MILK THISTLE

Also known as Silymarin and active ingredient silibinin, mostly known for its anti-inflammatory action in liver disease. Also a capable supplement for reducing insulin resistance, including in combination with berberine.

Clinical research as a supporting – adjuvant – therapy have sometimes shown benefits. A recent trial has reported protection of liver function during breast cancer oncology treatment. In colorectal cancer, a pilot study also showed silymarin reducing side effects during treatment. The reduced progression risks reported as not statistically significant, and need confirmation in more advanced trials. Also in topical form, for helping during protect skin radiotherapy. (see References)

While many studies have shown no measurable impacts on outcomes, a 2005 dutch study in prostate cancer of a supplement consisting of silymarin with soy isoflavones, selenium and other ingredients extended PSA doubling times over 2X ( see references). Like other natural compounds, this indicates the potential of combinations and would need further evidence.

Overall metabolic health benefits a shown in some clinical testing and mostly shown in liver function but also in glucose and cholesterol control. Whilst mixed, the studies available tend to show both significant anti-inflammatory actions and positive suppression of insulin levels both of which indicate protective potential for slowing cancer progression. There are several patented commercial products, some combined with berberine, or monokolin K from Red Yeast Rice. There is plenty of preclinical evidence of anti-metastatic effects but these need further evidence in direct or related human trials.

TYPICAL ABSORPTION LEVELS

15 – 30%

EXAMPLES OF IMPROVED OUTCOMES

SOME

PRE-DIAGNOSIS OR PREVENTION

PENDING

Highlighted Studies

The study group had longer survival periods than the control group in either PFS (12.6 months vs. 11.7 months) or OS (36.4 months vs. 23.0 months)…silymarin supplementation can reduce the occurrence of diarrhea and nausea in mCRC patients undergoing first-line FOLFIRI plus bevacizumab. Silymarin (150 mg) three times daily from the beginning of chemotherapy for 7 days is an effective and well-tolerated supplementation that does not interfere with antitumor efficacy for mCRC patients.

...

Prophylactic administration of silymarin topical formulation could significantly reduce the severity of radiodermatitis and delay its occurrence, in patients with breast cancer after 5 weeks of application… The scores increased significantly in both placebo and silymarin groups during radiotherapy, but there were a delay for radiodermatitis development and progression in silymarin group.

Results of this study showed that the dietary supplement significantly improved the slope of transformed PSA concentrations in comparison with placebo. (p = 0.041) The differences in transformed total PSA slopes between the supplement and placebo translate into a 2.6 fold increase in PSA doubling time with the use of the supplement.

Antioxidant and anti-inflammatory properties of silymarin, a polyphenolic flavonoid extract derived from Silybum marianum, may be useful in preventing chemotherapy-induced hepatotoxicity…Oral formulation of silymarin 420 mg/day for 63 days significantly prevented hepatotoxicity caused by doxorubicin in patients with non-metastatic breast cancer mostly based on liver ultrasonography but not laboratory parameters.

TABLE OF REFERENCES

Help grow the evidence. Login and use the form, or try Feedback and Ideas below.

