Silybin

Silybin (Silibinin): A Comprehensive Reference

1. Identity, Nomenclature, and Natural Source

Silybin (also spelled silibinin, and sometimes written as silybin A/B) is the principal bioactive flavonolignan of milk thistle (Silybum marianum (L.) Gaertn., family Asteraceae). It was discovered as the first member of a new family of natural compounds called flavonolignans in 1959, having been isolated from the seeds of the blessed milk thistle (Silybum marianum).

Silybin A is produced in the fruits of two species of milk thistle: Silybum eburneum, which grows in Spain and northern Africa, and the more common S. marianum, which is native to many countries around the world. Owing to its high adaptability, milk thistle has since spread across Europe, the Americas, South Australia, India, and China, and is even classified as an invasive species in some regions.

Diastereomeric nature: In nature, silybin occurs in the form of two trans diastereoisomers: A and B. These two diastereoisomers are differentiated with respect to reference positions C-10 and C-11 in the 1,4-benzodioxane ring. The molecule has a diastereomer, silybin B, that is formed in equal amounts by the plants; the combination of the two is simply called "silybin." Silibinin is a diastereomeric mixture of (2R,3R,10R,11R) silybin A and (2R,3R,10S,11S) silybin B.

Chemical class: Flavonolignans are plant polyphenols with a chemical structure consisting of a flavonoid and a lignan (phenylpropanoid) moiety. They are found in some species of the families Asteraceae, Fabaceae, Poaceae, and others. The oxeran ring is responsible for the biological activity of silymarin, and opening of this ring results in loss of activity. Only silybins and isosilybins contain the 1,4-dioxane ring system in their structure.

Botanical source — the silymarin complex: Silymarin represents 1.5–3% of the fruit's dry weight and is an isomeric mixture of unique flavonoid complexes — flavonolignans. The main representatives of this group presented in silymarin are silybin, isosilybin, silychristin, isosilychristin, silydianin, and silimonin. The chemical composition of milk thistle fruit besides flavonolignans also includes other flavonoids (such as taxifolin, quercetin, dihydrokaempferol, kaempferol, apigenin, naringin, eriodyctiol, and chrysoeriol), 5,7-dihydroxy chromone, dehydroconiferyl alcohol, fixed oil (60% linoleic acid; 30% oleic acid; 9% palmitic acid), tocopherol, sterols (cholesterol, campesterol, stigmasterol, and sitosterol), sugars (arabinose, rhamnose, xylose, and glucose), and proteins.

Silybin as the dominant constituent: Silymarin, a polyphenolic flavonolignan complex extracted from Silybum marianum (milk thistle), has long been recognized for its hepatoprotective, antioxidant, anti-inflammatory, and anticancer properties. Among its constituents, silybin is the most pharmacologically active and has been extensively studied in both preclinical and clinical settings. Its seeds contain about 70%–80% of the flavonolignans of silymarin and about 20%–30% of polymeric and oxidized polyphenolic compounds (such as tannins).

Common names and synonyms: Silybin, silibinin, Silybum substance E5/E6 (historical). Many controversies often arise, mainly due to the non-standard composition of phytopreparations, the use of various undefined mixtures, the misattribution of silymarin vs. silybin, and also the failure to consider the chemistry of the respective components of silymarin.

2. Traditional and Historical Use

Silybum marianum (milk thistle), a flowering plant native to the Mediterranean, is particularly renowned for its longstanding use in liver-related disorders. The genus name Silybum was designated by the ancient Greek physician Dioscorides, while the species name marianum derives from Christian legend, in which drops of the Virgin Mary's milk fell upon thistle leaves, leaving distinctive white markings.

Historical records trace the medicinal use of milk thistle back over 2,000 years. Dioscorides first documented it as a treatment for venomous snakebites around 40–50 A.D. Theophrastus (371–287 BC) was the first to mention milk thistle as Pternix, showing its long history of medicinal use. Both Pliny the Elder and Dioscorides described its uses in their works.

During the 16th century, British herbalists prescribed it for melancholy, and in the 17th century, Nicholas Culpeper recommended it for jaundice and hepatic obstructions. Interest in its healing properties continued until the 1960s, when German research renewed focus on its ability to treat liver disorders and protect the liver from harmful toxins.

Milk thistle has been used for more than 2,000 years for diseases of the liver and gallbladder. In Europe, milk thistle was used traditionally for curing jaundice and for inflammation in the biliary ducts. Traditionally, the plant has been used to increase milk secretion, relieve menstrual cramps, lessen depression, decrease gallstones, and jaundice as well as improve functions of the liver, spleen, and kidney.

