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Milk Thistle

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

Clinical Overview

Use

Although sufficient evidence from prospective clinical trial data is lacking, studies suggest potential applications for silymarin (a flavonoid lignan complex from milk thistle) in treating alcohol-related hepatitis, toxicity due to Amanita mushroom poisoning, antituberculosis drug–induced hepatoxicity, diabetes, and cancer. Limited clinical data suggest benefit in dyslipidemia.

Dosing

Oral consumption of milk thistle (standardized to 70% to 80% silymarin) at 420 mg/day in divided doses is considered safe for up to 41 months based on clinical trial data. One source suggests 12 to 15 g of drug fruits or 200 to 400 mg of silymarin extract as effective doses. Higher doses have been used in clinical trials.

Contraindications

Allergy to any plant in the Asteraceae family. Avoid use of aboveground parts of the plant in women with hormone-sensitive conditions due to the extract's possible estrogenic effects. These conditions include breast, uterine, and ovarian cancers, endometriosis, and uterine fibroids.

Pregnancy/Lactation

Avoid use because information is limited. Use in pregnant and breast-feeding women has been reported in limited clinical studies without apparent ill-effect, but further data are needed.

Interactions

Milk thistle should be used with caution at high doses.

Adverse Reactions

In most clinical trials, the incidence of adverse reactions was approximately equal in milk thistle and control groups. No serious adverse events were reported at recommended dosages. The most common effects after oral ingestion were brief GI disturbances.

Toxicology

There are no documented milk thistle toxicities in humans, and toxicity appears to be low in laboratory animals.

Botany

Milk thistle is indigenous to Europe and Asia, but has been naturalized in North and South America. The plant grows 1.5 to 3 m in height and has large, prickly leaves. When broken, the leaves and stems exude a milky sap. 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.1, 2

History

Milk thistle has been used medicinally since the 4th century BC. 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 17th century English herbalist Nicholas Culpepper wrote that milk thistle was beneficial in treating jaundice and for removing liver and spleen obstructions. The Eclectic medical system (19th to 20th century) used milk thistle to treat varicose veins, menstrual difficulty, and congestion in the liver, spleen, and kidneys. In homeopathy, a tincture of the seeds has been used to treat liver disorders, jaundice, gallstones, peritonitis, hemorrhage, bronchitis, and varicose veins. The fruit, stem, and seeds are considered to have medicinal value.

Early colonists introduced milk thistle to North America. The plant was grown in Europe and the despined leaves were used in salads and eaten as a vegetable; the stalks and root parts also were consumed. The flower portion was eaten "artichoke-style" and the roasted seeds were used as a coffee substitute.2, 3, 4

Chemistry

Milk thistle extract is composed of 65% to 80% silymarin. The remainder consists of polyphenolics and fatty acids such as linoleic acid. Silymarin is a complex of at least 7 flavolignans, including silibinin, isosilibinin, silychristin, isosilychristin, and silydianin, as well as the flavonoid taxifolin. Silybin A and B, diastereoisomers of silibinin, are considered the most biologically active components, although isosilibinin may be more potent.5 Other flavonolignans have been described, and various methods for chemical constituent analysis have been published.2, 6, 7, 8, 9, 10, 11

Uses and Pharmacology

Most studies evaluating milk thistle's mechanism of action have used silymarin or silibinin. Antioxidant properties have been demonstrated in various models using human cells such as platelets. A reduction in drug-induced hepatotoxic ischemic damage and iron-overload oxidative stress has also been shown. Silymarin stabilized hepatocyte and other cell membranes and stimulated macromolecular and protein synthesis. Anti-inflammatory action was demonstrated with inhibition of neutrophil-mediated histamine release, lipoxygenase and prostaglandin synthetase, and leukotriene synthesis.2, 12, 13, 14

The US National Institutes of Health clinical trials database lists a number of clinical trials in process, or preparing to recruit participants, to evaluate the efficacy of milk thistle extracts.15

Allergic rhinitis

Clinical data

In a study of 60 patients with allergic rhinitis and a positive allergy skin test, oral silymarin 140 mg given 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) when compared with control results (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 was not able to be determined from this study.49

Cancer

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, hepatocellular, gastric, and prostate cancer. Several molecular mechanisms have been proposed, including antioxidant, anti-angiogenic action, apoptosis via cell cycle arrest, inhibition of transcription factors, and modulation of hormone receptors and cell signaling.7, 16, 17, 18, 19, 20, 21, 22

Animal/In vitro data

In an SGC7901 cell line, silibinin was found to block cell growth and cause growth hormone phase arrest and apoptosis, suggesting possible use in treating gastric carcinoma in humans.22

