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Milk Thistle (Silybum marianum)

The seeds and fruit of Silybum marianum (SM), also known as milk thistle (not to be confused with blessed thistle), have been used to treat liver conditions since the 16th century. (Gillessen 2020) The World Health Organization (WHO) recognized it as an official hepatoprotective medicine in 1970. (Bijak 2017) Silymarin, the main extract from SM, is composed mostly of flavonolignans, flavonoids (i.e., taxifolin, quercetin) and polyphenols. Silybin is the main bioactive component of silymarin that appears to be responsible for any hepatoprotective effects. (Bijak 2017)

SM’s mechanisms of action are not fully understood, but it may act as an antioxidant, antifibrotic agent, insulin resistance modulator, glutathione production inducer, and anti-inflammatory agent through the downregulation of cyclooxygenase and tumor necrosis factor-alpha (TNF-ɑ). (de Avaler 2017)(Gillessen 2020)(Saller 2007)

Main uses

Cardiometabolic modulation
Hepatoprotection
Hormonal modulation

Formulations

Form	Bioavailability & safety
Non-proprietary standardized extracts	20-50% bioavailability for standardized extracts Up to 2,100 mg for up to 48 weeks, and 420 mg per day for up to four years has been shown to have only minor adverse effects that are less or equal to placebo (Gillessen 2020)
Eurosil 85®/Legalon®	30% greater area under the curve (AUC) versus standardized extracts (Kim 2003) Has been shown to have no serious adverse effects in studies up to 15 months in duration (Gillessen 2020)
Realsil® (silybin 94 mg, phosphatidylcholine 194 mg, vitamin E acetate 50% (α-tocopherol 30 mg) 89.28 mg)	Higher bioavailability reported with the addition of phosphatidylcholine and vitamin E (Derakhshandeh-Rishehri 2020) Magnitude of effect with addition of phosphatidylcholine may be 10x (Mendez-Sanchez 2019) Has been shown to have no serious adverse effects in studies up to 12 months in duration (Derakhshandeh-Rishehri 2020)
Silipide® (1:2 silybin to phosphatidylcholine)	4-10x greater bioavailability of silybin than standard SM preparations (Abenavoli 2010)(Barzaghi 1990) Has been shown to have no serious adverse effects in studies up to 12 months in duration (Federico 2006)

Dosing & administration

Acne
General outcomes from A-level evidence	No data currently available.
Dosing & administration	70 mg of Legalon® three times per day after meals to adolescents and adults
Outcomes	↓ number of lesions by 53% and decreased IL-8 by 80% after eight weeks ↑ serum glutathione (271%) (Sahib 2012)
Class of evidence	B

Alcoholic liver cirrhosis
General outcomes from A-level evidence	liver-related mortality by 50%, but not when only high-quality trials were examined (Rambaldi 2005)(Mayer 2005) Non-clinically significant reductions in AST and ALT (0.26 IU/mL and 0.53 IU/mL, respectively) was found in patients with liver disease (de Avaler 2017) ALT (9 IU/mL), with no significant decrease in mortality, liver histology, or AST in patients with liver disease (Jacobs 2002) liver related mortality in alcoholic liver disease in the silymarin group by 7.3% vs. placebo (Saller 2007)
Dosing & administration	420 mg of Eurosil® 85 per day for a minimum of 24 months to patients with mild-to-moderate graded cirrhosis
Outcomes	↑ four-year survival rate by 19% versus placebo (Ferenci 1989)
Class of evidence	B
Dosing & administration	200 mg of Legalon® three times daily for 12 months in patients with insulin-treated diabetes
Outcomes	↓ fasting blood glucose by 13% (no increase in hypoglycemic events), glucosuria by 41%, HbA1c by 0.7 (9% reduction), insulin requirements by 24%, and fasting insulin by 31% (Velussi 1997)
Class of evidence	C

Cardiometabolic health
General outcomes from A-level evidence	↓ HbA1C by 1.92% & fasting blood glucose by 38 mg/dL (Suksomboon 2011) ↓ HbA1C and fasting blood glucose (Rashidi 2013)
Dosing & administration	140 mg of Livergol® three times per day for 45 days in patients with non-insulin dependent type II diabetes
Outcomes	↓ fasting blood glucose (11%), insulin (14%), triglycerides (24%), LDL-C (8%), total cholesterol (7%) ↑ HDL-C (7%) (Ebrahimpour-Koujan 2018)
Class of evidence	B
Dosing & administration	200 mg of SM extract three times per day for four months in non-insulin dependent type II diabetics
Outcomes	↓ LDL-C, triglycerides, total cholesterol, fasting blood glucose, and HbA1C compared to placebo (Huseini 2006)
Class of evidence	B
Dosing & administration	200 mg of Legalon ® silymarin three times per day for 12 months in insulin-treated type II diabetics with alcoholic cirrhosis
Outcomes	↓ fasting blood glucose by 13% (no increase in hypoglycemic events), glucosuria by 41%, HbA1c by 0.7 (9% reduction), insulin requirements by 24%, and fasting insulin by 31% (Velussi 1997)
Class of evidence	D

Drug-induced liver injury
General outcomes from A-level evidence	↓ ALT, AST, & ALP by small but statistically significant amounts (SMD = 0.12-0.15) (Tao 2019)
Dosing & administration	80-320 mg silybin for 28 days in children receiving chemotherapy for acute lymphoblastic leukemia
Outcomes	↓ AST & ALT after 56 days but not 28 days (Ladas 2010)
Class of evidence	B
Dosing & administration	420 mg of silymarin per day was given for 12 weeks along adjunct to tacrine in Px with Alzheimer’s
Outcomes	↓ tacrine side effects (especially gastrointestinal) No impact was observed in ALT (Allain 1999)
Class of evidence	B

