- Milk thistle herbal preparations are produced from the seeds of Silybum marianum (L.) Gaertn.
- Preliminary evidence suggests milk thistle may reduce side effects such as hepatotoxicity, nephrotoxicity, radiation-induced mucositis and dermatitis, doxorubicin-induced cardiotoxicity, and hand-foot-syndrome
- There is no evidence from clinical trials to demonstrate chemopreventative effects or survival impacts for cancer patients
- Milk thistle is generally considered safe
Milk thistle herbal products are made from seeds of Silybum marianum. Milk thistle has a long history of medicinal use, particularly in the treatment of digestive and liver disorders. Claims in relation to cancer are that milk thistle prevents cancer initiation and development, reduces adverse effects of chemotherapy and radiotherapy, and supports the action of some anticancer drugs.
Numerous animal and in vitro models support these claims; however there is limited data from clinical studies. Twelve clinical trials have evaluated the impact of milk thistle in cancer populations for safety, absorption, and side effect management during cancer treatment. There is preliminary evidence from six controlled and one uncontrolled trials that oral milk thistle may reduce hepatotoxicity and nephrotoxicity in combination with certain chemotherapy agents. There is very preliminary evidence from two small controlled and one observational trials that oral milk thistle may reduce doxorubicin-induced cardiotoxicity, radiation-induced mucositis, and topically may reduce skin toxicity from radiation therapy and capecitabine treatment.
Milk thistle is generally well tolerated and appears safe.
Julia Green, Alexander Kalisch, CAM Cancer Consortium. Milk thistle (Silybum marianum) [online document], January 29, 20
Fully updated and revised in January 2019 by Ellen McDonell.
Assessed as up to date in January 2015 by Barbara Wider.
Summary first published in May 2013, authored by Julia Green and Alexander Kalisch.18
Milk thistle (Silybum marianum (L.) Gaertn.) synonym Carduus Marianus L. is a herbaceous plant belonging to the carduae tribe of the Asteraceae (daisy) family. The seeds are the part used.
Milk thistle has many common names including lady’s thistle, St Mary’s thistle, holy thistle, and variegated artichoke1,2. Examples of available products containing silymarin include Legalon SIL® and Thisilyn™: dried seed extracts standardized to 80% silymarin content. Siliphos™ and Silipide™ are silymarin extracts complexed with lipids. Leviaderm™ is a cream, containing silymarin amongst other herbal ingredients .
Ingredients / Components
The main effects of milk thistle are thought to stem from the flavonolignans combined with other ingredients2,3. A crude extract of dried seeds of milk thistle contains 65 – 80% of a flavonolignan complex termed silymarin . Silymarin itself is a complex of at least seven flavonolignans (silybin A and B, isosilybin A and B, silychristin, isosilychristin and silydianin) and the flavonoid taxifolin. Silybin A and B, isosilybin A and B are isomers. Silybin, synonymous with silibin and silybinin, is the processed form of silymarin and contains the isomers silybin A and B in equal amounts. Silybin is considered the main active ingredient of the milk thistle4,5,6. The seeds also contain fatty acids such as linoleic acid.
Application and dosage
Milk thistle is taken orally as tablets, tea or tincture39-41,44. Silymarin is poorly water-soluble; bio-availability is increased by lipid formulations48. In a phase II study 13g of a lipid formulation (Siliphos™) divided into 3 doses high plasma levels were achieved . A study of 2.8g daily of a silybin-phosphatidylcholine complex in women with breast cancer demonstrated detectable levels of silybinin in the plasma, healthy tissue, and breast tissue after 4 weeks of ingestion, with greater accumulation in breast cancer tissue47. Maximum tolerated dose (MTD) is not known. One very small trial enrolled three patients with advanced hepatocellular carcinoma and utilized a dose escalation protocol to determine the MTD. However, MTD was not determined as all three participants died prior to the 12-week dose escalation trial period46. Silybinin and silymarin have a short half-life (1.8 – 5 hours) after ingestion. The major part of orally administered silybinin is found as glucuronosised and sulfatated metabolites in blood following hepatic metabolism . It is not clear whether these metabolites also have anti-carcinogenic properties ., can be applied topically as cream, and in some location is available as injectable preparations (Legalon SIL®). Various oral dosages have been used often in the range of 12-15g milk thistle containing 200 - 600 mg silymarin/ day in divided doses. The most common dosing regimen in clinical trials for cancer has been 420mg of silymarin daily in three divided doses
History and providers
Milk thistle originates from North Africa, Asia Minor and southern Europe. It is now widely naturalized across Europe, Africa, the Americas and Australasia, as a weed and cultivated plant. Milk thistle is so called because of the white markings (variegation) on the leaves, which have been consumed as a vegetable. Roasted seeds have been used as a coffee substitute . The mature untreated seeds of milk thistle have been used for 2000 years in traditional medicine to treat melancholy, headache, digestive and liver complaints, detoxification and promote lactation . In the 1960s the ingredients of milk thistle were investigated. The mixture found was named silymarin . Research concentrated primarily on the use of milk thistle in the treatment of liver disorders and protection from liver injury . In the 1990s reports based on pre-clinical models suggested preventative, and therapeutic, potential in cancer warranted further research .
