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Milk Thistle

Medically reviewed by Drugs.com. Last updated on Mar 1, 2019.

Scientific Name(s): Silybum marianum (L.) Gaertn.
Common Name(s): Carduus marianus, Fructus cardui mariae, Fructus silybi mariae, Mariana mariana, Blessed milk thistle, Bull thistle, Chardon de Marie, Holy thistle, Lady's milk, Lady's thistle, Marian thistle, Mary thistle, Mild marian thistle, Milk thistle, Pternix, Shui fei ji, Silberdistil, Silibinin, Silybe, Silybon, Silybum, Silymarin, St. Mary's thistle, Thistle, Thistle of the Blessed Virgin, Wild artichoke

Clinical Overview

Use

Milk thistle has been investigated for its anti-inflammatory, antimicrobial, and CNS effects. It has been studied for use in allergic rhinitis, asthma, cancer treatment–related adverse effects, rheumatoid arthritis, type 2 diabetes, drug-induced hepatotoxicity, drug-induced nephrotoxicity, dyslipidemia, and thalassemia; however clinical trials supporting these uses are limited. Milk thistle is most commonly evaluated for use in the management of liver diseases (alcohol-induced and viral hepatitis) but the majority of clinical trials show equivocal results.

Dosing

Milk thistle is considered safe in dosages of 420 mg/day orally in divided doses for up to 41 months. One source suggests daily doses of 12 to 15 g of dry fruits for dyspepsia and disorders of the biliary system, while an extract containing 200 to 400 mg/day of silymarin is considered effective in various liver disorders.

Contraindications

Milk thistle is contraindicated in patients with allergy to any plant in the Asteraceae family. Avoid use of the aboveground parts of the plant in women with hormone-sensitive conditions (eg, breast, uterine, and ovarian cancers; endometriosis; uterine fibroids) unless under the supervision of a physician, due to the extract's possible estrogenic effects. The more commonly used milk thistle seed extracts are not known to have estrogenic effects.

Pregnancy/Lactation

Milk thistle has traditionally been used in pregnancy. Limited clinical studies in pregnancy demonstrate use without apparent adverse effects; however, further data are needed to confirm safety. Caution should be used in pregnant and breastfeeding women.

Interactions

There are mixed data regarding milk thistle's ability to exert inhibitory or inductive activity on cytochrome P450 (CYP-450) 1A2, 2C19, 2D6, 2E1, and 3A4, as well as P-glycoprotein. Therefore, close monitoring is warranted when drugs metabolized by these enzymes are given concomitantly with milk thistle.

Adverse Reactions

Silymarin is well tolerated; the most common adverse effects after oral ingestion were brief GI disturbances (eg, abdominal bloating, abdominal fullness or pain, anorexia, changes in bowel habits, diarrhea, dyspepsia, flatulence, nausea). Headache and pruritus have also been reported.

Toxicology

Toxic effects of silymarin have not been noted clinically at a dosage of 1,200 mg/day; however, mild allergies have been reported with dosages greater than 1,500 mg/day.

Scientific Family

  • Asteraceae (daisy)

Botany

Milk thistle is indigenous to Europe, Asia, and northern Africa, but has been naturalized in North and South America and Australia. The tall biennial plant grows 5 to 10 feet in height and has large, prickly leaves. The leaves have white markings or "milky veins." When broken, the leaves and stems exude a milky sap, from which the plant derives its name. The flowers are reddish-purple and ridged with sharp spines. The shiny, mottled, black- or grey-toned fruits, often referred to as "seeds," are used in making the extract. The fruits make up the thistle portion along with its silvery pappus, which readily falls away and is not used for the extract preparation.Mastron 2015, Neha 2016, NIH 2018, USDA 2018, WHO 2004

History

The name "milk thistle" comes from the story of the Virgin Mary who was sheltering under the thorny leaves of the milk thistle while nursing baby Jesus. A drop of Mary's milk fell, causing the distinctive white veins on the leaves of milk thistle.Chambers 2017, Mastron 2015 The fruit, stem, and seeds are considered to have medicinal value. Milk thistle has been used medicinally since the fourth century BC. Dioscorides (AD 40 to 90), a Greek physician and botanist, was the first to describe the healing properties of milk thistle.Siegel 2013 Its use in treating hepatobiliary diseases dates back to the 1700s, and its use as a liver protectant can be traced to Greek references. Pliny the Elder (AD 23 to 79) noted that the plant's juice was excellent for "carrying off bile." The ancient Greek and Romans used milk thistle for snake bites.Mastron 2015 The 17th century English herbalist Nicholas Culpepper described milk thistle as beneficial in treating jaundice and in removing liver and spleen obstructions. In the Eclectic medicine movement (19th to 20th century), milk thistle was used to treat varicose veins, menstrual difficulty, and congestion in the liver, spleen, and kidneys. In homeopathic medicine, a tincture of the seeds has been used to treat liver disorders, jaundice, gallstones, peritonitis, hemorrhage, bronchitis, and varicose veins.

