrosilibinin [2-3]. Silibinin is generally seen as the primary active component, although the other flavanolignans may also contribute to the therapeutic activity of silymarin [4-5].
The biological activity of silymarin can be attributed to many factors. One of the most important is its action as an antioxidant, and many of the other biological effects are downstream of this action. Silymarin scavenges free radicals and causes a significant reduction in lipid peroxidation, protecting and stabilizing cell membranes [2, 4]. Silymarin stimulates RNA and protein synthesis in the liver, leading to faster regeneration after injury [5-6]. Silymarin also has antiinflammatory activity and inhibits the production of tumor necrosis factor alpha (TNFalpha) both in vitro and in vivo [2, 7]. It also has antifibrotic and immunomodulating activity [2]. Silymarin may also bind directly to receptor sites in liver cells, prevent toxins from binding to those sites [8]. The effects are many, and the protective effect of milk thistle can be seen as the sum of many different mechanisms [5].
Liver protection
There is a large body of literature discussing experimental studies on the hepatoprotective (liver protecting) properties of silymarin. In rodent models, silymarin (or silibinin) reduced or prevented liver toxicity caused by chroquine (an antimalarial and antirheumatoid agent), amiodarine (an anti-arrhytmic drug), D-galactosamine, carbon tetrachloride, acetaminophen, paracetamol, heavy metals, ethanol, pyrogallol, phenylhydrazine, radiation, and Amanita phalloides (a toxic mushroom species) [4, 6, 8-12]. It was also protective against ischemic liver injury and a model of inflammatory liver disease [6, 13]. These benefits have been measured by changes in liver enzymes (such as AST, ALT, and ALP), changes in serum bilirubin, prevention of fibrosis, prevention of DNA strand breaks, decreased free radical generation, decreased cholestasis, and other methods [4, 6, 9, 13-14]. It has both preventative and curative activity [10].
Silymarin is commonly used in Europe and Asia to treat Amanita mushroom poisoning, cirrhosis, hepatitis, and other liver diseases [8, 15-16]. Many clinical trials have also been conducted to determine if it has a significant benefit. In a meta-analysis of all of these trials published in 2002, the authors concluded that there was no mortality benefit from silymarin and that there was small effect on serum alanine aminotransferase (a marker of liver injury). However, the authors did find evidence for a mortality benefit in some subsets of patients with alcohol-related cirrhosis. They also acknowledged that there were some limitations to the meta-analysis, namely that the number of subjects from the pooled analysis was small, limiting the statistical power to establish a significant effect, and that the results from studies on various liver conditions were pooled together, so liver conditions unresponsive to milk thistle may have skewed results [8]. Two other reviews found that there was evidence for a significant benefit from silymarin in the treatment of alcoholic liver cirrhosis, but that there was less evidence for a benefit in the treatment of other liver conditions, such as hepatitis [17-18]. One trial in hepatitis C patients did find a beneficial effect on AST and gamma-glutamyltranpeptidase level after seven days of treatment, but no significant effect on ALT or bilirubin levels [19].
Even in the case of alcoholic liver disease, while some research indicates a mortality benefit, not all clinical trials have indicated a benefit from silymarin. This may be due to variability in alcohol consumption and poor compliance. A study in baboons given high-alcohol diets indicated that those treated with silymarin had reduced plasma 4-hydroxynonenal (a marker of oxidative liver injury), ALT, steatosis, and fibrosis, although only two of the six subjects were fully protected from these effects [14]. The research collectively indicates a benefit from silymarin in some, but not all liver conditions.
Other effects
The experimental research has also suggested that silymarin may prevent and/or inhibit the growth of various cancers, although the data is still preliminary. The greatest amount of research has focused on inhibition of prostate cancer, which has been found both in cell culture and live animals. Possible mechanisms for this inhibitory effect include alteration in cell cycle progression and inhibition of mitogenic and cell survival signalling, and silibinin recently entered phase I clinical trials in prostate cancer patients [20]. Silymarin also has anticancer activity in rodent models of bladder cancer, colon cancer, skin cancer, and tongue cancer [21-24]. In vitro, silymarin inhibits the growth of breast cancer, glioma, and lung cancer cells [25-27].