URL	Rating	Category	Highlight	Highlight 2	Dose mg/kg
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420909/	4	Human study - adjunct	In our study, the mCRC patients who received silymarin as supplementation experienced a significant reduction in the occurrence of diarrhea; moreover, the occurrence of nausea was also markedly decreased. The study group had longer survival periods than the control group in either PFS (12.6 months vs. 11.7 months) or OS (36.4 months vs. 23.0 months). Besides, the patients of the study group have more KRAS mutations (75%) and worse ECOG performance status (>0: 90.6%) than the control group	In summary, silymarin supplementation can reduce the occurrence of diarrhea and nausea in mCRC patients undergoing first-line FOLFIRI plus bevacizumab. Silymarin (150 mg) three times daily from the beginning of chemotherapy for 7 days is an effective and well-tolerated supplementation that does not interfere with antitumor efficacy for mCRC patients.
https://journals.sagepub.com/doi/10.1177/10781552241268778	3.5	Human study - adjunct	Oral formulation of silymarin 420 mg/day for 63 days significantly prevented hepatotoxicity caused by doxorubicin in patients with non-metastatic breast cancer mostly based on liver ultrasonography but not laboratory parameters. Further investigations are suggested on different doses, durations and formulations of silymarin, particularly nano-formulations for increasing its oral bioavailability.	Antioxidant and anti-inflammatory properties of silymarin, a polyphenolic flavonoid extract derived from Silybum marianum, may be useful in preventing chemotherapy-induced hepatotoxicity. This study evaluated the effect of oral silymarin for preventing doxorubicin induced hepatotoxicity in non-metastatic breast cancer patients.
https://www.annalsofoncology.org/article/S0923-7534(19)42983-9/fulltext	3.5	Human study - adjunct	Prophylactic administration of silymarin topical formulation could significantly reduce the severity of radiodermatitis and delay its occurrence, in patients with breast cancer after 5 weeks of application.	Significant difference was observed between the treatment and placebo groups, regarding the NIH CTCAE and RTOG scores at the end of the 4th and 5th weeks (Pvalue<0.05) but not at the end of the first three weeks. The median NIH CTCAE and RTOG scores were significantly lower in silymarin group
https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-024-04627-7	3.5	Human study - adjunct	The study suggests that silymarin may have hepato-renal protective potential in breast cancer patients and improve patient tolerance to chemotherapy. The data presented on the efficacy and safety of silymarin may provide stronger foundation for further trials and for a possible use in clinical practice.	Also, there was no significant difference between the three groups both in general (PGroup>0.05) and each time point (P > 0.05 for all three time periods). However, the trend of changes in three groups for BUN and Cr were similar (PTime*Group=0.414). These findings indicate that the renal protective effect of silymarin on breast cancer patients was not considerable and did not result in any significant changes
https://patientenvoeding.nl/wp-content/uploads/2015/11/Schroder-Roobol-supplement-study-PSA-levels-2005-J-Eur-Urology.pdf	3.5	Human study	This translates into a 2.6 fold increase in the PSA doubling time from 445 to 1150 days for the supplement and placebo periods. No treatment-based changes in safety parameters were observed during the study. Conclusions: The soy-based dietary supplement utilised in this study was shown to delay PSA progression after potentially curative treatment in a significant fashion	Isoflavones from soy including the well-studied daidzein and genistein are major components of what has been termed ‘‘eastern diet’’ with supposed preventive properties for at least prostate and breast cancer [27]. More recent reviews and original experimental reports are confirmatory [28–32]. Evidence relating to tomato products and to lycopene, the red colour of the tomato, has recently been reviewed in [33]. Lycopene as well as selenium and Vitamin E have antioxidant function. Recent evidence has been summarised also for selenium
https://www.annalsofoncology.org/article/S0923-7534(20)40390-4/fulltext	3.5	Human study - adjunct	The co-administration of L-carnitine or silymarin with anthracycline-containing chemotherapy represents a new therapeutic strategy, especially silymarin, for better control of anthracycline-induced cardiotoxicity, as silymarin resulted in more beneficial effects on iron profile compared to anthracycline alone and anthracycline with L-carnitine.	adding silymarin to anthracycline chemotherapy had a significantly beneficial effect on anticardiolipin IgG (P=0.000), iron (p=0.001),ferritin (p= 0.000), TIBC (p=0.007), and % saturation (p=0.001) silymarin group showed a significant decrease in iron profile compared to the L-carnitine group, supporting the hypothesis of silymarin iron chelating activit