Early colonists introduced milk thistle to North America. The plant was first grown in Europe and the de-spined leaves were used in salads and eaten as a vegetable; the stalks and root parts were also consumed. The flower portion was eaten "artichoke-style" and the roasted seeds were used as a coffee substitute.Neha 2016, Schauenberg 1990, WHO 2004, Xiong 2017

Chemistry

The active ingredient in milk thistle is silymarin. Silymarin is composed of 65% to 80% of a complex of flavonolignans: silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin, silydianin, and the flavonoid taxifoline. The remainder consists of fatty acids, betaine, apigenin, silybonol, proteins, fixed oil, and polyphenolic compounds. Silybin A and B, diastereoisomers of silibinin in a 1:1 ratio, are considered the most biologically active components. Milk thistle has poor oral availability, and as such, phospholipid complexes of silibinin and silymarin help improve absorption.Chambers 2017, Esmaeil 2017, Mastron 2015, Neha 2016, Stolf 2017

Uses and Pharmacology

Allergic rhinitis/Asthma

Milk thistle may be beneficial in allergic rhinitis by reducing mast cell anaphylaxis-like reactions and stabilizing the mast cell membrane.Esmaeil 2017

Animal and in vitro data

In a murine model, pretreatment with silibinin reduced airway hyper-responsiveness and inflammation.Choi 2012

Clinical data

In a study of 60 patients with allergic rhinitis and a positive allergy skin test, oral silymarin 140 mg 3 times a day for 1 month in addition to antihistamine therapy significantly improved clinical symptom severity, as measured by the SinoNasal Outcome Test 20 (SNOT-20), compared with control (9.23±5.14 vs 2.20±2.69; P<0.001). Patients treated with silymarin also had a higher posttreatment serum immunoglobulin E level, which could indicate an allergic reaction to silymarin, but this effect could not be confirmed.Bakhshaee 2011

Anticlastogenic activity

Animal and in vitro data

Silymarin has demonstrated strong anticlastogenic activity (ie, inhibition of damage to chromosomes) in murine somatic and germ cells.Anwar 2018

Antimicrobial effects

Animal and in vitro data

In an in vitro study, silibinin exerted activity against Escherichia coli but not Pseudomonas aeruginosa and Staphylococcus aureus. Both silibinin and silymarin exerted activity against Candida albicans, Candida tropicalis, and Candida krusei.de Oliveira 2015 Additionally, silibinin demonstrated a membrane-damaging effect as well as antibiofilm activity on C. albicans.Yun 2017 Dehydroisosilybin A, a component of milk thistle, demonstrated synergistic effects with amphotericin B against Leishmania.Olías-Molero 2018 Another study found silybin may be an efflux pump inhibitor; the compound eliminated the plasmid from methicillin-resistant S. aureus (MRSA) 41577, restoring the bacteria's sensitivity to antibiotics. Further investigation is warranted.Wang 2018 Silibinin inhibited HIV-1 replication in vitro.McClure 2012

Antiosteoporotic activity

Animal data

In ovariectomized rats, treatment for 12 weeks with silymarin prevented bone loss, either through increasing formation via an effect on calcium, phosphorus, osteocalcin, and parathyroid hormone, or through direct action with estrogen receptor-beta.El-Shitany 2010 In another study of ovariectomized mice, silibinin or milk thistle extract 10 mg/kg/day administered for 8 weeks improved femoral bone mineral density and inhibited femoral bone loss caused by estrogen deficiency.Kim 2013

Autophagy

Silibinin may also induce autophagy, an evolving process of lysosomal proteolysis, which is vital for healthy organisms.Pallauf 2013