Thanks to its healthful properties, silymarin — an extract of milk thistle fruits — was classified by the WHO in the 1970s as an official medicine with hepatoprotective properties. The European Medicines Agency (EMA/HMPC) recognises certain milk thistle seed preparations for traditional use in the relief of digestive discomfort, based on long-standing, widespread use across Europe.

3. Key Constituents and Preparations

As described above, silybin is the primary active constituent of the broader silymarin complex. In a standardized extract context:

• Silybin (also called silibinin) is the most active and abundant component of the silymarin complex.
• Flavolignans (1.5–3%): silymarin (consisting of silybin A and silybin B), silychristin, silydianin, diastereoisomers isosilybin A and isosilybin B. A silibinin extract consists of equal parts of silybin A and silybin B, with flavolignans at their highest in the more mature seeds.

Pharmaceutical and commercial forms:

• Standardized oral extracts: Modern supplements typically use a standardized extract of milk thistle containing a specific percentage of silymarin (usually 70–80%) to ensure consistent potency and effectiveness.
• Silybin–phosphatidylcholine complex (phytosome): A phosphatidylcholine complex of silybin (SILIPHOS®) has been commercialized and is utilized in many dietary supplements for liver protection. The complex contains about 30% silybin. It has been reported that a phosphatidylcholine complex in oily-medium, soft-gel capsules displays 9.6 times higher bioavailability compared with conventional silybin tablets. Therefore, the recommended dosage of the complex is only 80–160 mg (equivalent to 24–48 mg of silybin), which is much lower than the typical silybin dosage of 140 mg.
• Intravenous formulation (Legalon® SIL): Legalon® SIL is a fully developed pharmaceutical formulation, whose active ingredient is silibinin-C-2′,3-dihydrogen succinate, disodium salt. It is a microcrystalline powder that results from the esterification of silibinin with succinic anhydride to form its hydrosoluble disuccinic acid ester for parenteral application.
• Other delivery systems under investigation: Various technological approaches aimed at improving the solubility and absorption of silybin have been developed, including self-microemulsifying drug delivery systems, solid dispersions, nanocrystals, liposomes, and phospholipid complexes.

4. Pharmacokinetics and Bioavailability

Silybin is classified as a Class II compound under the Biopharmaceutics Classification System (BCS). Despite the various therapeutic benefits and high tolerance of orally administered silybin, poor water-solubility (≤50 μg/mL) is the main restrictive physicochemical feature, which results in low oral bioavailability (23–47%) and large variability in absorption.

The rate of gastrointestinal tract absorption of silybin is 20–50%. This can be due to high reactivity of silybin with phase II conjugation, little permeability via epithelial cells in the gut, poor water solubility, and rapid elimination through bile and urine.

The administration in humans of 240 mg of pure silybin induces a peak concentration of 240 ± 54 ng/mL in about 2 hours that persists for 4 hours. After administration of a single oral dose of 560 or 600 mg silymarin (about equivalent in total to 240 mg of silybin), the fractions of the free, sulfated, and glucuronidated silybin in human plasma are about 17%, 28%, and 55% of the total dose, with a higher plasma percentage of glucuronidated silybin B (71%) than of glucuronidated silybin A.

Silymarin (silybin) undergoes extensive enterohepatic circulation after oral administration. Its half-life is reported to be approximately 6 hours. Following oral consumption, 3–8% of silybin is excreted in its intact form in the urine and about 80% of silybin (as conjugated form with bile) is excreted.

In healthy subjects, oral dosing of silymarin results in very low plasma concentrations of major flavonolignans in the range of 50–300 ng/mL due to their rapid metabolism to glucuronide and sulfate conjugates. The oral formulation achieves peak plasma concentrations 1–2 hours post-dosing, with elimination in 4–6 hours.

Transport and efflux: The major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP), based on results from transporter-overexpressing cell lines and MRP2-deficient (TR−) rats. Compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin.

5. Mechanisms of Action

5.1 Antioxidant Activity

Phenolic compounds exert their antioxidant effects through various mechanisms including (i) direct scavenging of reactive oxygen species (ROS), (ii) chelation of transition metal ions, (iii) inhibition of ROS-generating enzymes, and (iv) upregulation of antioxidant enzymes. Silybin has also been characterized as an iron chelator and an inhibitor of prooxidant enzymes such as xanthine oxidase and phagocyte NADPH oxidase.