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542639/	3	Human study - adjunct	In children with ALL with liver toxicity, MT was associated with a trend towards significant reductions in liver toxicity. MT does not antagonize the effects of chemotherapy agents used for the treatment of ALL. Future study is needed to determine the most effective dose and duration of MT and its effect on hepatotoxicity and leukemia-free survival.	Although not significantly different, chemotherapy doses were reduced in 61% of the MT group, compared to 72% of the placebo group. In vitro experiments revealed no antagonistic interactions between MT and vincristine or L-asparaginase in CCRF-CEM cells. A modest synergistic effect with vincristine was observed.
https://www.sciencedirect.com/org/science/article/pii/S0428029624001069	3	Lab study	Based on the information provided, we draw the conclusion that the combination of TQ [from black peppers] and silymarin demonstrated a synergistic anticancer effect against both the parent (EMT-6/P) and resistant (EMT-6/CPR) cell lines in vitro and in vivo through apoptosis induction and caspas-3 activation better than each treatment alone. But when TQ and silymarin were combined in novel ways, the tumor size reduction was superior to that of a single therapy	Firstly, our TQ and silymarin combination which reduced tumor size in the studied cell lines in vivo significantly with the highest percentage of reduction. The shrinking in tumor sizes were 92.6% and 56.4% in EMT-6/P and EMT-6/CPR, respectively. This was attained after i.p. daily injection of 25 mg/kg TQ and 50 mg/kg of silymarin for 10 days Tables 2, 3. However, this combination has never been tested before
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437094/	3	Human study - adjunct	Conclusion This study showed that Silymarin can decrease Cisplatin nephrotoxicity, so because of safety profile and minor adverse effect of Silymarin, we can use it as prophylaxis against Cisplatin nephrotoxicity in various Cisplatin-contained chemotherapy regimens.	There was no significant difference based on BUN and serum Cr in the beginning of study and three days after administration of Cisplatin in two groups of patients; however, after two weeks, BUN and serum Cr were significantly lower in the case group compared to the control group. Also, in the case group, BUN and serum Cr decreased and in the control group, they increased after two weeks after Cisplatin administration.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10888588/	3	Human study	Treatment with silymarin alone significantly reduced mean fasting plasma glucose (FPG) and HOMA-IR levels at 12 weeks compared to baseline values . Mean fasting plasma insulin (FPI), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (Tg), indirect bilirubin, and C-reactive protein (CRP) levels decreased compared to baseline values, although changes were non-significant. The overall results suggest that silymarin may offer a therapeutic alternative to improve IR in non-diabetic individuals with obesity.	Treatment with silymarin may be an alternative to help reduce IR caused by low-grade inflammation found in obesity. A decrease in IR may help to prevent or delay the onset of T2DM, which is often reached within ten to fifteen years after IR appears . The results showed that treatment with silymarin significantly decreased IR in a population of non-diabetic women with obesity and IR, which may have contributed to delaying the onset of T2DM.
https://www.sciencedirect.com/science/article/abs/pii/S0944711315000227?via%3Dihub	2	Human study	All 40 patients completed the study and did not report any adverse effects or symptoms with the silymarin supplementation. Silymarin supplementation significantly increased superoxide dismutase (SOD), glutathione peroxidase (GPX) activity and total antioxidant capacity (TAC) compared to patients taking the placebo, by 12.85%, 30.32% and 8.43%, respectively (p < 0.05). There was a significant reduction in hs-CRP levels by 26.83% (p < 0.05) in the silymarin group compared to the placebo group.	Silymarin supplementation improves some antioxidant indices (SOD, GPX and TAC) and decrease hs-CRP levels in T2DM patients.... All 40 patients completed the study and did not report any adverse effects or symptoms with the silymarin supplementation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173635/	1.5	Meta-analysis	According to the findings, it was found that the co-administration of silymarin/silibinin alleviates the doxorubicin-induced cardiac adverse effects. Silymarin/silibinin exerts its cardioprotective effects via antioxidant, anti-inflammatory, anti-apoptotic activities, and other mechanisms	Moreover, the anti-inflammatory effects of silymarin can mainly be because of inhibiting the NF-κB nuclear translocation/activation, resulting in preventing the aggregation of inflammatory cells as well as decreasing the expression of inflammatory cytokines and other certain inflammatory mediators ...the histological findings represented in this systematic review exhibited that the doxorubicin-induced cardiac inflammation is mitigated by the silymarin/silibinin co-administration