Clinical data

Clinical trials are lacking, and use of milk thistle preparations in cancer is not recommended outside of the trial setting.19 A small, phase 1 trial evaluating the tolerability of silibinin (commercial preparation Siliphos) in prostate cancer patients has been completed, and phase 2 trials are being planned.15, 23 Silibinin was administered to patients with colorectal adenocarcinoma over 7 days to evaluate the tissue concentrations of silibinin in the colorectal mucosa.19 However, the trial included silymarin combined with soy, isoflavones, lycopene, and antioxidants in patients with prostate cancer; therefore, outcomes cannot be attributed to any single ingredient alone.24 Use as an adjunct to chemotherapy to prevent drug-related hepatotoxicity has also been studied in limited trials, including 1 in which children with acute lymphoblastic leukemia (ALL) administered silibinin (as Siliphos) for 28 days achieved greater reduction in total bilirubin at day 28 compared with results seen with placebo.15, 25

Diabetes

Animal/In vitro data

In vitro and animal experiments suggest milk thistle may exert hypoglycemic effects.26, 27

Clinical data

Limited clinical trials have been conducted in types 1 and 2 diabetes and diabetes with comorbid conditions such as alcoholic liver disease.15, 25, 28, 29 Most trials recorded decreases in fasting and postprandial serum glucose, and coincidentally note improvements in the lipid profile; however, because the trials are mostly unblinded with small numbers of participants, no conclusions can be drawn. Milk thistle has hypoglycemic effects and should be used with caution in patients with diabetes.30 A small triple-blind, randomized, placebo-controlled trial (n=40) published recently 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 420 mg/day silymarin extract (range, P=0.001 to 0.04) after adjusting for covariates (ie, baseline glycemic and anthropomorphic values, oral hypoglycemic and dyslipidemic agents, duration of disease, caloric intake, and 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.110

Drug-induced hepatoxicity

Prevention of antituberculosis drug–induced liver injury (anti–TB DILI) was assessed in a double-blind, randomized, placebo-controlled trial in patients with newly diagnosed pulmonary tuberculosis (N = 55) 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 DILI 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 DILI at week 4 compared to placebo (3.7% vs 32.1%, respectively; P = 0.012). However, median ALT levels were not significantly different between groups. Silymarin was well tolerated.106 In contrast, a randomized controlled trial conducted in 370 patients in China who were administered anti-tuberculosis drug-induced liver injury therapy revealed no significant difference in the occurrence of probable or possible anti-tuberculosis liver injury between those given supplemental S. marianum (200 mg twice daily) versus those who were not. 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 were observed in the prevention of adverse drug reactions or treatment duration and outcome.107

Drug-induced nephrotoxicity

As a follow up to in vitro and in vivo data that suggested a nephroprotective effect of silymarin flavonolignans and flavonoids against cisplatin-induced nephrotoxicity, the first human study was conducted. A pilot, randomized, double-blind, placebo-controlled clinical trial administered 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.104

Dyslipidemia

Clinical data

In 124 euglycemic, dyslipidemic patients intolerant to high doses of statins, administration of half the statin dose plus twice daily dosing of a Berberis aristata 588 mg/S. marianum 105 mg combination product significantly reduced fasting plasma glucose, insulin, and insulin index and stabilized lipid levels compared to baseline and placebo in a 6-month double-blind, randomized, controlled trial. Lipid levels increased significantly during the study period in the placebo group. The intervention (a patented nutraceutical in Italy containing B. aristata extract standardized to 85% berberine plus S. marianum extract titrated to more than 60% flavanolignans) was well tolerated.105 In a triple-blinded, randomized, placebo-controlled trial (n=40) published in 2018, statistically significant improvements in some lipid parameters were observed in adults taking a standardized silymarin extract (490 mg/day x 45 days) compared to placebo. High-densitiy lipoprotein (HDL) (+4.57 mg/dL, P=0.035), triglycerides (−73.19 mg/dL, P=0.034), and triglyceride/HDL ratio (P<0.016) were improved significantly with silymarin compared to placebo; however, total cholesterol and low-density lipoprotein were not. Patients had at least a 6-month history of type 2 diabetes.110

Dyspepsia

Clinical data

A meta-analysis found a product containing Cardui mariae to be effective for the treatment of dyspepsia symptoms compared with placebo results. When the product was compared with cisapride, there were no differences in patient-reported responses.48

