Description
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.
Efficacy
Chemotherapy-induced hepatotoxicity: Among children, improved markers of liver function were reported in 4 RCTs, including AST, ALT, ALP (moderate-certainty evidence). Studies conducted among adults are inconclusive, while 2 RCTs showed no improvements in liver toxicity, two CCTs showed improvements in AST and ALT (low-certainty evidence).
Chemotherapy-induced nephrotoxicity: Results from two small RCTs are conflicting, while one reported reduced blood urea nitrogen and creatinine, another did not report any improvements (low-certainty evidence).
Chemotherapy-induced cardiotoxicity: Silymarin may decrease early doxorubicin-induced cardiotoxicity among children based on one RCT (moderate-certainty evidence). Silymarin may be a useful agent as it resulted in more beneficial effects on the iron profile reported in one small RCT (low-certainty evidence).
Chemotherapy-induced mucositis: Evidence from three small RCTs is conflicting: two reported reduced severity of mucositis, one thereof also delayed onset while the third reported no differences between groups for these outcomes (low-certainty evidence).
Radiation dermatitis: Milk thistle may delay radiodermatitis occurrence and slow down its progression according to two CCTs (low-certainty evidence).
Hand-foot syndrome: One RCT found topical silymarin to be the most useful for preventing capecitabine-induced hand-food syndrome compared with six other regimens (moderate-certainty evidence).
Safety
Milk thistle is generally well tolerated and appears safe.
Citation
Dana Mora, Ellen Conte, CAM Cancer Collaboration. Milk thistle (Silybum marianum) [online document], Jan 25, 2024.
Document history
Updated and revised in October 2023 by Dana Mora. Fully updated and revised in January 2019 by Ellen Conte. Assessed as up to date in January 2015 by Barbara Wider.
Summary first published in May 2013, authored by Julia Green and Alexander Kalisch.
Next update due: January 2027
Description and background
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 (USDA 2012).
Milk thistle has many common names including lady’s thistle, St Mary’s thistle, holy thistle, and variegated artichoke (USDA 2012, NMC 2023,). 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 (NatMed 2023).
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 (USDA 2012). 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 (NMD 2023).
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 (NatMed 2023, Wichtl 2004, Braun 2010, Hoh 2006). In the 1960s the ingredients of milk thistle were investigated.
The mixture found was named silymarin (Kroll 2007, Mills 2000). Research concentrated primarily on the use of milk thistle in the treatment of liver disorders and protection from liver injury (NatMed 2023, Loguercio 2011). In the 1990s reports based on pre-clinical models suggested preventative, and therapeutic, potential in cancer warranted further research (Kroll 2007, Greenlee 2007, Post-White 2007).
Milk thistle use has been reported in between 2% (Bright-Gbebry 2011) and 7% (Damery 2011, Werneke 2004) of cancer patients.
Ingredients and quality issues
The main effects of milk thistle are thought to stem from the flavonolignans combined with other ingredients (NatMed 2023, Cheung 2010). A crude extract of dried seeds of milk thistle contains 65 – 80% of a flavonolignan complex termed silymarin (Kroll 2007). 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 thistle (Loguercio 2011, Brantley 2010). The seeds also contain fatty acids such as linoleic acid.
Alleged indications
The main claim made for milk thistle is that it protects the liver (NatMed 2023, Braun 2010).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 (ESCOP 2009). 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 (NatMed 2023, Braun 2010, Mills 2000).
It has also been used in prostate cancer, pleurisy, malaria, depression, uterine complaints, allergic rhinitis, stimulating breast milk and menstrual flow (NatMed 2023, Braun 2010, Saller 2007). Intravenously, milk thistle is used as a supportive treatment for Amanita phalloides (death cap) mushroom poisoning (NatMed 2023, Braun 2010).
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 (Greenlee 2007, Post-White 2007). These claims rest on presumed and acknowledged effects of milk thistle extracts in pre-clinical trials and case reports (Deep 2010, Olaku 2011, McBride 2012, Deep 2007).
Application and dosage
Milk thistle is taken orally as tablets, tea or tincture (NatMed 2023, Wichtl 2004) , 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 (NatMed 2023, Braun 2010) 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 (Shahbazi 2015, Hagag 2018, Elyasi 2016).
Silymarin is poorly water-soluble; bioavailability is increased by lipid formulations (Barzaghi 2014). In a phase II study 13g of a lipid formulation (Siliphos™) divided into 3 doses high plasma levels were achieved (Cheung 2010, ESCOP 2009). 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 tissue (Lazzeroni 2016).
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 period (Siegel 2014).
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 (Flaig 2010). It is not clear whether these metabolites also have anti-carcinogenic properties (Cheung 2010).
Mechanisms of action
The precise mechanism of action is unclear with silymarin considered a multi-functional, multi-target drug (Saller 2007). Several mechanisms are thought to contribute to therapeutic effect in liver disease 2; Silymarin reduces hepatocyte membrane permeability to toxins (NatMed 2023, Braun 2010), and has antifibrotic action as demonstrated in an in vitro model of human hepatic fibrogenesis (Loguercio 2011). Silymarin demonstrates antioxidant and anti-inflammatory effects in several animal models NatMed 2023, Loguercio 2011).
