Milk Thistle (Silybum marianum) in Clinical Practice: What Every Clinician Should Know

Historical backgroundMilk thistle (Silybum marianum) has been used for centuries, with its application dating back to classical Greece, where it was used to treat liver and gallbladder diseases and to protect the liver from toxins. More recently, it has been investigated as a potential cytoprotective agent, anticancer compound, and supportive therapy for liver damage caused by poisoning with Amanita phalloides. The main active substance in milk thistle is silymarin (with silybin as the most important active component), which is found primarily in the seeds. Because silymarin undergoes enterohepatic recirculation, it reaches higher concentrations in liver cells than in serum.

Availability of silymarin products in Croatia

According to European Medicines Agency (EMA) regulatory requirements, herbal medicines can be categorized into three groups:

1. New herbal medicine – efficacy demonstrated by new clinical trials conducted according to current guidelines.

2. Well-established use – efficacy supported by scientific literature but without new clinical trials, with at least 10 years of use in the European Union.

3. Traditional use – no direct evidence of efficacy, but used traditionally for at least 30 years, including 15 years in the EU. Registration is allowed only for indications considered safe for use without medical supervision.

In Croatia, products containing silymarin are registered as dietary supplements or as traditional herbal medicines, with dosages varying by manufacturer. According to the EMA Committee on Herbal Medicinal Products (HMPC), silymarin does not meet the criteria for registration as a “well-established use” herbal medicine due to insufficient scientific evidence of efficacy in investigated indications.

Mechanism of action and results of non-clinical studies

Laboratory studies show that silymarin stabilizes cell membranes and stimulates the synthesis and activity of detoxification enzymes, particularly glutathione S-transferase, influencing intracellular glutathione levels (a potent antioxidant). It can also neutralize a wide range of free radicals.

In vitro studies demonstrate that silymarin regulates key inflammatory mediators such as TNF-alpha, various interleukins, nitric oxide, and interferon-gamma. Additional mechanisms include stimulation of neuronal differentiation, inhibition of leukotriene synthesis in Kupffer cells, and reduction of lipid peroxidation.

Animal studies have shown protective effects of milk thistle against drug-induced damage to the liver, pancreas, and kidneys (e.g., from paracetamol, cisplatin, and vincristine). Preclinical data also suggest anticancer potential.

However, it is important to emphasize that positive preclinical results do not guarantee efficacy in clinical practice. Human pharmacokinetics, dosing, absorption, and interactions may differ significantly, highlighting the need for well-designed clinical trials before routine clinical use.

Evidence for clinical use

Liver disease

Numerous clinical trials have investigated herbal preparations, including milk thistle, in chronic liver disease. However, most have the following limitations:

• Poor study design

• Unclear effective dosage

• Small sample sizes

Randomized placebo-controlled trials of silymarin in steatohepatitis, hepatitis B and C, and alcoholic liver disease generally did not show benefits compared with placebo.

Two meta-analyses concluded that due to significant methodological flaws, there is insufficient evidence to confirm clinical efficacy of milk thistle. Key limitations include patient heterogeneity, lack of standardized dosing, insufficiently defined inclusion criteria, and confounding factors such as co-existing viral hepatitis or ongoing alcohol use.

Anticancer effects

Preclinical studies suggest possible benefits such as inhibition of tumor cell growth and enhanced chemotherapy effects. However, clinical studies in humans have not provided sufficient evidence to recommend milk thistle for cancer treatment or prevention. Professional societies do not recommend its use outside well-designed clinical trials.

Amanita phalloides poisoning

Milk thistle shows potential as adjunct therapy in acute poisoning with Amanita phalloides (“death cap mushroom”). Silymarin inhibits toxin binding to hepatocytes and interrupts enterohepatic circulation. Case reports suggest possible benefits, but because milk thistle was always used as part of combination therapy, its independent effect cannot be determined. Clinical trials are still needed to confirm efficacy.

Safety and side effects

Milk thistle is generally well tolerated. Reported adverse effects are rare and usually mild, mainly gastrointestinal (laxative effect, occasional nausea, or dyspepsia). Allergic reactions are uncommon. Serious adverse events are rare, and significant drug interactions are unlikely, as silymarin inhibits CYP2D6 and CYP3A4 only at very high doses not typically reached with oral use.

Theoretical concerns exist that concurrent use with chemotherapy could reduce efficacy, particularly for agents whose cytotoxicity relies on free radical generation. This warrants caution and further study.

Conclusion

Milk thistle is a relatively safe dietary supplement or traditional herbal medicine, typically associated with rare and mild side effects. However, clinical efficacy in both acute and chronic liver disease remains uncertain. Potential exists in acute amatoxin poisoning, but it should not be recommended for cancer prevention or treatment outside of clinical trials.

Despite the lack of strong clinical evidence, its favorable safety profile means milk thistle will likely remain one of the most commonly used herbal supplements. Clinicians should educate patients on the limitations of current evidence, especially regarding viral hepatitis and alcoholic liver disease. In oncology, careful consideration of risks and benefits is warranted before recommending its use during chemotherapy.

Key Points for Clinicians:

• Hepatoprotection: Evidence is insufficient for routine use in chronic liver disease; may be considered only as adjunctive therapy.

• Mushroom poisoning: Some evidence supports its role in Amanita phalloides intoxication, though intravenous silibinin is not widely available.

• Cancer: Limited and conflicting evidence; not recommended outside clinical trials.

• Safety: Generally well tolerated, with mostly mild gastrointestinal side effects.

• Evidence limitations: Existing trials suffer from poor design, small sample sizes, and inconsistent dosing.

• Regulation: Available as a supplement or traditional herbal medicine, not subject to the same regulatory standards as approved drugs.

  
  

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