Milk Thistle (Silybum marianum 3)

Indications

Hyperlipidemia supporting liver function and metabolism of glucose, lipids, and hormones. Liver disease including cirrhosis, cancer prevention, hepatitis, and viral-induced inflammation and protection from exogenous chemicals and toxins¹ (parenteral preparations have become established as a viable treatment to save the liver after acute ingestion of hepatotoxins such as poison mushrooms^2,3). Diabetes, metabolic syndrome, hyperglycemia, and insulin resistance.

Mechanism of Action

Nearly all of the research on Silybum has focused on the silymarin complex, a mixture of flavonolignans obtained from the seeds. Silymarin includes the individual flavonolignans silybin A and silybin B (two isomers, together referred to as silibinin⁴), isosilybin A and isosilybin B (two isomers), silydianin, and silychristin. Silymarin also contains fatty acids⁵ and a flavanone dihydroquercetin (taxifolin),⁶ also credited with medicinal effects. Silybin is sometimes mixed with phosphatidylcholine to treat liver disease.⁷ Whole silymarin mixture has been shown to be a superior hypocholesterolemic medication compared with isolated silybin, one of the major flavonolignans found in silymarin.⁸

Silibinin is itself a mixture of two diastereoisomers, silybin A and silybin B.⁴ Silibinin is considered one of the most active hepatoprotective constituents of Silybum seeds, and it is one of the agents believed to protect mitochondrial function and has been shown to increase hepatocellular ATP when studied in isolation.⁹

Silybum flavonolignans are credited with significant antioxidant and membrane-stabilizing effects on hepatocytes.¹⁰ Unlike many statin drugs associated with muscle and liver toxicity, Silybum increases high-density lipoprotein, reduces liver cholesterol deposition, and offers hepatoprotective effects.⁸ Liver injury results in dyslipoproteinemia, which may lead to the development of atherosclerosis, particularly when associated with hypercholesterolemia.

Silybum improves hepatic regulation of plasma lipoproteins and may directly inhibit cholesterol biosynthesis.¹¹ Silybum significantly improves liver enzymes in nonalcoholic fatty liver disease.¹² Parameters indicative of early-stage atherosclerosis may be lowered by Silybum.¹² Silymarin has been shown promote superoxide dismutase and glutathione in liver cells in animals fed a high-sucrose diet, which can result in improved lipoprotein and triglyceride levels.¹³ Oil from Silybum seeds has been shown to attenuate oxidative damage and liver mitochondrial dysfunction in aging mice.⁵

Evidence-Based Research

Silybum has been studied for several decades now and is shown to have broad hepatoprotective and metabolic effects including antioxidant and anti-inflammatory activities, cell permeability regulation and membrane stabilization, stimulation of liver regeneration, and inhibition of deposition in collagen, which may contribute to cirrhosis.¹⁴ A 2014 review of Phase III clinical trials report silymarin to be the best medication for nonalcoholic fatty liver disease.¹⁵

A randomized controlled trial (RCT) dosed diabetic patients with either 1000 mg/day of berberine or a combo of 1000 mg of berberine and 210 mg of silymarin. Although both treatments improved fasting glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, and liver enzyme levels, glycosylated hemoglobin (HbA1c) values were reduced to a greater extent by the combination.¹⁶ A similar RCT investigated the effects of the combination of berberine and silymarin on cholesterol in patients with statin intolerance. The combination significantly reduced triglycerides, LDL cholesterol, fasting blood glucose, and glycosylated hemoglobin¹⁷ without inducing toxicity conditions seen with statins.¹⁸ Additional similar studies on this combination have shown positive effects on reducing insulin resistance¹⁷ and adipokine elevations¹⁹ and improved glycemic control with a glucagon challenge.²⁰

A study on Silybum combined with selenium was investigated in men after radical prostatectomy revealed the incidental finding of reduced LDL and total cholesterol.²¹

An RCT on diabetic patients investigated the effects of 200 mg of Silybum taken two times per day on glycemic indices compared with placebo. Silybum was associated with a significant decrease in HbA1c, fetal bovine serum, total cholesterol, LDL, and triglycerides serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase levels compared with placebo.²²

Safety in Pregnancy and Breastfeeding

Because of its long-standing history as a wild food—the leaves, the roots, and the seeds—Silybum is assumed safe during pregnancy. Silybum is considered safe in lactation and, in fact, is a folkloric galactogogue,²³ with modern clinical trials showing efficacy in promoting lactation in preterm mothers with infants in the neonatal intensive care unit.²⁴ Another study compared 429 mg of silymarin per day with placebo in nursing women with hypogalactia and reported clear galactogogue effects calculated to be an 85.94% increase in breast milk production from Silybum without side effects or difficulties in tolerance.²⁵

General Safety

Silybum is considered to be safe in both short- and long-term applications. Because of its extensive use as a modern natural medicine, Silybum has been the beneficiary of extensive studies by the National Institute of Environmental Health Sciences. The animal investigations found no significant toxicities, no interference with reproductive functions, and no carcinogenic effects²⁶. Animals with long-term Silybum exposure displayed a significantly lower incidence of bile duct hyperplasia, lower mean body weights, significantly decreased incidences of hepatocellular adenoma and hepatocellular carcinoma, and decreased incidences of mammary gland neoplasms in exposed groups of female rats.²⁷ A 2-year toxicity study dosing Silybum to rats and mice found no significant toxicity and a reduction in background tumors.²⁸

No adverse effects or toxicities were noted in any of the human trials cited. A 2007 review of clinical trials reported Silybum extracts to be safe, well tolerated, and toxic or adverse effects to be minimal.²⁹ The main side effects of silymarin seem to be rare gastrointestinal disturbances and allergic skin rashes.³⁰ Oral doses of silymarin up to 2.1 g/day have been shown to be well tolerated and not associated with side effects in human HCV patients.³¹

Silybum, and particularly isolated silybin, are potent inhibitors of cytochrome P2C9³² and cytochrome P3A³³ groups of enzymes; however, isolated silybin was not shown to have significant interactions with other drugs and at doses ²⁶ No antagonistic interactions are noted between Silybum and vincristine, and a modest synergistic effect has been demonstrated.³⁴ No drug-related adverse events were reported.³¹

Dosage

Silybum is generally considered safe at doses up to 700 mg per day. Because Silybum has been so widely studied, medicinal products and clinical studies are often standardized to approximately 80% silymarin content. Dosages may range from 50 to 200 mg or more of Silybum taken two or three times daily to support liver function, reduce cholesterol, and improve glycemic control.

Nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.³¹ Pharmacokinetic studies in human HCV patients have shown a nonlinear dose–blood level curve where doses of 140, 280, and 560 mg result in similar blood levels that suddenly jump at dose of 700 mg.³¹

Traditional Uses

The liver is greatly involved in processing lipids and cholesterol and liver herbs can be an important component of treatments for hyperlipidemia.

Silybum has been used as herbal medicine for the treatment of liver disease and liver cirrhosis and
to prevent liver cancer in Europe and Asia since ancient times. Silybum has also been used to treat gallbladder and biliary disease, jaundice, peritonitis, malarial fevers, bronchitis, insufficient lactation, varicose veins, and reduce insulin resistance. The roots of Silybum have been prepared as a medicinal food, and the spines can be cut from leaves and used a salad greens and pot herbs. Silybum seeds have been roasted brewed into teas and coffee substitutes. Recent research is also showing the Silybum can be useful for renal disease and inflammation and may have efficacy against hormonal cancers including breast, cervical, and prostate.