Cancer

Animal and in vitro data

In vitro experiments and limited animal studies investigated the potential of silymarin and silibinin in a variety of cancer cell lines, including bladder, breast, cervical, colorectal, hepatocellular, gastric, lung, oral, ovarian, renal, and prostate. Several molecular mechanisms have been proposed, including antioxidant and anti-angiogenic actions, apoptosis via cell cycle arrest and modulation of proteins, inhibition of cell migration, inhibition of transcription factors, inhibition of proliferation, and modulation of hormone receptors and cell signaling.Fan 2014, Imai-Sumida 2017, Ma 2015, Mastron 2015, Pirouzpanah 2015, Raina 2016, Singh 2016, Son 2015, Won 2018, Zhu 2016 Additionally, silibinin works synergistically with paclitaxel against gastric cancer cells through triggering cell cycle arrest and apoptosis.Zhang 2018

Clinical data

In a clinical trial of patients with prostate cancer and rising prostate-specific antigen (PSA) levels following radical prostatectomy or radiotherapy, a dietary supplement containing silymarin, soy, isoflavones, lycopene, and antioxidants delayed PSA progression; however, because the product contained several ingredients, outcomes cannot be attributed to any single ingredient.Schröder 2005

In another study, use of Legasil (a silibinin-based product) reduced peritumoral brain edema in 2 patients with brain metastases from lung cancer.Bosch-Barrera 2016

Use of milk thistle or its active components as adjunctive therapy to prevent chemotoxicities associated with chemotherapy and/or radiation has been studied. In one study in children with acute lymphoblastic leukemia (ALL), silibinin (as Siliphos) was administered for 28 days and compared to placebo. Those receiving silibinin achieved a greater reduction in total bilirubin at day 28 compared with placebo.Greenlee 2007, NIH 2018,

In a randomized, double-blind, placebo-controlled study, effects of silymarin 140 mg 3 times daily on radiation-induced oral mucositis were assessed in 27 patients with head and neck cancer. At the end of the first to sixth week, median World Health Organization and National Cancer Institute Common Terminology Criteria scores were significantly reduced in the patients treated with silymarin (P<0.05). During radiation therapy, scores significantly increased in both the silymarin and placebo groups, but the silymarin group experienced a delay in the development and progression of oral mucositis.Elyasi 2016

The effect of silymarin on capecitabine-induced hand-foot syndrome was evaluated in 40 patients with GI cancer in a double-blind, randomized, placebo-controlled trial. Silymarin gel (1%) containing 80% active ingredient based on silymarin flavonolignans was applied twice daily to the soles and palms for the 9-week chemotherapy cycle. By week 9, development and progression of hand-foot syndrome were significantly lower in the silymarin group compared to placebo (P=0.03).Elyasi 2017

CNS effects

Silymarin exerts antioxidant effects by inducing superoxide dismutase, increasing cellular glutathione content, and inhibiting lipid peroxidation.Esmaeil 2017, Milić 2013 Silymarin is a direct free radical scavenger.Surai 2015 It has been studied for its effects in CNS conditions such as Alzheimer and Parkinson disease.

Animal and in vitro data

In a murine model of Parkinson disease, pretreatment with silibinin improved motor disability, dopaminergic neuronal loss, and glial activation, as well as suppressed astroglial activation.Lee 2015

In a murine model of Alzheimer disease, silibinin exerted inhibitory activity against acetylcholinesterase and amyloid-beta aggregation.Duan 2015

Clinical data

A double-blind, randomized, comparator study in 35 patients with obsessive-compulsive disorder reported similar efficacy between 8-week treatment with milk thistle extract (600 mg/day [taken as 200 mg capsules 3 times a day]) and fluoxetine (30 mg/day [taken as 10 mg capsules 3 times a day]). No significant differences were observed between groups with regard to incidence of adverse effects or attrition rate.Sayyah 2010

Dermatological effects

Silybin and silymarin have been studied in the treatment of aging skin and rosacea, as well as in skin cancer prevention.Berardesca 2008, Chambers 2017, Singh 2005, Singh 2009 S. marianum may be beneficial in slowing skin aging due to its ability to inhibit radicals. It also plays a role in ultraviolet (UV) B-tumor initiation and promotion.Chambers 2017 Additionally, it has demonstrated antiglycation activity.Shin 2015

Diabetes

Milk thistle may be effective in the management of diabetes due to its effects on reducing glucose levels, increasing insulin sensitivity, and enhancing beta-cell regeneration.Stolf 2017, Tajmohammadi 2018