A number of other possible benefits of silymarin supplementation have been identified, related to its antioxidant and antiinflammatory effects. In humans, supplementation with silymarin significantly increases plasma antioxidant capacity [2]. Animal models have found it to reduce atherosclerosis and decrease cholesterol levels in animals fed high cholesterol diets [28]. Silymarin also has some direct cardioprotective properties [29-30]. In addition to protecting the liver from heavy metals, silymarin (or silibinin) may reduce other toxic effects of iron and mercury buildup [2, 31]. Because of its antiinflammatory properties, it may be useful in the treatment of inflammatory disorders, and it had antiarthritic activity in an animal model [29, 32].
Dosage & toxicity
The majority of the literature indicates that silymarin is virtually non-toxic and associated with few side effects [2, 22]. No significant adverse effects with silymarin as monotherapy, and few negative drug interactions have been reported [2, 8]. In clinical trials, reports of side effects are similar to those reported with placebo treatment [8, 10]. There are some a few case reports of gastrointestinal disturbances and allergic skin rashes [17]. In vitro studies indicate that silymarin may actually be hepatotoxic in high enough concentrations, and high concentrations of silymarin inhibit some drug metabolizing enzymes, but these are not significant concerns with normal supplemental doses [5, 33].
Although there are many references to the low oral bioavailability of silymarin, supplementation in sufficient quantities results in increased silymarin concentrations in various tissues, especially the liver [4, 34]. The dose used in most clinical trials is 420 mg, with a range of 210-800 mg [8]. Assuming the milk thistle being used is 70-80% silymarin, 200-400 mg of milk thistle daily is recommended as a general supplement to maintain good liver health, and 500-1000 mg is recommended in situations of high liver stress.
The biological activity of silymarin can be attributed to many factors. One of the most important is its action as an antioxidant, and many of the other biological effects are downstream of this action. Silymarin scavenges free radicals and causes a significant reduction in lipid peroxidation, protecting and stabilizing cell membranes [2, 4]. Silymarin stimulates RNA and protein synthesis in the liver, leading to faster regeneration after injury [5-6]. Silymarin also has antiinflammatory activity and inhibits the production of tumor necrosis factor alpha (TNFalpha) both in vitro and in vivo [2, 7]. It also has antifibrotic and immunomodulating activity [2]. Silymarin may also bind directly to receptor sites in liver cells, prevent toxins from binding to those sites [8]. The effects are many, and the protective effect of milk thistle can be seen as the sum of many different mechanisms [5].
Liver protection
There is a large body of literature discussing experimental studies on the hepatoprotective (liver protecting) properties of silymarin. In rodent models, silymarin (or silibinin) reduced or prevented liver toxicity caused by chroquine (an antimalarial and antirheumatoid agent), amiodarine (an anti-arrhytmic drug), D-galactosamine, carbon tetrachloride, acetaminophen, paracetamol, heavy metals, ethanol, pyrogallol, phenylhydrazine, radiation, and Amanita phalloides (a toxic mushroom species) [4, 6, 8-12]. It was also protective against ischemic liver injury and a model of inflammatory liver disease [6, 13]. These benefits have been measured by changes in liver enzymes (such as AST, ALT, and ALP), changes in serum bilirubin, prevention of fibrosis, prevention of DNA strand breaks, decreased free radical generation, decreased cholestasis, and other methods [4, 6, 9, 13-14]. It has both preventative and curative activity [10].