Silymarin, a flavonolignan complex derived from Silybum marianum, is particularly effective for liver protection. It activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, enhancing antioxidant enzyme expression and stabilizing mitochondrial membranes.

Existing research suggests that the beneficial effects of silymarin are also associated with the activation of the transcription factor NF-E2 p45-related factor 2 (Nrf2; also called NFE2L2). Nrf2 controls the antioxidant response element (ARE)-mediated expression of genes encoding various antioxidant and detoxication enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HMOX1), and glutamate-cysteine ligase. It has been reported that silymarin induces the expression of the HMOX1 gene in human hepatoma Huh-7 cells and modulates the levels of Nrf2-regulated proteins in animals exposed to various toxic agents.

5.2 Anti-Inflammatory Signaling

The hepatoprotective and antioxidant activity of silymarin is caused by its ability to inhibit the free radicals that are produced from the metabolism of toxic substances such as ethanol, acetaminophen, and carbon tetrachloride. The generation of free radicals is known to damage cellular membranes and cause lipoperoxidation. Silymarin enhances hepatic glutathione and may contribute to the antioxidant defense of the liver.

Its mitochondrial interaction occurs primarily through the stabilisation of mitochondrial membranes and modulation of oxidative phosphorylation, preserving ATP synthesis while preventing cytochrome c leakage and subsequent apoptosis. These synergise with receptor-mediated activation of Nrf2 and inhibition of NF-κB, promoting antioxidant defence. Moreover, by attenuating MAPK–ERK and PI3K/Akt/mTOR signalling cascades, silymarin reduces oxidative stress, thereby prolonging hepatocellular survival.

5.3 Anti-Fibrotic Activity

Silymarin has antifibrotic, immunomodulating, anti-inflammatory effects, and antioxidant properties by scavenging free radicals and increasing the glutathione concentrations.

5.4 Anti-Cancer Signaling (Preclinical Mechanisms)

The treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in the reduced activation of nuclear factor-kappa B (NF-κB), activator protein-1, and STAT3. These proteins are transcriptional regulators of several proliferative genes in melanomas. Silybin blocks the activation of these transcription factors and induces cell-cycle arrest at the G1 phase, which inhibits melanoma cell growth in vitro and in vivo.

A growing number of studies show that the respective diastereomers of flavonolignans have significantly different activities in anisotropic biological systems. Moreover, it is now clear that flavonolignans do not act as antioxidants in vivo, but as specific ligands of biological targets, and therefore their chirality is crucial.

5.5 Metabolic and Endocrine Modulation

Silymarin/silybin can inhibit gluconeogenesis and autophagy of pancreatic β-cells, and repair damaged cells, showing anti-diabetic effects. Mechanistic studies have clarified that silymarin's major bioactive constituents, like silibinin, silydianin, and silychristin, interact with redox-sensitive transcriptional pathways such as Nrf2/ARE and NF-κB, while also influencing metabolic regulators like AMPK and SIRT1.

6. Scientific Evidence by Area of Use

6.1 Liver Disease (Hepatoprotection)

Liver enzyme reduction and fatty liver disease (NAFLD/NASH/MASLD):

A total of 676 patients diagnosed with various liver conditions, including NAFLD, NASH, acute/chronic hepatitis, cirrhosis, and other liver disorders, were included in studies to evaluate the impact of silymarin on liver health outcomes. The patients ranged in age from 29 to 63 years old, and the studies were conducted in multiple countries, including Iran, Australia, Spain, Egypt, Finland, and Denmark. Patients were administered varying dosages — some standardized for silymarin amounts ranging from 140 to 600 mg daily, with a standard dose of 420 mg — for a follow-up period of 4 weeks to 12 months.

A few studies have pointed out a beneficial effect of silymarin therapy upon the evolution of NAFLD, but significant variability and methodological differences across available studies prevent the establishment of robust conclusions. A systematic review with meta-analysis including six clinical trials showed that silymarin reduced serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in NAFLD patients.

A placebo-controlled, double-blind, Phase III, randomized clinical trial with a silybin-vitamin E complex given for 1 year showed an improvement in liver enzymes, insulin resistance, and liver histology of NAFLD. A meta-analysis demonstrated that silybin (Realsil) intake led to a significant decrease in Gamma-Glutamyl Transpeptidase (GGT) levels (standardized mean difference (SMD) = −0.37; 95% confidence interval (CI): −0.68 to −0.06).