Animal and in vitro data

A review of in vitro and animal studies suggests that silybin (silibinin) acts as an aldose reductase inhibitor and can reduce glucose levels.Kazazis 2014 Another study determined that isosilybin A, one of silymarin's constituents, exerted agonist activity on the peroxisome proliferator-activated receptor (PPAR)-gamma.Pferschy-Wenzig 2014

Silymarin reduced oxidative stress and inflammation in a murine model of streptozotocin-induced diabetes.Stolf 2018 In another study of streptozotocin-induced diabetes in rats, 22 weeks of silybin administration prevented the development of obliterated retinal capillaries, suggesting a need for further research regarding a role in diabetic retinopathy.Zhang 2014

Clinical data

A small, triple-blind, randomized, placebo-controlled trial (N=40) documented statistically significant improvements in glycemic indices in adults with at least a 6-month history of type 2 diabetes. Serum glucose, insulin, insulin resistance, and insulin sensitivity were significantly improved after 45 days of silymarin extract 420 mg/day (range, P=0.001 to P=0.04) after adjusting for covariates (ie, baseline glycemic and anthropomorphic values, oral hypoglycemic and dyslipidemic agents, duration of disease, caloric intake, physical activity). Significant changes were also found in some, but not all, lipid parameters, with a negative correlation observed between insulin sensitivity and triglycerides (P=0.038) and a positive correlation noted between changes in insulin resistance and triglycerides (P=0.034). Treatment was well tolerated with no adverse events reported.Ebrahimpour-Koujan 2018

In a 2016 meta-analysis of 5 clinical trials in patients with type 2 diabetes (N=270), routine supplementation with silymarin reduced glucose levels (–26.86 mg/dL; 95% CI, –35.42 to –18.3) as well as hemoglobin A1c (–1.07%; 95% CI, –1.73% to –0.4%); however, no improvement in lipids was observed with silymarin.Voroneanu 2016 Because milk thistle has demonstrated glucose-lowering effects, blood glucose should be carefully monitored when using milk thistle–containing products in patients with type 2 diabetes.

Drug-induced hepatotoxicity

Milk thistle has demonstrated efficacy in liver damage associated with acetaminophen, arsenic, and carbon tetrachloride.Neha 2016

Animal and in vitro data

In a study of rats, silibinin mitigated the increases in liver function measures caused by combination therapy with isoniazid and zidovudine.Ramanathan 2017

Clinical data

Prevention of anti-tuberculosis (TB) drug–induced liver injury was assessed in a double-blind, randomized, placebo-controlled trial in patients with newly diagnosed pulmonary tuberculosis (N=55) who planned to receive standard therapy with isoniazid, rifampicin, pyrazinamide, and ethambutol. Patients were randomly assigned to also receive silymarin 140 mg 3 times daily or placebo. Maximum ALT level within 4 weeks and development of anti-TB drug–induced liver injury were the primary and secondary outcome measures, respectively. Enrollment was terminated early due to slow accrual and safety reasons. Although the sample size was relatively small, administration of silymarin significantly reduced the incidence of anti-TB drug–induced liver injury at week 4 compared with placebo (3.7% vs 32.1%, respectively; P=0.012). However, median ALT levels were not significantly different between groups. Silymarin was well tolerated.Luangchosiri 2015

In another similar study assessing the effects of silibinin on anti-TB drug–induced liver injury, different results were discovered. A group of 277 patients receiving conventional TB therapy and also given silibinin 70 mg 3 times daily for 8 weeks was compared with 291 patients receiving only conventional therapy for TB. At 2, 4, and 8 weeks, there were no differences between the 2 groups in the incidence of liver injury. Additionally, the number of patients diagnosed with drug-induced liver injury at 8 weeks was not different, nor was the percentage of patients with transient abnormal liver function tests. However, fewer cases of nausea and anorexia were reported in patients receiving silibinin compared with those who were not, and more patients in the silibinin group had negative smear cultures compared with those who did not receive silibinin.Gu 2015

In a randomized controlled trial conducted in China (N=370), patients received anti-TB therapy with either supplemental S. marianum (200 mg twice daily) or vitamin C; no significant difference in the occurrence of probable or possible anti-TB drug–induced liver injury was observed between the 2 groups. Of the 215 patients who experienced an above normal AST/ALT ratio, a significantly higher abnormal ratio was observed in the S. marianum group (RR=1.29; 95% CI, 1.08 to 1.53; P=0.004). No significant differences in the prevention of adverse drug reactions or treatment duration and outcome were observed.Zhang 2016