Lactation support
General outcomes from A-level evidence	No data currently available.
Dosing & administration	420 mg of silymarin per day for 63 days in healthy women
Outcomes	↑ daily milk production by 54% vs. placebo (Di Pierro 2008)
Class of evidence	B

Menopause
General outcomes from A-level evidence	No data currently available.
Dosing & administration	200 mg twice daily for 12 weeks to 80 women
Outcomes	↓ hot flash frequency (70%) on the Greene Climacteric Scale and severity (68%) on the Hot Flash Related Daily Interference Scale, with effects persisting for four weeks after treatment cessation (Saberi 2020)
Class of evidence	B

NAFLD & NASH
General outcomes from A-level evidence	↓ GGT (SMD=-0.37), with a failure to significantly improve AST and ALT, in Realsil® supplementation (Derakhshandeh-Rishehri 2020) ↓ AST and ALT by 6.6 and 9.1 UI/L, with highest effectiveness found in this trial when used without other therapeutics (Zhong 2017)
Dosing & administration	420 mg or 700 mg (as Legalon®) per day for 48 weeks in patients with NASH
Outcomes	No significant improvement in histology (Navarro 2019)
Class of evidence	B
Dosing & administration	70 mg (as Livergol®) three times per day of Livergol® for eight weeks in patients with NASH
Outcomes	Failed to improve AST and ALT significantly more than placebo (Solhi 2014)
Class of evidence	B
Dosing & administration	700 mg (as Legalon®) three times daily for 48 weeks in patients with NAFLD
Outcomes	↓ markers of liver injury and fibrosis compared to placebo. It failed to improve NAFLD Activity Score, steatosis, liver cell ballooning, and prevention of fibrosis (Kheong 2017)
Class of evidence	B

Viral hepatitis
General outcomes from A-level evidence	↓ liver-related mortality by 50%, but not when only high-quality trials were examined (Rambaldi 2005)(Mayer 2005) Note: non-clinically significant reductions in AST and ALT (0.26 IU/mL and 0.53 IU/mL, respectively) was found in patients with liver disease (de Avaler 2017) There was no evidence for favorable outcomes found in viral hepatitis, in particular in hepatitis C (Abenavoli 2010)(Saller 2007) No significant difference was found in HCV RNA, ALT, and quality of life in chronic hepatitis C patients (Yang 2014)
Dosing & administration	140 mg of silymarin three times a day for eight weeks in Px with acute hepatitis
Outcomes	↓ dark urine, jaundice, scleral yellowing, and indirect bilirubin, with no improvements in direct bilirubin, AST, and ALT (El-Kamary 2009)
Class of evidence	B

Adverse effects

A 2005 Cochrane review found no significant increase in adverse effects from SM supplementation. (Rambaldi 2005) Silymarin extracts have been used at doses up to 420 mg per day for up to four years and for up to 48 weeks at 2,100 mg per day. Adverse effects reported have been rare and minor and tend to occur as often or less often than with placebo. (Gillessen 2020)(Jacobs 2002) For example, in placebo-controlled trials of over 600 participants, the most common adverse effects were pruritus (in 1.01% and 1.35% of the SM and placebo groups, respectively) and headache (in 1.35% and 3.7% of the SM and placebo groups, respectively). (Saller 2007) Less common effects were diarrhea (0.20%), irregular stools (0.10%), nausea (0.13%), and dyspepsia (0.08%). (Saller 2007) Milk thistle is a member of the Asteraceae family of plants, so those with allergies to plants such as ragweed may also have a sensitivity to milk thistle. Therefore, caution is urged in these patients. (Gillessen 2020)

With regards to drug interactions, no evidence was found of induction or inhibition of cytochrome P450 enzymes CYP 1A2, 2C9, 2D6, 2E1, 3A4, or 3A5 in healthy volunteers. (Doehmer 2008) SM was theorized to interact with statins as they may inhibit transport into the liver; however, a human trial found no impact of SM on rosuvastatin pharmacokinetics in healthy males. (Gillessen 2020)

Pharmacokinetics

Absorption

Oral bioavailability of SM’s flavonolignans is low due to their rapid conjugation in the intestines and liver and rapid excretion back into the gastrointestinal tract by the liver through bile (Tvrdy 2021)
The nonlinear pharmacokinetics of silybin A and silybin B suggest silymarin has low bioavailability; only 20 to 50% appears to be absorbed (Gillessen 2020)(Hawke 2010)
Peak plasma levels of silybin were reached two hours after administration (Saller 2007)

Distribution

No data is currently available

Metabolism

Silybin is rapidly metabolized by phase I and II biotransformation, undergoing extensive enterohepatic circulation (Gillessen 2020)
It is not clear which cytochromes are primarily responsible for SM’s metabolism (Bijak 2017)
SM has a half-life of two to six hours, so it is frequently dosed two to three times per day (Hawke 2010)(Saller 2007)

Excretion

1 to 8% of the administered dose of SM is eliminated by the kidneys, with the majority being eliminated into the gastrointestinal tract as bile (Tvrdy 2021)(Saller 2007)
80% of silybin is excreted as glucuronide and sulfate conjugates with bile; 20 to 40% is recovered, whereas the remainder is excreted in feces (Gillessen 2020)