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637733/	1	Lab study	Our quantitative imaging and metabolomics endpoints in tumor xenograft study clearly showed that silibinin treatment leads to a significant inhibition of angiogenesis (DCE-MRI) and lipogenesis. This vascular and metabolic reprograming occurs in the absence of direct cytotoxic effects since FDG uptakes (PET) and cell density (ADCs in DWI) were not affected by in vivo silibinin treatment. These findings provide a direct evidence for the specific targeted action of silibinin without exhibiting the conventional cytotoxic profile attributed to classical chemotherapeutics. Overall, results from the present study suggest that silibinin strongly inhibits HIF-1α expression in PCa cells and tumors as well as strongly inhibits hypoxia-induced biological effects. These results are clinically significant as human consumption of silibinin is safe and hepatoprotective against various toxic conditions. Therefore, silibinin could be useful either alone or in combination with other treatments such as radiotherapy where hypoxia is the major reason for treatment failure.	In vivo, silibinin feeding (200 mg/kg body weight) to male nude mice with 22Rv1 tumors, specifically inhibited tumor vascularity (measured by dynamic contrast-enhanced MRI) resulting in tumor growth inhibition without directly inducing necrosis (as revealed by diffusion-weighted MRI). Silibinin feeding did not significantly affect tumor glucose uptake measured by FDG-PET; however, reduced the lipid synthesis measured by quantitative 1H-NMR metabolomics. IHC analyses of tumor tissues confirmed that silibinin feeding decreased proliferation and angiogenesis as well as reduced HIF-1α, FASN and ACC levels. Together, these findings further support silibinin usefulness against PCa through inhibiting hypoxia-induced signaling.	200
https://pmc.ncbi.nlm.nih.gov/articles/PMC9584967/	3	Human study	This randomized, double-blind placebo-controlled clinical trial was performed on 70 women with endometriosis which was divided into two groups of intervention and control. The intervention was 140 mg silymarin (or matching placebo) administered twice daily for 12 weeks. The volume of endometrioma lesions, the level of IL-6 concentration in serum, pain, sexual function, and QoL were analyzed before and after the intervention. The means of endometrioma volume (P = 0.04), IL-6 (P = 0.002), and pain (P 0.05). Silymarin significantly reduced interleukin-6 levels, sizes of endometrioma lesions, and pain-related symptoms	The results also showed that oral administration of silymarin 280 mg/day decreased the IL-6 concentration levels significantly during the study period within the intervention group. Arafa Keshk et al. evaluating the potential protective effects of silymarin against indomethacin-induced gastric injury in rats, have demonstrated that suppression in gastric inflammation by decreasing myeloperoxidase activity, TNF- α, and IL-6 expression levels along with NF-κB expression. Meanwhile, silymarin prevent gastric OS via inhibition of lipid peroxides formation, enhancement of glutathione peroxidase, superoxide dismutase activities and up-regulation of Nuclear Factor-Erythroid-2-Related Factor 2 (Nrf2), the redox-sensitive master regulator of OS signaling
https://link.springer.com/article/10.1007/s10787-023-01423-6	2.5		Fifteen RCTs were included in this meta-analysis. Our findings showed that Silymarin consumption significantly decreased CRP (WMD, − 0.50 mg/L; 95% CI, (− 0.95 to − 0.04); p = 0.03), MDA (WMD, − 1.19 nmol/mL; 95% CI, (− 1.99 to − 0.38); p = 0.004), and IL-6 (WMD, − 0.44 pg/ml; 95% CI, (− 0.75 to − 0.12); p = 0.006). Silymarin consumption had no significant effects on IL-10, TAC, and GSH. A significant non-linear relationship was observed between the duration of the intervention and MDA changes.	Silymarin can help reduce inflammation in patients with diabetes and thalassemia by reducing MDA as an oxidative stress marker and CRP and IL-6 as inflammatory markers....Silymarin consumption had no significant effects on IL-10, TAC, and GSH. A significant non-linear relationship was observed between the duration of the intervention and MDA changes.