Drug-induced nephrotoxicity

Animal and in vitro data

In a murine model, silybin protected against cisplatin-induced acute kidney injury through improving mitochondrial function via regulation of sirtuin 3 expression.Li 2017

Clinical data

In a pilot, randomized, double-blind, placebo-controlled clinical trial, hospitalized patients receiving cisplatin were administered placebo or oral silymarin 420 mg/day in 3 divided doses starting 1 to 2 days prior to cisplatin initiation and continuing through the end of 3 cycles of 21-day chemotherapy. Data from the 24 patients who completed the study reflected no difference between the intervention and control groups. Silymarin was well tolerated.Shahbazi 2015

In a study of patients with liver cirrhosis, silymarin did not exert protective effects against contrast-induced nephrotoxicity.Kuo 2018

Dyslipidemia

Milk thistle is reported to possibly be effective in dyslipidemia due to a reduction in hydroxymethylglutaryl coenzyme A (HMG CoA) reductase as well as de novo synthesis in cholesterol.Stolf 2017

Animal and in vitro data

In a rat model of hereditary hypertriglyceridemia, 4 weeks of silymarin administration significantly reduced triglyceride and total cholesterol levels, and increased high-density lipoprotein (HDL) cholesterol levels.Poruba 2015

Clinical data

In a triple-blind, randomized, placebo-controlled trial in adults with at least a 6-month history of type 2 diabetes (N=40), statistically significant improvements in some lipid parameters were observed in those receiving a standardized silymarin extract (490 mg/day for 45 days) compared to placebo. HDL (+4.57 mg/dL; P=0.035), triglycerides (−73.19 mg/dL; P=0.034), and triglyceride/HDL ratio (P<0.016) were significantly improved with silymarin compared with placebo; however, total cholesterol and low-density lipoprotein (LDL) were not.Ebrahimpour-Koujan 2018

Immunomodulatory/Anti-inflammatory effects

Silymarin exerts anti-inflammatory effects through inhibition of nuclear factor kappa B and tumor necrosis factor alpha (TNF-alpha) activation. At low doses, silymarin inhibits T-lymphocyte function; however, high doses have been associated with activation of inflammation.Esmaeil 2017 It also inhibits the migration of neutrophils to the site of inflammation.Neha 2016

In vitro data

In human liver and T cells, silymarin induced stress signaling and suppressed inflammation.Lovelace 2015

Clinical data

In a study of healthy men and women, silibinin reduced the expression of interleukin 17 (IL-17) and TNF-alpha, upregulated estrogen receptor-beta expression, induced apoptosis, and inhibited proliferation. In patients with active rheumatoid arthritis, the same effects on apoptosis, proliferation, and cytokine production were noted. Thus, silibinin may have a therapeutic role in states of inflammation such as rheumatoid arthritis.Dupuis 2018

Adding the silymarin supplement Livergol to standard rheumatoid arthritis drug therapy was reported to significantly improve various disease severity parameters. In a single-arm, non-randomized trial (n=44), 420 mg/day of silymarin given for 3 months improved joint tenderness, pain, swelling, erythrocyte sedimentation rate, C-reactive protein, and disease severity scores.Shavandi 2017

Liver diseases

Milk thistle is believed to exert its hepatoprotective effects through the promotion of hepatocyte growth and inhibition of oxidation and inflammation in the liver.Ward 2013 Milk thistle may also increase protein synthesis in liver cells, a positive effect in degenerative liver diseases.Awang 2009 Some reports suggest that oral silybin as a phytosome complex is better for the treatment of liver conditions.Polachi 2016

Animal and in vitro data

In a study of alcohol-induced inflammation of guinea pig hepatocytes, silymarin 25 mg per 100 g of body weight given for 30 days was associated with a reduction in liver function markers (ie, AST, ALT, gamma-glutamyltransferase [GGT]) compared with controls (alcohol abstention group). However, guinea pigs receiving ethanol plus ascorbic acid had a greater reduction in ALT and GGT compared with those receiving silymarin.Abhilash 2013

