The milk thistle of commerce is a standardized preparation extracted from the fruits (seeds) of Silybum marianum (L.) Gaertn., Asteraceae (syn. Carduus marianus L.), a plant native to the Mediterranean. The leaves have been used since Greco-Roman times as an herbal remedy for a variety of ailments, particularly liver problems. Eclectic physicians in the United States in the latter nineteenth and early twentieth centuries acknowledged the clinical benefits of preparations from the milk thistle seeds (technically the fruits) for "Congestion of the liver, spleen, and kidneys " (Felter and Lloyd, 1983). It is widely used in German phytotherapy for "chronic hepatitis of all types," and especially for fatty liver (cirrhosis) associated with alcoholics (Weiss, 1988).
Milk thistle is an example of a preparation that is required to be in the standardized, concentrated form in order to fully convey the desired, in this case, hepatoprotectant, effects. Milk thistle preparations are usually standardized to a concentration of 70 to 80% of three flavonolignans (silibinin, silychristin, and silydianin), collectively known as silymarin. According to research conducted by the original manufacturer and primary researcher of milk thistle extract, Madaus AG of Cologne, Germany, this level of concentration of silymarin is required to survive degradation by gastric fluids and in order to enter into the bloodstream via the intestinal wall. Silymarin is poorly absorbed (2050%) from the gastrointestinal tract; thus, the concentrated extract is recommended (Foster and Tyler, 1999; Robbers and Tyler, 1999).
The original product in Germany contains 70 mg silymarin. The Commission E approved uses and the subsequent use of milk thistle standardized extracts in the United States are based on a significant amount of chemical, pharmacological, and clinical research. There have been an estimated 120 clinical studies carried out on the proprietary milk thistle preparation from Madaus, known in Germany as Legalon®. A comprehensive and detailed review of the pharmacokinetics and clinical pharmacology of Legalon® has been published in English by the manufacturer (Anon., 1989).
Clinical studies suggest or confirm the efficacy of milk thistle extract for various hepatic disorders, including hepatitis A, alcoholic cirrhosis, and exposure to hazardous chemicals. Another relatively esoteric use is as a preventive and/or antidote to poisoning by the deathcap mushroom, Amanita phalloides. A preparation of the silibinin fraction is available in Germany as an intravenous (i.v.) drip for such acute cases.
A primary use for silymarin is in the treatment of liver damage due to ingestion of alcohol. An early double-blind study examined 66 patients, most with alcohol-induced toxic liver disease (Fintelmann and Albert, 1980). The 31 patients who received 420 mg/day of Legalon® showed a significant influence on serum levels of glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), and Gamma-GT over those 35 patients receiving placebo, with levels returning to normal more quickly in the treated group than placebo. Another double-blind study with 36 patients suffering from alcohol-induced liver disease found that pathological liver parameters (GOT, GPT, Gamma-GT, and bilirubin) were significantly reduced in the patients receiving silymarin (Legalon®) after six months of treatment compared to the placebo group (Feher et al., 1990). However, a multicenter study conducted in Spain from 1986 to 1989 found no effect for silymarin on the survival of patients or the clinical course of alcohol-induced cirrhosis (Pares et al., 1998). In another study, a randomized, controlled trial was performed to determine the effect of silymarin in the treatment of patients with alcohol- and non-alcohol-induced cirrhosis (Ferenci et al., 1989). Of the 170 patients, 87 received 420 mg of silymarin daily, compared with 83 placebo patients. The mean observation period was 41 months, with 10 dropouts in the placebo group and 14 in the treatment group. The four-year survival rate was 58+/9% in the silymarin-treated patients, and 39+/9% in the placebo group (p=0.036). No adverse side effects of drug treatment were observed.
In another double-blind, controlled study, the effects of silymarin on chemical, functional, and morphological alterations of the liver were examined (Salmi and Sarna, 1982). The 106 patients with liver disease in the study were selected on the basis of elevated serum transaminase levels. A total of 97 patients completed the four-week trial (47 treated and 50 placebo). A dose of 420 mg a day of silymarin produced a statistically significant greater decrease of GPT and GOT liver enzymes in the treated group than in the control. Serum total and bilirubin decreased more in the treated than in the control group, but the differences were not statistically significant.
Some forms of hepatitis have responded to silymarin treatment. A study reported on 67 subjects treated as outpatients for toxic metabolic liver damage, chronic hepatitis, and bile duct inflammation (Poser, 1971). After three months of treatment (525 mg/day of silymarin), chronic hepatitis was found to be significantly improved bioptically. Conditions associated with bile duct inflammation also responded particularly well. Another double-blind study looked at the effect of silymarin in the treatment of acute viral hepatitis (Magliulo et al., 1978). A daily dose of 420 mg therapeutically influenced the increased serum levels of bilirubin, GOT, and GPT characteristically associated with acute viral hepatitis. After five days of treatment, the laboratory parameters regressed more in the treated group than for the placebo group. After three weeks, more patients in the treated group had attained normal values than in the placebo group. A statistical analysis showed a difference between GOT and bilirubin values in the silymarin and placebo groups, with a regression of GPT values in favor of silymarin. A recent case report of chronic infection by hepatitis B virus and hepatitis C virus demonstrated potential efficacy of treatment with milk thistle (10 g ground-up seeds in oatmeal with standardized (70%) milk thistle extract capsules three times daily) in combination with another herb known for its hepatoprotectant activity, Phyllanthus amarus (200 mg, three times daily) (McPartland, 1996).