Silymarin 700 mg three times daily for 48 weeks, a well-tolerated and safe dose, was associated with greater fibrosis improvement compared with placebo. For this reason, silymarin seemed to be useful for fibrosis improvement in biopsy-proven NASH patients.

The NASH evidence remains inconclusive at the individual trial level: The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered one study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin-treated patients, and the unanticipated effect of placebo on fibrosis, indicating the need for additional clinical trials.

Cirrhosis: A large, randomized, controlled trial performed in the pre-liver transplantation era and before the discovery of HCV indicated that long-term treatment with silymarin may decrease mortality in patients with cirrhosis, mostly in those consuming ethanol.

Summary of evidence strength — hepatic outcomes: The clinical evidence for silybin/silymarin in reducing liver enzymes (ALT, AST, GGT) is moderate, supported by multiple RCTs and meta-analyses. Evidence for clinically meaningful anti-fibrotic effects in NASH is preliminary and mixed. Well-designed large confirmatory trials are still required. In most clinical trials on this topic, a better definition of endpoints, such as the progression of fibrosis or the reduction of transaminase levels, is needed. Well-designed, double-blind, placebo-controlled studies are still required.

6.2 Amatoxin (Mushroom) Poisoning — Antidotal Use

More than 90% of all fatal mushroom poisonings worldwide are due to amatoxin-containing species that grow abundantly in Europe, South Asia, and the Indian subcontinent. Many cases have also been reported in North America. Initial symptoms of abdominal cramps, vomiting, and a severe cholera-like diarrhea generally do not manifest until at least six to eight hours following ingestion and can be followed by renal and hepatic failure. Outcomes range from complete recovery to fulminant organ failure and death.

Silibinin has been shown to interact with specific hepatic transport proteins, blocking cellular amatoxin re-uptake and thus interrupting enterohepatic circulation of the toxin. There are no controlled clinical studies available due to ethical reasons, but uncontrolled trials and case reports describe successful treatment with intravenous silibinin (Legalon® SIL). In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10%, in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin.

Silybin and its more bioavailable derivatives are approved in Europe for treating liver poisoning, such as that caused by eating toxic mushrooms.

Evidence strength: Substantial observational and case-series evidence supports IV silybin (Legalon® SIL) for amatoxin poisoning. No randomized controlled trials exist due to ethical constraints.

6.3 Viral Hepatitis (Hepatitis C)

There is a striking observation that Legalon SIL — an intravenous, aqueous-soluble formulation of silybin A and silybin B — reduces viral load in HCV-infected patients. This has led to other studies showing that Legalon SIL prevents re-infection of the graft during liver transplantation through its pretransplant antiviral effect.

At the opposite end of the spectrum is the report from the randomized, double-blind, placebo-controlled SyNCH trial using the highest oral doses of silymarin to date (700 mg per day), which showed lack of any demonstrable effect of orally administered silymarin in reduction of HCV viral loads and ALT in infected patients.

In a small clinical trial on HCV patients, the group of HCV patients treated with a silybin-vitamin E-phospholipid complex showed an improvement trend of hepatic indices and viral load, and had a significant and persistent reduction of ALT (P = 0.02) and AST serum level (P = 0.01). In this group, cytokines showed a statistically significant increase of IL-2 (P = 0.03) and IL-6 were significantly reduced (P = 0.02).

In a prospective, randomized, placebo-controlled, double-blind clinical trial, 32 subjects with chronic hepatitis C received Pegylated-Interferon-α2b plus Ribavirin and placebo, while 32 subjects received the same dosage of Pegylated-Interferon-α2b plus Ribavirin plus an association of Silybin 47 mg + vitamin E 15 mg + phospholipids 97 mg in two pills for 12 months.

Evidence strength: IV silybin shows antiviral activity in HCV with stronger evidence. Oral formulations show no significant reduction of HCV viral loads at doses studied, likely due to bioavailability limitations. Evidence in this area is mixed and insufficient to support routine clinical use of oral silybin for HCV viral suppression.

6.4 Cancer — Preclinical and Early Clinical Data

Silybin has demonstrated remarkable anti-cancer as well as cancer chemopreventive efficacy in preclinical cell culture and animal models of several epithelial cancers including skin, bladder, colon, prostate, and lung. Based upon these promising preclinical results, silybin has also been tested in human cancer patients in Phase I–II pilot clinical trials, where it was reported to be well tolerated and showed plasma and target-tissue bioavailability.