https://www.frontiersin.org/articles/10.3389/fphar.2018.00021/full	1	Lab study	silibinin, as an anti-fibrosis drug, exhibits the anti-metastasis effects in several cancers, but the mechanism is poorly understood. In this study, we confirmed the association between LOX expression and lung adenocarcinoma poor prognosis. Meanwhile, our data also showed that LOX was regulated by the EGFR pathway in NSCLC. In addition, we confirmed that the EGFR/LOX pathway might contribute to the anti-metastasis effects of silibinin (Figure 9). In this regard, our results elucidated a new pathway of the EGFR signaling and suggested the potential therapeutic target of LOX for the treatment in tumor metastasis. Importantly, our data revealed a novel mechanism that might provide a specific basis for the development of silibinin.	Our study proposed a new mechanism for silibinin in cancer therapy, provided a scientific basis for the development of silibinin in further clinical research. For further evaluation, we are preparing to confirm the therapeutic effect of silibinin on NSCLC via patient-derived xenograft (PDX) models. Since multiple steps are involved in the formation of tumor fibrosis (Semenza, 2016), PLOD2 and P4HA also mediate essential sections of metastasis (Gilkes et al., 2013; Du et al., 2017b). Their involvement in the anti-metastasis effect of silibinin also deserves further study. In summary, our research confirmed that LOX expression is regulated by EGFR via the PI3K/AKT, MEK/ERK and SAPK/JNK pathways, which revealing a new pathway of the EGFR signaling in NSCLC. In addition, the study also showed that the EGFR/LOX pathway may play a role in the anti-metastasis effects of silibinin in NSCLC. Importantly, LOX as an important effector in tumor metastasis, may be a potential target for cancer therapy in the future.	70
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507490/	1	Lab study	Overall, in this study we show that the antitumoral properties of SBN can be extended to the head and neck carcinoma through inhibition of HIF-1α and tumor glucose metabolism. In addition, we find that these effects are associated with reductions in tumor extracellular acidification and expression of the immune checkpoint inhibitor PD-L1, indicating the SBN may be of benefit to treat reccurent tumors relying on the se mechanisms. Considering the recent success met in targeting the PD-1/PD-L1 pathway in NPC, SBN utilization may constitute an accessible therapeutic agent for countries with low income to treat EBV associated head and neck carcinoma.	With regards to the fact that HIF1-α has been incriminated in regulating PD-L1 expression – a major mediator a tumor escape from immune system destruction 49 – we hypothesized that SBN targeting of HIF1-α would also lead to a down-regulation of PD-L1 in NPC tumors. To our surprise, not only expression of the immune checkpoint inhibitor was negatively affected by SBN, but we also found that, that event would most likely concur with an inhibition of HIF1-α and lactate synthesis. Our demonstration on the effect of SBN on PD-L1, is in line with the findings reported by Cuyàs et al. in lung carcinoma 34. Despite the fact that further analyzes are necessary to understand the significance of this event, we speculate that LDH-A/lactate signaling inhibition would impair PD-L1 signaling and restore a functional anti-tumoral immune response, including those related to T and NK cell function
https://www.nature.com/articles/s41419-020-02866-3	1	Lab study	To verify the treatment effect of silibinin on glioma cells in vivo, C6 cells were xenografted subcutaneously into the flank of nude mice. After being treated with silibinin at the dosage of 100 mg/kg each day for consecutive 12 days, the volumes of the xenografted tumors were found to decrease markedly when compared with those in control group (Fig. 7a). This was also confirmed by statistical analysis of tumor volumes (Fig. 7b). Then, the tumors removed from the sacrificed mice were homogenized and silibinin-induced changes in autophagy marker proteins......silibinin triggered obviously upregulation of ATG5 and LC3-II, but reduction of p62.... This indicated that silibinin induced autophagy activation in glioma cells in vivo.	Overactivation of autophagy has been established to be an effective way to eradicate cancer cells7,8,22, and silibinin is confirmed to be a potent lethal autophagy inducer for various types of cancer cells such as human breast cancer cells, fibrosarcoma cells, and renal carcinoma cells7,8,23. Different from previous report showing that silibinin triggered protective autophagy in glioma cells24, we found in this study that blocking autophagy with 3MA, bafilomycin A1 or by knocking down ATG5 with SiRNA significantly rescued silibinin-induced glioma cell death. This verified that autophagy contributed to silibinin-induced death in glioma cells. Moreover, different types of programmed cell death could be induced by the same chemical or under the same pathological condition