Claims of efficacy/ alleged indications
The main claim made for milk thistle is that it protects the liver. Orally, milk thistle is used for liver disorders including toxic liver damage caused by chemicals, Amanita phalloides mushroom poisoning, jaundice, chronic inflammatory liver disease, hepatic cirrhosis, chronic hepatitis, gallbladder complaints, hangover and indigestion . It has also been used in prostate cancer, pleurisy, malaria, depression, uterine complaints, allergic rhinitis, stimulating breast milk and menstrual flow . Intravenously, milk thistle is used as a supportive treatment for Amanita phalloides (death cap) mushroom poisoning . In cancer the claims are that milk thistle can be protective by inhibiting tumour development, and supportive in ameliorating adverse treatment effects as well as enhancing chemotherapeutic effect. These claims rest on presumed and acknowledged effects of milk thistle extracts in pre-clinical trials and case reports .. Milk thistle fruits have a positive European Scientific Cooperative on Phytotherapy (ESCOP) monograph for the following therapeutic indications: toxic liver damage; supportive treatment in patients with chronic inflammatory liver conditions and hepatic cirrhosis
Mechanism(s) of action
The precise mechanism of action is unclear with silymarin considered a multi-functional, multi-target drug. Several mechanisms are thought to contribute to therapeutic effect in liver disease 2; Silymarin reduces hepatocyte membrane permeability to toxins , and has antifibrotic action as demonstrated in an in vitro model of human hepatic fibrogenesis. Silymarin demonstrates antioxidant and anti-inflammatory effects in several animal models . Silybinin is thought to have anti-cancer properties in different tumour types via e.g. apoptotic, tumour growth modulating, anti-carcinogenic, anti-inflammatory, anti-metastatic and anti-angiogenic mechanisms . The presumed modes of action are varied and include enhancement of pro-apoptotic molecules (e.g. caspases), enhancement of growth inhibitory proteins, presumed interaction with tumour necrosis factor (TNF), and inhibition of cell proliferation via a number of pathways including inhibition of various protein kinases (e.g. mitogen activated protein kinase MAPK), and inhibition of anti-apoptotic signalling .
In animal experiments and in vitro studies, anti-carcinogenic effects were seen for skin cancer, breast cancer, lung cancer, colon cancer, urinary bladder cancer, prostate cancer, ovarian cancer, leukaemia and cervical cancer. In an animal experiment with nude mice exposed to UV-B rays topical cutaneous application of silymarin was investigated in skin carcinogenesis. A reduction in skin cancer incidence was seen.. In in-vitro studies a synergistic action with different chemotherapeutic agents has been seen . Tests of in vitro effects of silibin on the chemotherapeutic agents vincristine and L-asparaginase on an experimental acute lymphoblastic leukaemia cell line showed no inhibition of their chemotherapeutic effects at low concentrations and a synergistic effect at higher concentrations with vincristine but not L-asparaginase
Prevalence of use
Milk thistle products are widely available in pharmacies, health food and grocery stores and on the Internet. In the US, milk thistle is included in the United States Pharmacopoeia-National Formulary. It is available as a “dietary supplement” under the Dietary Supplement Health and Education act 1994. Silymarin extracts have drug status in several countries. Milk thistle is covered by a Commission E monograph, an ESCOP monograph and the European Medicines Agency has a community monograph in preparation.. In the UK it is available as a registered traditional medicine under the Traditional Herbal Medicines Directive
Cost(s) and expenditures
On the Internet prices for milk thistle tablets can vary significantly. A month’s supply of 7-12 g milk thistle seed containing 400-600 mg silymarin daily can range between €5-40.