Hepatoprotective effects

Milk thistle is believed to exert its hepatoprotective effects through the promotion of hepatocyte growth and inhibition of oxidation and inflammation in the liver.31 Milk thistle may also increase protein synthesis in liver cells, a positive effect in degenerative liver diseases.32

Animal/In vitro data

In a study of alcohol-induced inflammation of guinea pig hepatocytes, silymarin 25 mg per 100 g body weight given for 30 days was associated with a reduction in liver function markers (ie, AST, ALT, gamma-glutamyltransferase [GGT]) compared with that of controls. However, guinea pigs receiving ascorbic acid had a greater reduction in ALT and GGT compared with those receiving silymarin.33

Clinical data

A number of meta-analyses have been conducted on the efficacy of milk thistle in alcohol-induced and viral hepatitis.34, 35, 36, 37, 38, 39 No effect on all-cause mortality was found, and no effect on complications of liver disease or on liver histology could be established.34, 36 Although a decrease in liver-related mortality was demonstrated when only high-quality trials were included, no effect on mortality was found (relative risk [RR], 0.57; 95% confidence interval [CI], 0.28 to 1.19).30, 34, 35 In some trials a reduction in serum transaminases was demonstrated, but with no effect on liver histology or clinical progression.36, 40, 41 Symptoms related to biliary retention resolved faster in 1 subsequent trial, but with no effect on quality of life measures.42 One small, open-label study in viral hepatitis demonstrated a reduction in viral load with high-dose intravenous (IV) administration of silibinin.41 However, orally administered silymarin did not produce significant 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 2014.103 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 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.43 The American Association for Study of Liver Disease (AASLD) practice guideline for primary biliary cirrhosis (2009) states that the addition of silymarin to ursodiol provided no additional benefit. Clinical evidence is lacking regarding safety or efficacy of other herbal products.

A meta-analysis evaluated English and Chinese placebo-controlled randomized controlled trials from 1966 to December 2011 to determine safety and efficacy of silymarin as mono- and combination therapy for treatment of chronic hepatitis B.99 Data from 12 trials (N = 1,096) suggested silymarin had an equivalent effect on serum transaminases, viral load, and hepatic fibrosis markers compared with antiviral or hepatoprotective drugs. However, when silymarin was combined with these agents, serum indices and hepatic markers were significantly reduced. Although the majority of studies were of poor quality, the positive synergistic effect is an important finding.99

Milk thistle was used in children with ALL and concomitant hepatic toxicity. Patient-reported adverse reactions in the milk thistle group included diarrhea, flatulence, irritability, and stomach ache.3, 44

Considering the low toxicity profile of milk thistle, clinical reviewers have suggested its use in treating alcoholic-related cirrhosis.35, 36 However, its use in viral hepatitis outside of clinical trials is not supported by current data.34, 36, 39, 45, 46

Milk thistle may be useful in Amanita toxin poisoning by saturating receptor sites on liver cell membranes before the toxin can bind and enter the cell.32 The use of silymarin in the treatment of Amanita mushroom poisoning is also supported by retrospective data analysis, but prospective clinical trial data are not available.12, 15, 36, 47 A case report describes Amanita mushroom ingestion (Amanita ocreata) by a 72-year-old woman and her 45-year-old son who were treated with N-acetylcysteine, high-dose penicillin, cimetidine, and silibinin (both oral and IV) during their hospitalization. Both patients recovered and were asymptomatic 1 month after discharge.31

Thalassemia

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 tumor necrosis factor-alpha were decreased significantly in both groups after silymarin therapy, whereas production of interferon-gamma and interleukin-4 were increased. No adverse effect was observed on frequency or function of immune cells. Together, these data indicate recovery of immune status and cytokine production.100 The iron-chelating effects of silymarin were evaluated in 82 patients with transfusion-dependent beta-thalassemia. Placebo or silymarin 420 mg/day (given in 3 divided doses) was administered orally as adjunctive therapy to a relatively stable iron chelation regimen in a triple-blind, randomized, placebo-controlled crossover design for 12 weeks with a 2-week washout. 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 found to be significantly reduced with administration of silymarin (P=0.02). Treatment was well tolerated with no report of side effects.109

Other uses

Silybin and silymarin have been studied in the treatment of aging skin and rosacea, as well as in skin cancer prevention.50, 51, 52 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 (11%) 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, the hand-foot development and progression in the silymarin group were significantly lower compared to placebo (P=0.03).108 (Elyasi, 2017)

In older studies, silybin has been evaluated in patients with cholestasis.53, 54, 55 Silybin possesses antibacterial activity against gram-positive bacteria, but shows no activity against gram-negative bacteria or fungi.56 Milk thistle extract demonstrates neuroprotective effects in animal studies.12, 57, 58, 59