In a murine model of nonalcoholic steatohepatitis (NASH), treatment with silybin reduced hepatic steatosis, fibrosis, and inflammation through activation of nuclear factor erythroid 2-related 2 (Nrf2) pathway, suppression of nuclear factor kappa B signaling, and downregulation of inflammation-related gene expression.Ou 2018 In another murine model of nonalcoholic fatty liver disease, S. marianum oil reduced lipid accumulation, oxidative stress, and inflammation, and improved the metabolism of lipids.Zhu 2018

Clinical data

A number of meta-analyses evaluating the efficacy of milk thistle in alcohol-induced and viral hepatitis have been conducted.Liu 2003, Rambaldi 2005, Rambaldi 2007, Saller 2001, Saller 2008, Verma 2007 No effect on all-cause mortality was found, and no effect on complications of liver disease or on liver histology could be established.Saller 2008 In a Cochrane review of 18 randomized clinical studies assessing use of milk thistle versus placebo or no intervention in patients with alcoholic or hepatitis B or C virus liver disease, milk thistle had no significant effects on mortality, complications of liver disease, or liver histology. Liver-related mortality was significantly reduced by milk thistle when all trials were assessed (relative risk [RR], 0.5; 95% CI, 0.29 to 0.88) but not in high-quality trials (RR, 0.57; 95% CI, 0.28 to 1.19).Rambaldi 2007 In some trials, a reduction in serum transaminases was demonstrated but with no effect on liver histology or clinical progression.Ferenci 2008, Mayer 2005, Saller 2008 Symptoms related to biliary retention resolved faster in 1 subsequent trial, but with no effect on quality-of-life measures.El-Kamary 2009 One small, open-label study in viral hepatitis demonstrated a reduction in viral load with high-dose intravenous (IV) administration of silibinin.Ferenci 2008 However, orally administered silymarin did not produce differences in serum hepatitis C virus titers, ALT, or quality-of-life measurements compared with placebo, according to a meta-analysis of 5 randomized clinical trials (N=389) published through April 2014.Yang 2014 The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial assessed the long-term use of silymarin in 1,049 patients with advanced fibrosis or cirrhosis after peginterferon and ribavirin therapy had failed. Use of silymarin was associated with less fibrosis as measured by the Ishak fibrosis score, but this association was not noted for clinical outcome measures.Freedman 2011 The American Association for Study of Liver Disease (AASLD) practice guidelines for primary biliary cirrhosis (2009) and primary biliary cholangitis (2018) state that the addition of silymarin to ursodeoxycholic acid provided no additional benefit.Lindor 2009, Lindor 2019

A meta-analysis evaluated English and Chinese randomized placebo-controlled trials from 1966 to December 2011 to determine the safety and efficacy of silymarin as monotherapy and combination therapy for treatment of chronic hepatitis B.Wei 2013 Data from 12 trials (N=1,096) suggest silymarin is equivalent to antiviral or hepatoprotective drugs with regard to effects on serum transaminases, viral load, and hepatic fibrosis markers. However, when silymarin was combined with these agents, serum indices and hepatic markers were reduced. Although the majority of studies were of poor quality, the positive synergistic effect is an important finding that can help inform future clinical studies.Wei 2013

In patients with hepatitis C, beneficial effects have not been noted with use of silymarin. In a multicenter, double-blind, placebo-controlled trial, 154 patients with chronic hepatitis C and elevated ALT levels who were unsuccessfully treated with interferon, silymarin 420 mg or 700 mg 3 times daily for 24 weeks did not significantly reduce ALT levels.Fried 2012 In a study of children 5 to 16 years of age with nonalcoholic fatty liver disease, silymarin given for 12 weeks improved fatty liver infiltration, liver function tests, and triglyceride levels; however, LDL and HDL cholesterol levels were not altered.Famouri 2017

Milk thistle may be useful in acute hepatotoxicity due to amatoxin poisoning from ingestion of Amanita phallides or other Aminata mushrooms. Mechanisms include saturating receptor sites on liver cell membranes before the alpha-faloidine and alpha-amanitin toxins can bind and enter the cell.Awang 2009, Milić 2013 Other potential mechanisms of action include competing with amatoxin for transmembrane transport, interrupting biliary secretion and thus enterohepatic recirculation of the toxin, inhibiting the release of TNF-alpha in damaged hepatocytes, and stimulating the synthesis of proteins in damaged liver cells.Mengs 2012 A review of the literature found that use of IV silibinin (Legalon SIL) resulted in mortality rates of less than 10% in patients with amatoxin poisoning.Mengs 2012