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 (Cheung 2012, Loguercio 2011) . 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 (Cheung 2012, Loguercio 2011, Deep 2007).
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 (Cheung 2012, Deep 2010, Deep 2007). In in-vitro studies a synergistic action with different chemotherapeutic agents has been seen (Cheung 2012, Colombo 2011, Scambia 1996).
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 (Ladas 2010).
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 (Deep 2007).
Legal issues
Milk thistle products are widely available over the counter. In the European Union, milk thistle is considered a traditional herbal medicinal product for the symptomatic relief of digestive disorders, sensation of fullness and indigestion, and to support the liver function exclusively based upon long-standing use (“traditional use”),(EMA 2018).
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 (NatMed 2023, Braun 2010, Mills 2000). In the UK, it is available as a registered traditional medicine under the Traditional Herbal Medicines Directive (MHRA 2022).
Supportive/palliative care
Clinical trials and reviews have evaluated the impact of milk thistle on the adverse effects related to chemo- or radiation therapy.
A comprehensive review of silymarin as a preventive or therapeutic measure for chemotherapy and radiotherapy-induced adverse reactions was published in 2023. The review summarizes preclinical and clinical data and included 16 randomized clinical trials (RCTs), one non-randomized controlled clinical trials (CCT), three case reports, and 42 in vivo/in vitro studies (Ghodousi 2023).
The RCTs and CCT are discussed below (Description of included studies) and in Table 1. Of the 17 RCTs and CCT included in the review, seven RCTs are evaluated effects on hepatotoxicity, two on nephrotoxicity, two on cardiotoxicity, three on mucositis, two on radiodermatitis and one on hand-foot syndrome. Most trials have small sample sizes and methodological shortcomings.
Description of included studies
Chemotherapy-induced hepatotoxiticy
Seven controlled clinical trials have evaluated milk thistle for its impact on hepatotoxicity from chemotherapy agents (Chang 2021, Ghazizadeh 2021, Hagag 2016, Ladas 2010, Moezian 2022, Mohaghegh 2015, Mshemish 2011).
Three studies have evaluated the impact of milk thistle on chemotherapy-related toxicity in children receiving treatment for acute lymphocytic leukaemia (ALL) ,(Ladas 2010, Hagag 2016, Ghazizadeh 2021). In a double-blind, placebo-controlled RCT 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 AST were significantly reduced (P=0.05), and ALT showed a trend towards reduction (P=0.07) (Ladas 2010).
A placebo-controlled RCT evaluated 80 children receiving methotrexate-based chemotherapy for ALL who were randomized to 420mg per day silymarin or placebo for 1 week following methotrexate administration (Hagag 2016). Several markers of hepatic and renal function were measured.
The silymarin group had significantly lower levels of AST, ALT, 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. A double-blind RCT studied the efficacy of milk thistle in ALL patients with chemotherapy-induced hepatotoxicity (Ghazizadeh 2021).
Ninety children with leukaemia participated in the study. Participants were evaluated for 70 days; the intervention group received 7 mg/kg milk thistle daily while the control received a placebo pill. The study found that milk thistle improves ALT and AST mean serum levels when compared to the placebo (p<0.001).
In an RCT of 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 hepatotoxicity associated with taxane-based chemotherapy for breast cancer (Mohaghegh 2015).
An RCT in 30 patients investigated the efficacy of oral administration of silymarin in managing the doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) (AC-T) regimen induced hepatotoxicity among non-metastatic breast cancer patients (Moezian 2022).
Chemotherapy-induced nephrotoxicity
The milk thistle extract silymarin has been evaluated for its ability to reduce nephrotoxicity of cisplatin chemotherapy with mixed results from two small RCTs.
The first RCT (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 alone (Momeni 2015).
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 treatment. (Shahbazi 2015) Differences may be due to different outcome measures used and length of pre-treatment (7 days versus 1-2 days).
Chemotherapy-induced cardiotoxicity
Two RCTs including one in children have evaluated the effects of silymarin for chemotherapy-induced cardiotoxicity.
A RCT among 80 children diagnosed with ALL under doxorubicin therapy treated 40 patients with silymarin 420 mg /day for week to assess its effect on early doxorubicin-induced cardiotoxicity (Hagag 2019, also included in the SR by Singh 2023). The trial found that silymarin significantly decreased early Doxorubicin-induced left ventricular systolic function disturbances.
In 83 patients diagnosed with cancer and receiving anthracycline chemotherapy the use of silymarin and L-carnitine was evaluated as a cardioprotective agents against the chemotherapy treatment (Zalat 2020). In this RCT, participants were divided in two treatment groups and a control group. Over a treatment period of 6 months, the first treatment group was given 3 gm capsules of L-carnitine (500mg) one day before the chemotherapy cycle and 1 gm during the following 21 days. The second treatment group received 140mg silymarin once daily during the chemotherapy cycle. The authors found that silymarin is a useful agent as it resulted in more beneficial effects on iron profile.