In a review of important European clinical studies ranging from 1971 to 1988 (including those summarized above), the authors found the data suggests the effectiveness of silymarin not only in toxic and metabolic liver damage, but also in acute and chronic hepatitis (Hikino and Kiso, 1988). Silymarin's ability to stabilize the cell membrane and stimulate protein synthesis, while accelerating the process of regeneration in damaged liver tissue, was found to be important in its therapeutic efficacy.
The hepatoprotectant effect of milk thistle fractions (silymarin) is documented in other studies: these compounds can produce both a protective and curative effect on liver damage resulting from the highly toxic compounds phalloidin and alpha-amanitin (from the deathcap mushroom, A. phalloides). A multicenter trial conducted from 1979 to 1982 involved 220 cases of Amanitapoisoning treated in German, Swiss, and Austrian hospitals (Hruby, 1984). Silibinin (administered i.v.) in supportive treatment was used. The mortality rate was 12.8%, compared to a mortality rate of 22.4% in a study where only 16 of the 205 patients were treated with 20 to 50 mg/kg/day of silibinin (Floersheim et al., 1982). Hruby concluded that the use of silibinin in addition to current methods of treating Amanita poisoning could lower mortality rates below any previously achieved.
A literature review noted that Legalon® is the best documented agent for the treatment of toxic liver impairment (Morazzani and Bombardelli, 1995). These authors also reviewed studies which suggest future use in dermatological and cosmetic products, based on a number of activities including promoting healing at wound sites, improved burn healing, and counteracting skin degeneration and aging via anti-inflammatory and free radical scavenging mechanisms. A more recent review concluded that despite some flaws in methodology of some of the clinical studies, Legalon® has not demonstrated adverse side effects and it "may be effective in improving the clinical courses of both acute and chronic viral, drug- and toxin-induced and alcoholic hepatitis" (Flora et al., 1998).
Because the well-documented antioxidant activity of silymarin has been shown to prevent lipoperoxidative hepatic damage by xenobiotic compounds (e.g., alcohol and certain pharmaceutical drugs), researchers attempted to determine whether milk thistle would be helpful for patients being administered psychotropic drugs. In a double-blind, placebo-controlled study, the efficacy of silymarin was evaluated in patients receiving psychotropic drugs as long-term therapy (Palasciano et al., 1994). Sixty women in the psychiatric ward of an Italian hospital were selected for the trial, all having been treated with either phenothiazines and/or butyrophenones for at least five years. They were randomly divided into four groups, with the silymarin patients receiving 800 mg a day for 90 days. Results showed that 800 mg/day of silymarin may be useful in the treatment of some instances of lipoperoxidative hepatic damage, such as the damage that may occur during long-term treatment with the psychotropic drugs.
Milk thistle extract has become increasingly popular in the United States as a dietary supplement for people with livers compromised by alcohol or exposure to toxic chemicals. Based on the increasing number of clinical studies indicating its safety and suggesting efficacy, consumers are also using this preparation as a means to ensure proper liver function and to assist in "detoxification" measures. Given this phytomedicine's well established safety and its reasonable documentation of efficacy, future clinical use of milk thistle extract should be explored as an adjunct therapy in chemotherapy to help offset the effects of powerful and potentially hepatotoxic conventional drugs.
U.S. pharmacopeial grade milk thistle consists of the dried ripe fruit of S. marianum with its pappus removed. It must contain not less than 2% of silymarin, calculated as silybin, as determined by a USP spectrophotometric assay method. Botanical identification must be confirmed by thin-layer chromatography (TLC) and macroscopic and microscopic examinations (USP 24NF 19, 1999). German pharmacopeial grade milk thistle also consists of the ripe fruit with the pappus removed. However, it must contain not less than 1.5% silymarin, calculated as silybin with reference to the dried drug. Total silymarin must be determined by a liquid chromatagraphic method (DAB method V.6.20.4). Botanical identity must be confirmed by TLC, macroscopic and microscopic examinations, and organoleptic evaluations. For example, the seed husk should have a bitter taste while the seed has an oleaginous taste, and it may not smell or taste rancid (DAB, 1997). The German Homeopathic Pharmacopoeia monograph requires that it contain not less than 1% of silymarin, calculated as silybin (GHP, 1993).
Milk thistle fruit consists of ripe seed of S. marianum (L.) Gaertner [Fam. Asteraceae], freed from the pappus, and its preparations in effective dosage. The preparation contains silibinin, silydianin, and silychristin.