Thalassemia

Blood transfusions are the cornerstone of treatment for patients with thalassemia. In turn, patients can develop iron overload, leading to oxidative stress and organ damage.Moayedi Esfahani 2015 Milk thistle has been suggested to be an iron chelator and has been evaluated in thalassemia for its ability to mitigate these effects.Neha 2016

Clinical data

A small trial (N=30) investigated the humoral and cell-mediated immunomodulatory effects of silymarin (140 mg 3 times daily) added to desferrioxamine therapy (40 mg/kg/day) for 12 weeks in patients 12 years and older with beta-thalassemia; 5 patients who were unable or unwilling to take desferrioxamine therapy received silymarin monotherapy. Neopterin, a marker of cellular immune system activation, and TNF-alpha were decreased in both groups after silymarin therapy, whereas production of interferon-gamma and IL-4 were increased. No adverse effect on frequency or function of immune cells was observed. These data indicate recovery of immune status and cytokine production.Gharagozloo 2013

The iron-chelating effects of silymarin were evaluated in a triple-blind, randomized, placebo-controlled crossover trial of patients with transfusion-dependent beta-thalassemia (N=82). Placebo or silymarin 420 mg/day (given in 3 divided doses) was administered orally as adjunctive therapy to a relatively stable iron chelation regimen for 12 weeks, with a 2-week washout between treatments. Data from the 69 patients who completed the trial reflected a significant treatment effect on median changes in some iron-chelating markers, with reductions in iron levels (P<0.001) and an improvement in total iron binding capacity (P=0.05). Liver iron concentration was also significantly reduced with administration of silymarin (P=0.02). Treatment was well tolerated with no reported adverse effects.Darvishi-Kherzi 2018

Varicocele-induced damage

Animal data

Silymarin 50 mg/kg/day for 42 days protected against varicocele-induced testicular atrophy in Wistar rats. Additionally, varicocelized rats receiving silymarin had higher testosterone levels and a larger percentage of sperm with nuclear maturity compared with varicocelized rats not receiving treatment.Moshtaghion 2013

Dosing

Milk thistle is considered safe in dosages of 420 mg/day orally in divided doses for up to 41 months.Milić 2013, Tamayo 2007 One source suggests daily doses of 12 to 15 g of dry fruits for dyspepsia and disorders of the biliary system, while an extract containing 200 to 400 mg/day of silymarin is considered effective in various liver disorders.van Wyk 2004

A dose of 140 mg of silymarin 3 times daily has been suggested for hepatic cirrhosis.Stolf 2017

S. marianum leaf extract 600 mg/day (200 mg capsules 3 times daily) given for 8 weeks was as effective as fluoxetine in adults with obsessive-compulsive disorder in a small study.Sayyah 2010

A phase 1 clinical study in prostate cancer patients determined a phase 2 dosage recommendation of silibinin (as Siliphos) 13 g/day orally in 3 divided doses.Flaig 2007, Ramasamy 2008

A preparation consisting of 150 mL of boiling water poured over 3.5 g of crushed milk thistle seed, steeped for 10 to 15 minutes, and given 3 to 4 times daily 30 minutes before meals has been suggested for digestive disorders.Blumenthal 2003 Consumption of silymarin in the form of tea may not be effective, as silymarin is poorly soluble in water.Awang 2009

Pregnancy / Lactation

Milk thistle has traditionally been used in pregnancy. Limited clinical studies in pregnancy demonstrate use without apparent adverse effects; however, further data are needed to confirm safety.Deep 2007, Greenlee 2007 Caution should be used in pregnant and breastfeeding women.

Pregnancy

In vitro and animal studies suggest potentially beneficial effects with milk thistle in pregnancy. In a study of rats receiving ethanol during specific weeks of the gestational period, coadministration of silymarin with ethanol resulted in no deficits in spatial working memory in rats on postnatal day 60, suggesting silymarin provided a protective effect against alcohol-induced learning issues.Neese 2004 In a study of peripheral blood mononuclear cells from preeclamptic women, silibinin inhibited nuclear factor kappa B activation and production of inflammatory cytokines.Giorgi 2012

Breastfeeding

Milk thistle may possess galactagogue effects by increasing prolactin levels.Dietz 2016 A study evaluated the efficacy and safety of silymarin to promote milk production in 50 women who had elected to stop breastfeeding because their infants did not consume the milk. Milk production was enhanced with no change to its chemical composition.Di Pierro 2008