Silibinin does not present a high antioxidant activity per se, but many reports suggest that it has manifold inhibitory effects against various cancer cells including growth inhibition, anti-inflammation, cell cycle regulation, apoptosis induction, inhibition of angiogenesis, invasion, and metastasis.

In vitro cell-based and in vivo animal studies have demonstrated that silibinin is a lead compound for the design of new drugs for the treatment of prostate cancer. Silibinin has also been tested in prostate cancer patients in Phase I–II pilot clinical trials, where it was reported to be well tolerated and showed plasma and target-tissue bioavailability.

The potential anticancer activity of silymarin extract and its main constituent silibinin — in breast, skin, colon, cervix, ovary, prostate, lung, and hepatocellular cancers, among others — has stimulated the interest of the pharmaceutical industry to develop medications with the therapeutic properties of these substances.

Evidence strength: Preclinical evidence across multiple cancer models is extensive and promising. Human clinical evidence for anti-cancer activity is limited to early-phase (Phase I–II) pilot trials, primarily establishing safety and bioavailability rather than efficacy. No Phase III trials have established a therapeutic role in cancer. This remains a research area.

6.5 Cardiovascular Risk Factors

Preclinical studies including in vitro tests or animal models have predominantly implicated the following effects of silymarin and its constituents: (1) antioxidant, (2) hypolipidemic, (3) hypoglycemic, (4) anti-hypertensive, and (5) cardioprotective. However, a direct amelioration of atherosclerosis and endothelial dysfunction after silymarin administration seems weak based on scarce data.

In clinical trials, the most important findings are improved glycemic and lipid profiles in patients with type 2 diabetes mellitus and/or hyperlipidemia, while the anti-hypertensive effects of silibinin/silymarin seem very modest. The changes in clinical endpoints are not robust enough to draw a firm conclusion. There are significant limitations in clinical trial design, including the great variety in doses and cohorts, the underlying conditions, the small sample sizes, the short duration, and the absence of pharmacokinetic/pharmacodynamic tests prior to study commitment. More data from well-designed and high-quality preclinical and clinical studies are required to firmly establish the clinical efficacy of silibinin/silymarin and its possible therapeutic application in cardiovascular diseases.

Evidence strength: The evidence for cardiovascular benefits is preliminary. Modest clinical signals exist for glycemic and lipid profile improvement, but trial quality and sample sizes are insufficient to support clinical recommendations.

6.6 Diabetes and Metabolic Syndrome

Silymarin/silybin can inhibit gluconeogenesis and autophagy of pancreatic β-cells, and repair damaged cells, showing anti-diabetic effects. In studies with silibinin, it has been reported that it increases the activity of pancreatic beta cells and insulin sensitivity and has a hyperglycemia-reducing effect.

In patients with hepatic steatosis treated with silybin-phospholipid complex (Realsil), the treated group showed a significant decrease in ALT (P = 0.02), AST (P = 0.008), gamma-GT (P = 0.004), alkaline phosphatase (P = 0.05), total cholesterol (P = 0.03), fasting glucose (P = 0.008), insulinemia (P = 0.0006), HOMA value (P = 0.002), and C-reactive protein (CRP; P = 0.04). There was a significant reduction of IFN-γ, TNF-α, and IL-6.

Evidence strength: Animal models and small clinical trials suggest metabolic benefits, particularly on glucose metabolism and insulin resistance. Larger confirmatory RCTs are needed.

6.7 Neuroprotection and Alzheimer's Disease

Silybin has potential therapeutic effects for Alzheimer's disease (AD) via counteracting the toxicity of Aβ (amyloid beta), which is the central peptide responsible for AD. This evidence is, however, based primarily on in vitro and animal studies. There are numerous studies regarding the anti-diabetic and neuroprotective effects of silibinin, but at present, human clinical evidence for neuroprotection specifically attributed to silybin is very limited and insufficient to draw conclusions.

6.8 Chronic Hepatitis B and Steatosis

Silibinin capsules (SC) is a silybin-phospholipid complex containing silybin as the bioactive component, which exerts a remarkable biological effect on various liver diseases, including NAFLD. The purpose of one study was to investigate the effect of SC combined with therapeutic lifestyle changes (TLC) compared with TLC alone on hepatic steatosis in patients with chronic hepatitis B (CHB). Silybin reduces intrahepatic fat accumulation, lobular inflammation, ballooning and serum fat levels in that patient population.