Milk thistle seed contains 1.53% flavone lignans, collectively referred to as silymarin (Bruneton, 1995; Wichtl and Bisset, 1994); 2030% fixed oil, of which approximately 60% is linoleic acid, approximately 30% is oleic acid, and approximately 9% is palmitic acid; 2530% protein; 0.038% tocopherol; 0.63% sterols, including cholesterol, campesterol, stigmasterol, and sitosterol; and some mucilage (Meyer-Buchtela, 1999; Wichtl and Bisset, 1994). The three principle components of silymarin are the flavanolignans silybin, silychristin, and silidianin (Bruneton, 1995; Leung and Foster, 1996; Wichtl and Bisset, 1994).
The Commission E reported that silymarin acts as an antagonist in many experimental liver-damage models: phalloidin and amanitin (deathcap toxins), lanthanides, carbon tetrachloride, galactosamine, thioacetamide, and the hepatotoxic virus FV3 of cold-blooded vertebrates.
The therapeutic activity of silymarin is based on two sites or mechanisms of action:
(a) It alters the structure of the outer cell membrane of the hepatocytes in such a way as to prevent penetration of the liver toxin into the interior of the cell.
(b) It stimulates the action of nucleolar polymerase A, resulting in an increase in ribosomal protein synthesis, and thus stimulates the regenerative ability of the liver and the formation of new hepatocytes.
Milk thistle extract provides hepatocellular protection by stabilizing hepatic cell membranes (McPartland, 1996). Other actions include interruption of enterohepatic recirculation of toxins, stimulation of protein synthesis and regeneration of damaged hepatocytes, as well as antioxidant activity (McPartland, 1996).
Recent research on silibinin and silichristin to promote faster regeneration of diseased liver tissue has focused on the ability of silibinin to stimulate the activity of the DNA-dependent RNA-polymerase I, causing an increase in rRNA synthesis and an accelerated formation of intact ribosomes. This results in a general increase in the rate of synthesis of all cellular proteins. In vivo and in vitro molecular modeling experiments indicate that silibinin may imitate a steroid hormone by binding specifically to polymerase I, thus stimulating enzyme activity (Sonnenbichler et al., 1998).
The Commission E approved the internal use of crude milk thistle fruit preparations for dyspeptic complaints. Formulations* are approved for toxic liver damage and for supportive treatment in chronic inflammatory liver disease and hepatic cirrhosis.
*[Ed. note: A "formulation" refers to an extract standardized to at least 7080% silymarin, the collective name for the three compounds listed in the Description section.]
The German Standard License for milk thistle seed tea infusion indicates its use for digestive disorders, particularly for functional disturbances of the biliary systems (Braun et al., 1997).
Crude preparation: None known.
Formulations: A mild laxative effect has been observed in occasional instances.
No restrictions known.
Unless otherwise prescribed: 12-15 g per day of powdered seed for making infusions and other galenical formulations to be taken by mouth. Formulations (e.g., dry extract noted below) equivalent to 200-400 mg per day of silymarin, calculated as silibinin.
For liver diseases:
Dry extract 40-70:1 (w/w), 70-80% silymarin: Swallow one capsule containing 100-200 mg of silymarin, twice daily in the morning and evening. Swallow with sufficient amounts of fluid; or, take one capsule containing approximately 140 mg of silymarin, two to three times daily (Brown, 1996).
For digestive disorders:
Decoction: Place approximately 3.0 g seed in 150 ml cold water, bring to a boil and simmer for 20 to 30 minutes, three to four times daily (Wichtl and Bisset, 1994).
Infusion: Steep approximately 3.5 g seed in 150 ml boiled water for 10 to 15 minutes, three to four times daily one half-hour before meals (Braun et al., 1997; Meyer-Buchtela, 1999; Wichtl and Bisset, 1994).
[Note: Silymarin is poorly soluble in water; teas have been analyzed with only about 10% of the original levels of silymarin from the fruits. Thus, for hepatic benefits, the concentrated extract is recommended (Foster and Tyler, 1999).]
Tincture: 15-25 drops, four to five times daily (Lust, 1974); 1-2 ml, three times daily (Hoffmann, 1992).
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- This material was adapted from The Complete German Commission E MonographsTherapeutic Guide to Herbal Medicines. M. Blumenthal, W.R. Busse, A. Goldberg, J. Gruenwald, T. Hall, C.W. Riggins, R.S. Rister (eds.) S. Klein and R.S. Rister (trans.). 1998. Austin: American Botanical Council; Boston: Integrative Medicine Communications.
- 1) The Overview section is new information.
- 2) Description, Chemistry and Pharmacology, Uses, Contraindications, Side Effects, Interactions with Other Drugs, and Dosage sections have been drawn from the original work. Additional information has been added in some or all of these sections, as noted with references.
- 3) The dosage for equivalent preparations (tea infusion, fluidextract, and tincture) have been provided based on the following example:
- Unless otherwise prescribed: 2 g per day of [powdered, crushed, cut or whole] [plant part]
- Infusion: 2 g in 150 ml of water
- Fluidextract 1:1 (g/ml): 2 ml
- Tincture 1:5 (g/ml): 10 ml
- 4) The References and Additional Resources sections are new sections. Additional Resources are not cited in the monograph but are included for research purposes.
- This monograph, published by the Commission E in 1994, was modified based on new scientific research. It contains more extensive pharmacological and therapeutic information taken directly from the Commission E.