Interactions

There is mixed data regarding milk thistle's ability to exert inhibitory or inductive activity on CYP1A2, 2C19, 2D6, 2E1, and 3A4, as well as P-glycoprotein. Therefore, close monitoring is warranted when drugs metabolized by these enzymes are given concomitantly with milk thistle.Asher 2017, Milić 2013, Polachi 2016, Sprouse 2016

Antiretrovirals: Milk thistle may reduce the efficacy of protease inhibitors, integrase inhibitors, and non-nucleoside reverse transcriptase inhibitors. Caution and close monitoring is warranted if using these agents concomitantly with milk thistle.Jalloh 2017

CYP2C9 Substrates: Milk thistle may decrease concentrations of medications that are metabolized by CYP2C9, such as warfarin, phenytoin, and diazepam. Losartan may be impacted depending on the CYP2C9 genotype. Monitor therapy if coadministering.Asher 2017

Deferiprone: UGT1A6 inhibitors may increase the serum concentration of deferiprone. Monitor therapy.Benoit-Biancamano 2009, Ferriprox February 2015, Ferriprox November 2015, Limenta 2008

Iron/Copper-containing supplements: Data are mixed regarding milk thistle's ability to chelate iron and copper. Caution should be used when coadministering iron/copper-containing supplements with milk thistle.Tvrdý 2018

Raloxifene: Coadministration of milk thistle and raloxifene may lead to 4- to 5-fold increases in raloxifene systemic exposure due to inhibition of intestinal glucuronidation by silybin A and silybin B. Monitor therapy and for adverse effects from raloxifene if administering together.Gufford 2015

Simeprevir: Concomitant use of simeprevir with milk thistle may result in increased plasma concentrations of simeprevir. Avoid combination.Doehmer 2011, Olysio November 2017, Wu 2009

Sirolimus: Milk thistle may increase the serum concentration of sirolimus. Monitor therapy.DiCenzo 2003, Jiao 2009, Mills 2005, Piscitelli 2002

Adverse Reactions

In most clinical trials, the incidence of adverse reactions was approximately equal in milk thistle and control groups.Zhu 2018 The US Agency for Healthcare Research and Quality and the German Commission E reported no serious adverse events associated with milk thistle within the recommended dosage range.Post-White 2007, Rainone 2005

Silymarin is well tolerated; the most common effects after oral ingestion were brief GI disturbances (eg, abdominal bloating, abdominal fullness or pain, anorexia, changes in bowel habits, diarrhea, dyspepsia, flatulence, nausea). Headache and pruritus have also been reported.Tamayo 2007 A tea made from crude milk thistle resulted in a case report of anaphylaxis.WHO 2004 High dosages in cancer trials have been associated with asymptomatic hyperbilirubinemia and increases in ALT enzymes.Tamayo 2007

A case report describes a 57-year-old woman with a 2-month history of intermittent episodes of sweating, nausea, colicky abdominal pain, diarrhea, vomiting, and weakness/collapsing. She recalled taking milk thistle for headaches and liver cleansing for about 2 months. Upon further questioning and cessation, it was determined that milk thistle was related to her symptoms.ADRAC 1999

Toxicology

Avoid use of the aboveground parts of the plant in women with hormone-sensitive conditions (eg, breast, uterine, and ovarian cancers; endometriosis; uterine fibroids), unless under the supervision of a physician, due to the extract's possible estrogenic effects. The more commonly used milk thistle seed extracts are not known to have estrogenic effects.Kidd 2005

Oral consumption of milk thistle (standardized to 70% to 80% silymarin) at 420 mg/day is considered safe for up to 41 months based on clinical trial data.Schandalik 1992 Acute oral toxicity of silymarin in rats, dogs, and monkeys has been estimated at dosages greater than 5 g/kg. Subacute toxicity studies suggest no toxicity in rats and monkeys at dosages up to 2 g/kg for 13 weeks, and up to 1 g/kg in rats and dogs for up to 26 weeks. Investigations, including urine analysis and postmortem studies, showed no evidence of toxicity. No evidence of effect on reproduction in rats has been found, and silymarin was not mutagenic in several tests.Plísková 2005, WHO 2004

Toxic effects of silymarin have not been noted clinically at a dosage of 1,200 mg/day; however, mild allergies were reported with dosages greater than 1,500 mg/day.Milić 2013

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