Ovariectomized rats were treated for 12 weeks with silymarin, which 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.60 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 cause by estrogen deficiency.61

Silymarin 50 mg/kg/day for 42 days was found to protect 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.62

Silibinin may also induce autophagy, an evolving process of lysosomal proteolysis, which is vital for healthy organisms.63

Dosing

Oral consumption of milk thistle (standardized to 70% to 80% silymarin) at 420 mg/day in divided doses is considered safe for up to 41 months based on clinical trial data.64 One source suggests 12 to 15 g of fruits or 200 to 400 mg of silymarin extract as effective doses.65

Silibinin (as Siliphos) has been administered at 13 g/day in phase 1 clinical trials.19, 23 As adjunctive therapy, Siliphos has been used in children at dosages of 5.1 mg/kg/day.25

A preparation consisting of 150 mL of boiling water poured over 3.5 g of crushed seed, steeped for 10 to 15 minutes, and given 3 to 4 times daily 30 minutes before meals has been suggested for digestive disorders.66 Consumption of silymarin in the form of tea may not be effective, as silymarin is poorly soluble in water.32

Pregnancy / Lactation

Avoid use because information is limited. Use in pregnant and breast-feeding women has been reported in limited clinical studies without apparent ill-effect, but further data are needed.21, 25

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.67

Milk thistle may possess galactagogue effects by increasing prolactin levels.68 A study evaluated the efficacy and safety of silymarin to promote milk production in 50 women who had elected to stop breast-feeding because their infants did not consume the milk. Milk production was enhanced with no change to its chemical composition.69

Interactions

ARIPiprazole: CYP3A4 Inhibitors (Weak) and CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Monitor therapy.70, 71, 72, 73

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy.74, 75

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy.76

Deferiprone: UGT1A6 Inhibitors may increase the serum concentration of Deferiprone. Monitor therapy.77, 78, 79

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Consider therapy modification.80

Losartan: Milk Thistle may increase the serum concentration of Losartan. Monitor therapy.81, 82, 83, 84, 85, 86

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination.87, 88, 89, 90

Simeprevir: Concomitant use of simeprevir with milk thistle may result in increased plasma concentrations of simeprevir due to CYP3A inhibition by milk thistle. It is not recommended to coadminister simeprevir with milk thistle.98

Sirolimus: Milk Thistle may increase the serum concentration of Sirolimus. Monitor therapy.91, 92, 93, 94

Other interaction data

Some studies have reported insignificant pharmacokinetic drug interactions with natural products. Limited information as well as potentially high interpatient variability in clinical response warrants cautious interpretation and/or application of these data in practice.

A standardized milk thistle extract containing 175 mg dried extract of achenes (140 mg silymarin) produced no significant influence on CYP1A2, CYP2C9, CYP2D6, or CYP3A4/5 activity in healthy volunteers (n = 9) as measured by maximal drug concentration and area under the curve using high-performance liquid chromatography (HPLC) tandom mass spectrophotometry (MS) on a Surveyor HPLC autosampler, Surveyor MS quaternary pump, and TSQ Quantum Discovery triple-quadruple mass spectrometer.101

Adverse Reactions

In most clinical trials, the incidence of adverse reactions was approximately equal in milk thistle and control groups.34 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.13, 47 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.53

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). Milk thistle was used in children with ALL and concomitant hepatic toxicity. Patient-reported adverse reactions in the milk thistle group were diarrhea, flatulence, irritability, and stomach ache.42 Other reported adverse reactions were headache, impotence, and skin reactions (eg, eczema, pruritus, rash, urticaria).64 A tea made from crude milk thistle resulted in a case report of anaphylaxis.2 High dosages in cancer trials have been associated with asymptomatic hyperbilirubinemia and increases in ALT enzymes.64

A case report describes a 57-year-old woman with a 2-month history of sweating, nausea, colicky abdominal pain, diarrhea, vomiting, and weakness/collapsing. She was well between these intermittent episodes. 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.95

Toxicology

Avoid use of aboveground parts of the plant in women with hormone-sensitive conditions due to the extract's possible estrogenic effects. These conditions include breast, uterine, and ovarian cancers, endometriosis, and uterine fibroids. The more commonly used milk thistle seed extracts are not known to have estrogenic effects.96

Acute oral toxicity of silymarin in rats, dogs, and monkeys has been estimated at dosages greater than 5 g/kg. Subacute toxicity studies suggested no toxicity in rats and monkeys for dosages of 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.2, 97

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