Systematic reviews of the effectiveness of milk thistle in human trials have been published but are limited to its use in the treatment of liver disorders, and on pharmacokinetics e.g..
A narrative review of milk thistle published in 2007 summarizes clinical trials on pharmacokinetics, liver diseases and cancer; the studies are included below under either clinical trials or safety if they were investigating pharmacokinetics.
Several clinical trials have evaluated the impact of milk thistle for people with cancer; they are described in Table 1 under Evidence tables.
Hepatotoxicity and nephrotoxicity
Milk thistle as an extract of Silymarin has been evaluated for its ability to reduce nephrotoxicity of cisplatin chemotherapy with mixed results. One small clinical trial (n=60) found that 7 days of silymarin administration at 140mg twice daily prior to cisplatin infusion reduced blood urea nitrogen (BUN) and creatinine at day 14 following cisplatin administration when compared to cisplatin administration alone38. However, a second randomized, placebo-controlled pilot trial (n=24) did not find any benefit to acute kidney injury or urinary electrolyte wasting following the use of 420mg silymarin for 24-48 hours prior to cisplatin infusion and continued for 3 cycles of cisplatin treatment39. Differences may be due to different outcome measures used and length of pre-treatment (7 days versus 1-2 days). Larger and more long-term studies are warrantied to evaluate this effect further.
Three studies have evaluated the impact of milk thistle on chemotherapy-related toxicity in children receiving treatment for acute lymphocytic leukaemia (ALL)31,40,41. In a randomized double-blind placebo-controlled trial of fifty children with ALL with hepatic toxicity receiving chemotherapy, oral milk thistle administration, at 5.1mg/kg/day for 28 days resulted in a trend towards reduced hepatic toxicity at 56 days: liver enzymes aspartate transaminase (AST) were significantly reduced (P=0.05), and alanine transaminase (ALT) showed a trend towards reduction (P=0.07). A 2016 study evaluated 80 children receiving methotrexate-based chemotherapy for ALL who were randomized to 420mg per day silymarin or placebo for 1 week following methotrexate administration40. Several markers of hepatic and renal function were measured. The silymarin group had significantly lower levels of AST, ALT, alkaline phosphatase (ALP), blood urea, creatinine, cystatin C and urinary N-acetyl-beta-D-glucosaminidase compared to the placebo group after chemotherapy indicating improvements in some markers of liver and kidney function. In a third randomized trial of 80 children with ALL, milk thistle administration at 420mg daily for 1 week following doxorubicin treatment reduced doxorubicin-induced cardiotoxicity as measured by echo-Doppler and serum troponin levels compared to placebo41.
In 99 patients with breast cancer being treated with taxane-based chemotherapy, the addition of 80mg 3x/day silymarin resulted in a significantly smaller rise in AST and ALT following treatment compared to a placebo group. Silymarin therefore may alleviate the hepato-toxicity associated with taxane-based chemotherapy for breast cancer42.
In 22 patients with a metastatic colorectal cancer who had progressed on all standard treatment options, the use of regorafenib daily was studied with the addition of silybin (188mg with phosphatidylcholine and vitamin E complex) at the onset of grade 1 liver toxicity in a prospective single-arm (uncontrolled) pilot study43. The addition of silybin significantly reduced AST, ALT, and bilirubin levels, was not associated with any added toxicity, and resulted in a median overall survival of 17.6 months. The authors deemed this to be a promising combination for added anti-tumour activity and reduction of liver toxicity, and randomized controlled trials are warranted.
Mucositis and radiation-dermatitis
A pilot RCT in 27 patients with head and neck cancer receiving radiation therapy found that prophylactic administration of 420mg daily in 3 divided doses of silymarin significantly reduced the onset and severity of mucositis compared to placebo44.
