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File: ■ Milk Thistle (Silybum marianum, Asteraceae)
■ Silymarin
■ Safety/Toxicity

 HC 091944-640

Date: May 15, 2020

RE: Review of Milk Thistle's Safety and Toxicity

Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: an updated review. Phytother Res. June 2019;33(6):1627-1638. doi: 10.1002/ptr.6361.

Milk thistle (Silybum marianum syn. Carduus marianus, Asteraceae), indigenous to southern Europe, Australia, North and South America, northern Africa, and parts of Asia, has been used since ancient times for liver diseases and to boost lactation. It has been used to treat snake bites and remove excess bile from the gall bladder. Silymarin, the major constituent of milk thistle extract, is a collection of flavonolignans which includes silybin A and B, isosilybin A and B, silibinin, silydianin, and silychristin, and is found in the plant’s seeds, leaves, and fruits. Bioavailability of silymarin is low, as it is poorly soluble in water. Silybin, the major constituent of silymarin, is the most bioactive of these flavonolignans, and newer formulations may improve solubility and absorption.

Silymarin exerts positive effects in nonalcoholic steatohepatitis, nonalcoholic fatty liver disease (NAFLD), and fibrosis in human hepatocytes. Studies show that it lowers oxidative stress, insulin resistance, and liver fat accumulation. It boosts liver function and reduces hepatotoxicity of high doses of acetaminophen. In patients with hepatitis C (HCV), silymarin had antiviral effects in addition to being hepatoprotective. At some concentrations, milk thistle is antibacterial and can inhibit biofilm formation. Silymarin had anti-inflammatory effects in patients with arthritis. In vitro and in vivo studies have reported anticancer effects, with reduced toxicity and adverse effects (AEs) associated with chemotherapy and radiotherapy. Oral and topical formulations have wound healing and skin protecting effects. Silymarin was used in patients undergoing peritoneal dialysis to reduce inflammation through its immunomodulatory effects. It is useful in metabolic syndrome, especially with berberine, found in many plants. In patients with type 2 diabetes (T2D), silymarin reduced postprandial plasma glucose levels and progression of diabetic complications.

The authors conducted an electronic database search for human studies reporting on milk thistle safety, toxicity, or AEs published through 2018. In vivo toxicity studies, cell culture studies of mutagenicity and genotoxicity, and studies of safety during pregnancy in humans or animals are also discussed. A table of 43 human studies lists findings with a variety of populations, administration routes, doses, and durations. Three used topical silymarin; two, intravenous; one was administered via an infusion; the remainder were oral formulations. In patients with a variety of medical conditions (40 studies), a daily oral dose of 140 mg three/d was most used, but doses ranged from 70 mg single doses given to women with preeclampsia three and 24 h after delivery to 700 mg three/d, given to patients with HCV in two trials. Administration times ranged from the two acute doses given to parturient women with preeclampsia to 41 months in patients with cirrhosis. In healthy individuals (three studies), doses ranged from 400-420 mg/d and administration times from 10-63 days. In most studies, silymarin was co-administered with another agent or agents.

Overall, silymarin was safe, with only transient gastrointestinal (GI) AEs. In NAFLD, HCV, and other liver diseases, oral and intravenous formulations were safe at various doses and combined with other agents including ribavirin and interferon. Besides GI AEs, some patients reported flushing/heat sensation, weight loss, muscle or joint pain, irritability, or hypercholesteremia. Slightly elevated bilirubin levels were seen in one trial.

The same pattern was seen in patients with allergic rhinitis, tuberculosis, human immunodeficiency virus (HIV), cancer, and ulcerative colitis. In a randomized, double-blind, placebo-controlled clinical trial, patients with a history of prostate cancer (PC) took 570mg silymarin plus selenium daily for two to three months after a prostatectomy. The regimen prevented PC progression, with no AEs, during the six month study. In another PC study, besides mild GI effects including, in this instance, halitosis, patients had slightly elevated creatinine and calcium.

In patients with T2D, silymarin was safe and lacked serious AEs. Combined with Indian barberry (Berberis aristata, Berberidaceae) extract, transient AEs included asthenia and headache as well as GI complaints. In patients with knee osteoarthritis, 300 mg/d for eight weeks caused no serious AEs or toxicity and reduced inflammatory interleukins vs. nonsteroidal anti-inflammatory drugs (NSAIDs). In one study with women diagnosed with preeclampsia, silymarin was safe, and alanine aminotransferase and aspartate aminotransferase were reduced. In children and adults with various blood diseases, silymarin had iron-chelating ability, and no toxicities or major AEs occurred. Only two studies reported on the safety of oral silymarin in pregnant women, and while their results were positive, more studies are needed.

No AEs were reported in studies of topical silymarin use.

While oral silymarin at therapeutic doses did not significantly affect the metabolism of any drug in one study, in another, some of its constituents inhibited CYP2C9 and CYP3A4, members of the cytochrome P450 mechanism. Use of silymarin with drugs such as warfarin should be done with caution.

In vitro, silymarin had mutagenic effects in some bacterial strains tested. Neither genotoxic nor cytotoxic effects were seen in mouse and blood platelet studies. Teratogenic effects were seen in pregnant rats given silymarin in one study, with lower fetal weights and facial and skeletal anomalies. In male rats given silymarin, sperm quality decreased; in mice, it did not. More studies are needed regarding teratogenic effects and reproductive toxicity in animals and humans.

With a variety of milk thistle formulations available, the authors suggest study on specific components of silymarin, especially silybin. While the quality of studies included in this review was not formally assessed, it is clear that more detail is needed regarding the formulation, solubility, and bioavailability of silymarin agents in future studies.

—Mariann Garner-Wizard