Milk thistle (Silybum marianum L. Gaertn.), also known as wild artichoke, is a medicinal plant that has been used for thousands of years to treat various conditions, particularly liver diseases. The use of this medicinal plant has been classified as "traditional use" by the European Medicines Agency (EMA). Milk thistle is an annual or biennial plant belonging to the Asteraceae family. References to the use of milk thistle can be found as early as the Old Testament (Genesis 3:18). In ancient times, Silybum marianum was used to treat liver dysfunction. It was also used in traditional Indian and Chinese medicine to treat liver and gallbladder disorders [1]. Its hepatoprotective effect has been investigated in numerous scientific studies [2–5]. Various standardised milk thistle preparations in different dosages are available on the German market, e.g. Legalon® forte, Silymarin STADA®, Silymarin AL and Silymarin forte-CT.
Silymarin, an extract derived from milk thistle, is a complex mixture of plant compounds consisting primarily of flavonolignans, flavonoids (such as taxifolin and quercetin), and polyphenolic substances [6]. These constituents are particularly renowned for their antioxidant properties [7]. The four primary isomers of the flavonolignans present in silymarin are silibinin, isosilibinin, silichristin, and silidianin. Of these components, silibinin – also known as silybin – is the most quantitatively and biologically significant. Silibinin accounts for approximately 50–60% of the total silymarin complex, while the remaining isomers together contribute about 35%: silichristin about 20%, silidianin approximately 10%, and isosilibinin around 5% [8,9]. Silibinin undergoes Phase I and Phase II biotransformation in the liver. In Phase II, a number of conjugation reactions have been observed, including the formation of glucuronide and glucuronide sulfate derivatives [6, 10]. The crude silymarin extract is characterised by its lipophilic nature and low water solubility, factors that result in its absorption from the gastrointestinal tract after oral administration being limited to approximately 20–50% [11]. In order to enhance the oral bioavailability and solubility of silymarin, a range of galenic strategies have been developed (for example, Eurosil 85®) [12, 13].
Silymarin has been studied experimentally for its ability to induce or inhibit cytochrome P450 (CYP450). At supratherapeutic concentrations (1 µmol/l), silymarin exhibited negligible inhibition of the CYP450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9 and 2E1, a slight inhibition (< 20%) of CYP3A4, and a moderate inhibition (< 40%) of CYP2C19 and 2D6. Due to the significantly lower therapeutic plasma concentration (~0.2 µmol/l), the risk of clinically relevant hepatic interactions at standard doses is considered low [14]. Studies in healthy volunteers and clinical data also show no relevant effect of silymarin on the enzymes CYP1A2, 2C9, 2D6, 2E1, 3A4 and 3A5. In two multiple-dose studies (160–450 mg every 8 hours), the plasma concentration of the CYP3A4 substrate indinavir also remained unchanged [15]. Nevertheless, potential interactions should not be ruled out when taken concomitantly with CYP450 substrates and should be monitored clinically. It has been demonstrated that silymarin is capable of inducing interactions with other pharmaceutical agents in experimental animal models. These include effects on oestrogen therapy, reduced clearance of glucuronidated drugs and increased absorption of P-glycoprotein substrates. There is a potential for interactions with statins, as silymarin and silibinin have been shown to inhibit the organic anion-transporting polypeptide 1B1 and the breast cancer resistance protein in vitro. However, a study conducted on healthy male subjects demonstrated that the pharmacokinetics of rosuvastatin remained unaltered. In kidney transplant patients with hepatic impairment, a reduction in sirolimus clearance due to silymarin was observed [15].
Several pharmacological effects of silibinin have been identified, including antioxidant properties, anti-inflammatory properties, anti-fibrotic effects and the modulation of insulin resistance.
Antioxidant effect
In vitro, silibinin demonstrated a marked ability to scavenge reactive oxygen species (ROS) in various cell models (including rat liver microsomes, human platelets, leukocytes, endothelial cells, erythrocytes and fibroblasts) [16, 17]. It also inhibited superoxide and nitric oxide radicals in isolated Kupffer cells (IC₅₀: 80 µmol/l) [18]. Furthermore, silymarin promotes glutathione synthesis in the liver by increasing the availability of precursors such as cysteine, thereby contributing to the liver’s antioxidant activity [19]. Silymarin is also believed to inhibit the expression of tumour necrosis factor-alpha (TNF-α), interferon-gamma, interleukin (IL)-2 and IL-4 as a result of blocking the activation of the hepatic nuclear factor kappa B (NFκB), which is induced by toxic mushrooms such as α-amanitin toxin [20–22]. These hepatoprotective properties are mainly attributed to the antioxidant activities of silibinin.