Silymarin is commonly used in Europe and Asia to treat Amanita mushroom poisoning, cirrhosis, hepatitis, and other liver diseases [8, 15-16]. Many clinical trials have also been conducted to determine if it has a significant benefit. In a meta-analysis of all of these trials published in 2002, the authors concluded that there was no mortality benefit from silymarin and that there was small effect on serum alanine aminotransferase (a marker of liver injury). However, the authors did find evidence for a mortality benefit in some subsets of patients with alcohol-related cirrhosis. They also acknowledged that there were some limitations to the meta-analysis, namely that the number of subjects from the pooled analysis was small, limiting the statistical power to establish a significant effect, and that the results from studies on various liver conditions were pooled together, so liver conditions unresponsive to milk thistle may have skewed results [8]. Two other reviews found that there was evidence for a significant benefit from silymarin in the treatment of alcoholic liver cirrhosis, but that there was less evidence for a benefit in the treatment of other liver conditions, such as hepatitis [17-18]. One trial in hepatitis C patients did find a beneficial effect on AST and gamma-glutamyltranpeptidase level after seven days of treatment, but no significant effect on ALT or bilirubin levels [19].
Even in the case of alcoholic liver disease, while some research indicates a mortality benefit, not all clinical trials have indicated a benefit from silymarin. This may be due to variability in alcohol consumption and poor compliance. A study in baboons given high-alcohol diets indicated that those treated with silymarin had reduced plasma 4-hydroxynonenal (a marker of oxidative liver injury), ALT, steatosis, and fibrosis, although only two of the six subjects were fully protected from these effects [14]. The research collectively indicates a benefit from silymarin in some, but not all liver conditions.
Other effects
The experimental research has also suggested that silymarin may prevent and/or inhibit the growth of various cancers, although the data is still preliminary. The greatest amount of research has focused on inhibition of prostate cancer, which has been found both in cell culture and live animals. Possible mechanisms for this inhibitory effect include alteration in cell cycle progression and inhibition of mitogenic and cell survival signalling, and silibinin recently entered phase I clinical trials in prostate cancer patients [20]. Silymarin also has anticancer activity in rodent models of bladder cancer, colon cancer, skin cancer, and tongue cancer [21-24]. In vitro, silymarin inhibits the growth of breast cancer, glioma, and lung cancer cells [25-27].
A number of other possible benefits of silymarin supplementation have been identified, related to its antioxidant and antiinflammatory effects. In humans, supplementation with silymarin significantly increases plasma antioxidant capacity [2]. Animal models have found it to reduce atherosclerosis and decrease cholesterol levels in animals fed high cholesterol diets [28]. Silymarin also has some direct cardioprotective properties [29-30]. In addition to protecting the liver from heavy metals, silymarin (or silibinin) may reduce other toxic effects of iron and mercury buildup [2, 31]. Because of its antiinflammatory properties, it may be useful in the treatment of inflammatory disorders, and it had antiarthritic activity in an animal model [29, 32].
Dosage & toxicity
The majority of the literature indicates that silymarin is virtually non-toxic and associated with few side effects [2, 22]. No significant adverse effects with silymarin as monotherapy, and few negative drug interactions have been reported [2, 8]. In clinical trials, reports of side effects are similar to those reported with placebo treatment [8, 10]. There are some a few case reports of gastrointestinal disturbances and allergic skin rashes [17]. In vitro studies indicate that silymarin may actually be hepatotoxic in high enough concentrations, and high concentrations of silymarin inhibit some drug metabolizing enzymes, but these are not significant concerns with normal supplemental doses [5, 33].
Although there are many references to the low oral bioavailability of silymarin, supplementation in sufficient quantities results in increased silymarin concentrations in various tissues, especially the liver [4, 34]. The dose used in most clinical trials is 420 mg, with a range of 210-800 mg [8]. Assuming the milk thistle being used is 70-80% silymarin, 200-400 mg of milk thistle daily is recommended as a general supplement to maintain good liver health, and 500-1000 mg is recommended in situations of high liver stress.
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