https://www.elsevier.es/es-revista-annals-hepatology-16-articulo-silymarin-is-an-ally-against-S1665268120301708	1	Meta-analysis	Later, a recent study with 90 NAFLD patients and 30 healthy controls (diagnosed with reflux disease), tested a new formulation similar to RealSIL®, with vitamin D, RealSIL 100D® (303mg of silymarin, vitamin E (used to stabilize the formula) and vitamin D in a silybin–phospholipid complex) twice daily for six months with follow-up at 12 months. The results showed significant improvement (normalization of the specific variable under the upper limit of the normality range level) in IR, by reducing insulin and HOMA-IR, as well as steatosis in treated patients [89]. Later, the same formulation (RealSIL 100D®) and dosage as in the previous study, were tested in a separate clinical trial in 32 male NAFLD patients exposed to BPA. Treatment improved IR by decreasing insulinemia and HOMA-IR levels, as well as several other metabolic parameters, including ALT and AST, C-reactive protein, and TNFα	A previously used formulation of silymarin with berberine was tested, however, combined with fermented rice extract, in another study. Silymarin (210mg daily, Berberol® K), or placebo was given to 143 overweight normotensive patients with hypercholesterolemia in addition to an adequate diet plus physical activity in a three month randomized, double-blind trial. Results demonstrated a significant decrease in TC, LDL, Tg, high sensitive C-reactive protein, TNFα, and IL-6 levels in treated patients with no significant decrease in FBG or HOMA-IR [84]. Another trial that used silymarin in combination with berberine only, was carried out in 136 obese individuals with T2D, IR, and other altered glucose and lipid parameters. Patients were given 210mg silymarin or placebo and followed a low-calorie diet for 52 weeks. Treatment reduced IR, HOMA-IR, HbA1c, TC, LDL, Tg and uric acid levels
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535778/	1	Meta-analysis	In the present study, we enrolled 16 articles to reassess the therapeutic effects of silymarin for patients with glucose/lipid metabolic dysfunction. Overall, the pooled results showed that compared with control treatment, silymarin supplementation significantly reduced levels of FBG, HOMA-IR, HbA1c, TC, TG, LDL-C, CRP, and increased HDL-C. Subgroup analyses indicated the FBI could also be significantly decreased in patients who underwent silymarin monotherapy for longer than 3 months. Silymarin did not influence ALT, AST, creatinine phosphokinase, creatinine, and the complication rate.	Silymarin was proved to have anti-inflammatory functions in several diseases. For example, Hussain et al[41] concluded that silymarin treatment for 8 weeks significantly reduced serum levels of IL-1 alpha and IL-8, C3, and C4 for patients with knee osteoarthritis compared to the pretreatment levels. Silymarin also exerted hepatoprotective actions through combating inflammatory conditions.[42,43] The inhibition targets of silymarin also included p65 NF-κB, and its downstream IL-1β and TNF-α.[44] Theoretically, CRP could also be reduced after the addition of silymarin for DM and dyslipidemia subjects, which was confirmed in our study.
https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-024-04627-7	2.5		The results of this clinical trial study showed that supplementation with 140 mg of silymarin two times daily could significantly lower the serum levels of Bili and ALP in breast cancer patients with increased levels of liver enzymes. The results of this study may provide a valuable opinion on whether silymarin can be used as adjuvant therapy for the management or treatment of liver disease of cancer patients. The data presented on the efficacy and safety of silymarin may provide more foundation for further trials and for a possible use in clinical practice.	Furthermore, Mean bilirubin period indicated significant change over study in group G3 (PTime =0.042). However, there was not significant difference in group G1 (PTime =0.57), and group G2 (PTime=0.55). Also, there was no significant difference between three groups both generally (PGroup = 0.314). However, the trend of bilirubin changes among three groups after a period of 6 weeks was significant (PTime*Group = 0.046). These findings demonstrate that silymarin’s hepatoprotective effects on breast cancer patients are notable in certain parameters, such as ALP and Bilirubin, potentially leading to improved liver function.