Anti-inflammatory and immunomodulatory effects
Chronic inflammation is associated with liver diseases such as fibrosis and cirrhosis. Silymarin exhibits anti-inflammatory properties by inhibiting NF-κB and LTB4 formation in Kupffer cells [23]. In 1999, Manna et al. published in vitro data on silymarin, which blocks tumour necrosis factor (TNF-α)-induced activation of NF-κB in a dose- and time-dependent manner [24]. These findings were corroborated in subsequent years by further experimental studies [25]. Immunomodulatory effects were also demonstrated in human CD4⁺ T cells isolated from peripheral blood mononuclear cells (PBMCs) of healthy volunteers [26]. Furthermore, a reduction in the phosphorylation of P65/NF-κB was observed, indicating an inhibition of NF-κB-mediated T-cell activation. Furthermore, the research group demonstrated that treatment with silymarin (100 µM) induces a pronounced G1 cell cycle arrest in activated T lymphocytes, accompanied by reduced phosphorylation of the ribosomal protein S6 and inhibition of mTOR activity. However, the immunomodulatory effects were dose-dependent. Further studies were called for to confirm these effects and to assess their clinical relevance.
Antifibrotic effect
Silibinin and silymarin exhibit antifibrotic effects in animal and in vitro models. In hepatic fibrogenesis, silibinin inhibits the production of procollagen in activated hepatic stellate cells in an in vitro model [27]. A study on alcohol-induced liver fibrosis in primates shows that the administration of silymarin reduces the increase in type I collagen in the liver [28]. Chronic alcohol treatment led to an increase in type I collagen in liver biopsy samples, which was mitigated by the administration of silymarin [29,30].
Further effects have mainly been demonstrated experimentally, including anti-atherogenic [31], anti-osteoporotic [32] and antiviral effects [33].
A PubMed search using the terms ‘milk thistle and rheumatoid arthritis’ yields four results. An Iranian non-randomised clinical trial published in 2017 involving 57 RA patients who received a silymarin preparation (140 mg three times daily for three months) as an adjunct to DMARD therapy showed a significant improvement (p<0.001) in the DAS28 score [34]. However, the poor quality of the study must be taken into account. There was no control group, patients with high disease activity were excluded, and the baseline medication could not be altered in cases of persistent disease activity. The same Iranian research group investigated the effect of silymarin (140 mg three times daily for three months) on the levels of TNF-α and IL-1β in RA patients. The authors concluded that the addition of silymarin to the treatment of patients with RA had no significant effect on serum levels of TNF-α and IL-1β [35]. Clinical parameters and patient-reported outcomes were not recorded.
A recent systematic review (2024) concluded that, in experimental studies, Silybum marianum, silymarin and silibinin showed promising effects on RA and OA symptoms. However, further clinical trials in this area are required to obtain and justify reliable results and to justify the clinical use of these substances [36]. The authors attributed the observed effect on OA to two Iraqi clinical studies. The first study utilised the Knee Injury and Osteoarthritis Outcome Score (KOOS) to assess the effect, while the second study employed serum levels of IL-1 alpha and IL-8, C3 and C4.
An animal study investigated the effect of silibinin (SIL) on MTX-induced hepatotoxicity in rats with adjuvant-induced arthritis. Rats were treated with SIL (100 mg/kg) and/or methotrexate (2 mg/kg). Silibinin demonstrated antioxidant and hepatoprotective effects by alleviating the systemic effects of arthritis, reducing joint damage and preventing histopathological changes in the liver. Furthermore, silibinin reduced oxidative stress in liver tissue by decreasing lipid peroxidation and enhancing the antioxidant defence system [37]. A clinical trial investigated the use of silymarin in children with acute lymphoblastic leukaemia (ALL) receiving MTX-based chemotherapy. Silymarin improved some liver and kidney functions in children, but the authors call for further studies to confirm the protective effect [38].
Although silymarin has anti-inflammatory properties, there is currently insufficient scientific evidence to suggest that milk thistle preparations constitute an effective treatment for rheumatic diseases. Two poor-quality clinical trials produced contradictory results and failed to provide convincing data on clinical efficacy [34, 35].
Interesting data from animal studies suggest that silibinin and silymarin have hepatoprotective effects in arthritic rats by improving the balance between pro-oxidants and antioxidants in liver tissue [39]. Antifibrotic effects have previously been demonstrated in animal studies and in vitro [27-30]. A clinical study in children with ALL receiving MTX-based chemotherapy suggested that silymarin had hepatoprotective and nephroprotective effects [38]. These results are based on a limited number of cases and are insufficient to make a therapeutic recommendation for use in patients with inflammatory rheumatic diseases.
High doses (20 g/day) of silymarin may lead to increased levels of bilirubin and ALT. The authors of the pharmacokinetic study concluded that doses up to 13 g/day are safe [40]. In experimental studies, silymarin showed only a slight to no inhibitory effect on CYP450 enzymes at therapeutic doses, meaning that the risk of clinically relevant drug interactions is considered low [15]. Studies in healthy subjects confirm no relevant influence on key CYP isoenzymes [14, 40]. Nevertheless, potential interactions should be considered and monitored when taken concomitantly with CYP450 substrates.
The evidence base in rheumatology regarding the disease-modifying effects of milk thistle preparations is considered insufficient. Consequently, no recommendation can be made regarding their use as an anti-inflammatory medication for inflammatory rheumatic diseases. Whether milk thistle preparations are suitable for mitigating or preventing the hepatotoxic effects of basic therapeutic agents such as MTX cannot be substantiated on the basis of the available data.
Last updated: March 11, 2026