7. Dosage Forms and Doses Reported in Clinical Studies

Doses reported vary significantly across studies and formulations. The following are doses as stated in published sources:

• In liver disease clinical trials, patients were administered varying dosages — some standardized for silymarin amounts ranging from 140 to 600 mg daily, with a standard dose of 420 mg, for follow-up periods of 4 weeks to 12 months.
• Doses in clinical studies varied between 140 mg to 700 mg daily depending on the severity of the condition.
• Silymarin 700 mg three times daily for 48 weeks was reported to be a well-tolerated and safe dose, associated with fibrosis improvement in NASH patients.
• In one double-blind RCT for chronic hepatitis C, the silybin component was dosed as Silybin 47 mg + vitamin E 15 mg + phospholipids 97 mg in two pills for 12 months, alongside antiviral therapy.
• A phosphatidylcholine complex in oily-medium, soft-gel capsules displays 9.6 times higher bioavailability compared with conventional silybin tablets. The recommended dosage of the complex is only 80–160 mg (equivalent to 24–48 mg of silybin), which is much lower than the typical silybin dosage of 140 mg.
• The highest oral doses of silymarin used in any reported trial to date were 700 mg per day (the SyNCH trial for HCV).
• Oral silymarin was also well-tolerated by patients with chronic hepatitis C even at a high dose of 700 mg thrice daily for 24 weeks.
• Clinical trials have revealed that silymarin is safe at high doses (greater than 1,500 mg/day) in humans.

8. Safety, Adverse Effects, and Drug Interactions

8.1 General Tolerability

Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.

Based on an estimated 9,000 patients treated, silymarin extract infusion therapy can be considered safe. Silymarin extract has no reported serious adverse events, indicating it is safe for use in chronic HCV cirrhotic patients at both high dose (1,050 mg/day) and regular dose (420 mg/day).

The US Food and Drug Administration has not approved silybin for any medical use, but it has registered silymarin as a dietary supplement.

8.2 Reported Adverse Reactions

Adverse drug reactions with silymarin are relatively uncommon. Examples include nausea, vomiting, diarrhea, allergic reactions, headaches, and arthralgia.

Intravenous formulation: From drug surveillance and periodic safety updates over the years since introduction of the IV product in 1984, no serious adverse drug reactions have been reported. Flushing during the intravenous treatment is not uncommonly reported but appears to be of mild degree.

Silymarin was safe without any major side effect in a clinical trial involving tuberculosis patients.

8.3 Drug–Drug Interactions

Silybin exhibits low drug–drug interactions and does not have major effects on cytochrome P-450 at its therapeutic dose range in humans.

In vitro studies indicate that silymarin may decrease the activities of CYP3A4, CYP2C9, and uridine diphosphoglucuronosyltransferases (UGTs), though as noted above, these effects are considered unlikely to be clinically significant at typical doses.

The major efflux transporters of silybin are MRP2 and BCRP. Compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin.

8.4 Renal Impairment

There is no suggestion for adjusting the dose of silymarin or silibinin in patients with impaired kidney function based on available evidence.

8.5 Regulatory Notes

Silybin and its more bioavailable derivatives are approved in Europe for treating liver poisoning, such as that caused by eating toxic mushrooms. Its intravenous form (Legalon® SIL) has been available in Europe since 1984 for amatoxin poisoning. As an oral dietary supplement, silybin/silymarin is broadly marketed in North America, Europe, and Asia without formal approval for any specific medical indication in most jurisdictions.

9. Body Systems and Health Areas of Association

• Hepatobiliary system: Liver enzyme normalization, hepatoprotection against toxins, antifibrotic effects in steatohepatitis and cirrhosis, antidote for amatoxin mushroom poisoning (IV form). This is the best-supported area clinically.
• Metabolic / Endocrine system: Improvements in fasting glucose, insulin sensitivity (HOMA), and lipid profiles observed in clinical studies of patients with fatty liver and type 2 diabetes.
• Cardiovascular system: Antioxidant, hypolipidemic, and modest antihypertensive effects in preclinical and limited clinical studies; clinical evidence is preliminary.
• Oncology (chemoprevention): Extensive preclinical data across multiple cancer types; only early-phase clinical safety/bioavailability data in humans.
• Neurology: Potential neuroprotection via Aβ toxicity counteraction; evidence currently limited to animal models and in vitro studies.
• Immune system: Silymarin/silybin has antioxidant, anti-inflammatory, protein synthesis-enhancing, and anti-fibrotic activities as well as a good safety profile.
• Reproductive / Galactagogue: Milk thistle is a galactagogue and has traditionally, and is still now, used to promote breast milk in breastfeeding mothers.

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