Topically, silymarin may be helpful at reducing skin toxicity associated with some cancer treatments based on two small studies45,34. Silymarin as a gel reduced the time to onset and severity of capecitabine-induced hand food syndrome (HFS) in a study of individuals with gastrointestinal malignancies. The placebo-controlled RCT of 40 individuals found that twice daily application of 1% siylmarin gel from day 1 to 9 weeks of capecitabine treatment significantly reduced the median WHO HFS score (P < 0.05)45.
An observational study with 101 participants investigated a combination cream including milk thistle as an adjunct to radiotherapy
Small trials using combination products including milk thistle have produced contradictory results on PSA levels in prostate cancer patients. Because these trials were of combination products, it is not possible to evaluate milk thistle’s individual action in these trials.
One paper reported on two cases of the use of a milk thistle product called Legasil (210mg of 60% silybinin per capsule) given to two individuals with brain metastases from non small cell lung cancer (NSCLC) which both demonstrated clinical and radiological improvement52. In both cases, the chemotherapy treatment was discontinued due to worsening clinical symptoms and radiological evidence of progression. Both patients initiated Legasil (5 capsules/day for one, and 3 capsules/day for the other), and within 4 weeks, both patients experienced improved performance status (PS). One patient then chemotherapy and continued Legasil, after several month of this regime imaging revealed radiological response of the brain metastases to treatment and the patient had a PS of 0. In the second patient, imaging after 8 weeks of Legasil alone demonstrated reduced tumor volume and edema, the patient had a PS of 1, and the patient then began second-line chemotherapy.
Overall, there is some promising data for the use of milk thistle to reduce toxicities of cancer treatments, in particular heptatoxicity and nephrotoxicity. However, studies to date are small and larger multi-centre trials are needed to better understand the impact of this herb, including any impact on disease outcomes. There is insufficient data available to comment on any possible anti-cancer actions of milk thistle, or chemo-preventative effects.
Orally milk thistle is usually well-tolerated37. One participant receiving high dose silybin phytosome who subsequently had surgery developed a thrombo-embolism: this could have been due to the surgery .. The rate of reported adverse events of oral milk thistle is low or equivalent to placebo group in most clinical trials . Described adverse effects were difficult to distinguish from symptoms of the underlying condition or concomitantly utilized cancer treatment. In rare cases there were complaints of intestinal symptoms, headache and dizziness . In a phase I trial in which high doses of silybin phytosome (up to 20g) were given mild transient elevation of bilirubin, and the liver enzymes aspartate transaminase and alanine transaminase (AST and ALT) were reported
In vitro evidence suggests that milk thistle may alter the activity of cytochrome P450 substrates2,6, however the majority of human studies have not confirmed this49,50,51. Two studies found that milk thistle extract may have inhibitory effects on CYP 2C936,37. However, one study utilized a high-dose silybin phytosome supplement (up to 20g daily) , the other found differing effects of milk thistle based on variation in CYP2C9 genotype36. A study in 9 healthy volunteers evaluated the impact of 14-days of oral ingestion of 140mg silymarin taken three times daily on cytochrome P450 enzymes49. Before and after 14-days of silymarin consumption, P450 enzyme activity was analysed using four drug probes: caffeine, tolbutamide, dextromethorphan, and midazolam. The study found no significant influence of milk thistle on CYP1A2, CYP 2C9, CYP2D6, or CYP3A4 . A phase II clinical trial of 600mg silymarin in cancer patients found no in vivo effect on irinotecan, CYP34A or UGT1A1 pharmacokinetics. These studies confirm findings from other human trials of milk thistle on drug pharmacokinetics showing no impact from milk thistle use50,51.
Overall, the majority of human data has found that milk thistle does not clinically or statistically significantly alter pharmacokinetics of drugs metabolized by CYP1A2, CYP2C9, CYP2D6, or CYP3A4, but it should be noted that there are a few trials that have found inhibitory effects.
In an animal experiment and in an experiment with an oestrogen responsive breast cancer cell line (MCF-7) a tumour growth was seen when adding silymarin. This raises the theoretical risk silymarin could have an oestrogen-like action in women with oestrogen-responsive breast cancer. However the more commonly used milk thistle seed extracts are not known to have oestrogenic effects in vivo. Cautions have been recommended in patients with a known hypersensitivity to plants in the Asteraceae family
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