Chemotherapy-induced mucositis
Three RCTs evaluated the effect of silymarin on the severity and onset of mucositis. (Altaei 2012, Elyasi 2016, Hosseini 2021).
A RCT including 65 cancer patients was conducted to assess the efficacy of silymarin compared to indomethacin on chemotherapy-induced oral mucositis. (Altaei 2012) Two treatment groups were created.
One group received 140mg /cap of silymarin, another group received 25 mg/cap of Indomethacin, and the third group received a placebo daily for 14 days. The author concluded that silymarin decreases the incidence and severity of mucositis in the silymarin group compared to the other groups.
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 placebo. (Elyasi 2016).
Thirty-one patients diagnosed with head and neck cancer undergoing radiotherapy were included in a double-blind RCT. (Hosseini 2021) The trial evaluated the effect of 5mL nano-silymarin 3x/day for 6 weeks on the prevention of radiotherapy-induced mucositis. The study found no significant differences between the treatment and placebo groups in the prevention of radiotherapy induced mucositis.
Radiation dermatitis
Two CCTs evaluated topical silymarin and concluded that it may be helpful at reducing radiodermatitis associated with some cancer treatments. (Becker-Schiebe 2011, Karbasforooshan 2019) These two RCTs were also included in a SR measuring the efficacy of medicinal plant preparations in the alleviation of radiodermatitis in patients with breast cancer. (Baharara 2023)
An RCT among 40 breast cancer patients with planned course of post mastectomy assessed the preventive effect of silymarin 1% gel compared with placebo once a day for 5 weeks on radiodermatitis occurrence (Karbasforooshan 2019). The authors concluded that the application of silymarin may delay radiodermatitis occurrence and slow down its progression.
A non-randomized controlled trial with 101 participants investigated a combination cream including milk thistle as an adjunct to radiotherapy (Becker-Schiebe 2011). The Silymarin-based cream was applied topically during breast radiotherapy to 51 patients, and median time to toxicity was significantly longer in the treatment group compared to controls receiving standard care. (45 days versus 29 days, p<0.0001) This study was not randomized and as a combination product was used, the specific effect of silymarin cannot be established.
Chemotherapy-induced hand-foot syndrome
In a placebo-controlled RCT of 40 individuals, the authors found that twice daily application of 1% silymarin gel from day 1 to 9 weeks of capecitabine treatment significantly reduced the median WHO hand-foot-syndrome score (P < 0.05). (Elyasi 2017) This study was also included in a SR (n=12) investigating the best preventive regimen for hand-food syndrome induced by capecitabine regimes. It concluded that topical silymarin was the most useful regimen compared with pyridoxine, TJ-28, Mapisal, urea cream, celecoxib, Evoskin PSMC (Kao 2022).
Adverse events
Orally milk thistle is usually well-tolerated (NatMed 2023, Cheung 2010, Tamayo 2007). The rate of reported adverse events of oral milk thistle is low or equivalent to placebo group in most clinical trials (ESCOP 2009, Flaig 2010, Hoh 2006, Ladas 2010, Schröder 2005, Vidlar 2010, Becker-Schiebe 2011, van Erp 2005, Han, 2009, Momeni 2007, Mohaghegh 2015, Elyasi 2016, Lazzeroni 2016).
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 (Cheung 2010, Hoh 2006, Schröder 2005).
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 (Flaig 2007). One participant receiving high dose silybin phytosome who subsequently had surgery developed a thrombo-embolism: this could have been due to the surgery (Flaig 2010).
Contraindications
Milk thistle has been assessed as likely safe when used orally and appropriately (NatMed 2023). There is insufficient information to assess safety in pregnancy and lactation (NatMed 2023).
Interactions
In vitro evidence suggests that milk thistle may alter the activity of cytochrome P450 substrates (NMCD 2012, Brantley 2010) , however the majority of human studies have not confirmed this (Kawaguchi-Suzuki 2014, Gurley 2008, Gurley 2004). Two studies found that milk thistle extract may have inhibitory effects on CYP 2C9 (Han 2009, Flaig 2007). However, one study utilized a high-dose silybin phytosome supplement (up to 20g daily) (Flaig 2007) , the other found differing effects of milk thistle based on variation in CYP2C9 genotype (Han 2009).
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 enzymes (Kawaguchi-Suzuki 2014). 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 (van Erp 2005). These studies confirm findings from other human trials of milk thistle on drug pharmacokinetics showing no impact from milk thistle use (Gurley 2004, Gurley 2008).
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.
Warnings
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 (Cheung 2010). 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 (NatMed 2023, Braun 2010). Cautions have been recommended in patients with a known hypersensitivity to plants in the Asteraceae family (NatMed 2023, Braun 2010, Mills 2000).
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