Zeus [Discontinued] by Immortal Labs

POSSIBLY EFFECTIVE

• Diabetes. Oral milk thistle extracts of silymarin seem to improve glycemic control in diabetic patients. Details: A meta-analysis of 7 small heterogeneous clinical trials in patients with type 2 diabetes shows that taking milk thistle containing silymarin 210-600 mg alone or with other ingredients daily for up to 6 months reduces fasting blood glucose and glycated hemoglobin when compared with control. Sub-group analyses suggest that studies conducted for less than 3 months seem to have a greater glycemic benefit than those lasting 3 months or longer. Furthermore, there was a greater glycemic benefit when milk thistle was used in combination with other natural ingredients (105054). Most studies in the analysis used silymarin in divided doses of 420-600 mg daily, while only one study used 200 mg daily (15102,63190,97626,105054). Most of these studies were conducted in the Middle East, so it is unclear whether these results are generalizable to other geographic locations. Most studies of combination products have been conducted in Italy and involve a specific product (Berberol, PharmExtracta) containing milk thistle standardized to silymarin 105-210 mg with tree turmeric standardized to berberine 500-1000 mg (96141,105054). In addition to improving glycemic indices in patients with type 2 diabetes (105054), this product has shown glycemic benefit in patients with concomitant obesity and metabolic syndrome (97624) and in patients with type 1 diabetes (96142).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral or topical milk thistle is beneficial in patients with acne when used alone or in combination with other treatments. Details: A small clinical trial in patients with acne vulgaris shows that taking a milk thistle extract standardized to silymarin 140 mg daily for 2 months does not improve acne severity based on the Global Acne Grading system scale when compared with doxycycline 100 mg daily, and silymarin is less effective than doxycycline when evaluated using the Acne Severity Index (ASI) scale. In addition, using silymarin in combination with doxycycline does not appear to be more effective than doxycycline alone (101160). There is also interest in using milk thistle topically for acne. A clinical study in adults with acne vulgaris shows that applying a specific topical product (Silymarin CF, Skinceuticals) containing silymarin 0.5%, vitamin C 15%, salicylic acid 0.5% and ferulic acid 0.5%, twice daily for 3 months moderately improves acne scores when compared to baseline (110488). Additionally, a small quasi-experimental study in adults with mild to moderate acne suggests that applying silymarin 1.4% cream twice daily for 3 months improves global acne scores and appearance of acne when compared to baseline, but not when compared with biweekly salicylic acid chemical peels (113143). However, the interpretation of these results is limited by the use of subjective outcomes. Similarly, observational research in patients aged 12-25 years with mild-to-moderate acne has found that applying a specific cream (Cleanance Comedomed, Pierre Fabre Dermo-Cosmetique) containing milk thistle fruit extract 25% twice daily for 8-12 weeks as initial or add-on therapy moderately improves acne scores when compared to baseline (111175). The interpretation of these results is limited by the lack of a comparator group. Further, most patients were also prescribed other skincare products or treatments.
• Alcohol-related liver disease. It is unclear if oral milk thistle is beneficial in patients with alcohol-related liver disease, as evidence is conflicting. Details: Some preliminary research shows that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 420 mg orally daily for one month to 4 years improves some liver function tests (2613,2618,17228,63260,63339). Some studies also report improvements in liver histology and survival (2616,17228,63278). However, in other studies, taking a similar dose of the same product for 3 months to 2 years is not associated with any benefit over placebo (7321,7322,7355,63158). A meta-analysis of clinical research also shows that milk thistle extract does not reduce mortality or complications related to liver disease in patients with alcohol-related liver disease (63192). Reasons for the conflicting findings are unclear but might relate to the low methodological quality of many of these studies.
• Allergic rhinitis (hay fever). It is unclear if oral milk thistle is beneficial in patients with allergic rhinitis. Details: One preliminary clinical trial shows that taking a milk thistle extract of silymarin 140 mg orally three times a day plus cetirizine (Zyrtec) 10 mg daily for one month decreases the severity of allergic rhinitis symptoms when compared with placebo plus cetirizine (18105).
• Alzheimer disease. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a supplement containing a milk thistle extract of silymarin 150 mg in combination with ferulic acid, gamma-oryzanol, and apigenin orally twice daily for 3 months to 2 years may stabilize mental functioning in patients with Alzheimer disease when compared to baseline (63223). It is unclear if this effect is due to milk thistle, other ingredients, or the combination.
• Amanita mushroom poisoning. While an intravenous milk thistle constituent, silibinin, has been studied for treating Amanita mushroom poisoning, this product is not readily available in the U.S. Details: Preliminary evidence from uncontrolled studies shows that administering silibinin, a constituent of milk thistle, intravenously (IV) within 48 hours of Amanita phalloides (death cap) mushroom poisoning, followed by oral therapy, may lessen liver damage (2615,63293). However, silibinin is not readily available in the US.
• Benign prostatic hyperplasia (BPH). Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a milk thistle extract of silymarin 190 mg along with selenium 80 mcg orally three times daily for 6 months may improve lower urinary tract symptoms, urinary flow rates, and residual volumes in adults aged 45-70 years with BPH when compared with placebo (88155). It is unclear if these effects are due to milk thistle, selenium, or the combination.
• Beta-thalassemia. Meta-analyses of clinical studies in patients with beta-thalassemia suggest that oral silymarin, a constituent of milk thistle, reduces serum ferritin levels. Details: Most small clinical studies and meta-analyses of these studies show that taking silymarin in conjunction with conventional iron chelation medications such as deferiprone, deferasirox, or deferoxamine, is more effective for reducing serum ferritin levels than taking a conventional medication alone (88154,98452,107375). In one meta-analysis, the combination of silymarin and deferasirox appeared to be more effective than combinations with other iron chelation medications (107375). However, one preliminary clinical study in patients 12 years of age and older with beta-thalassemia shows that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 140 mg orally three times daily for 3 months, in conjunction with deferoxamine, does not improve serum ferritin when compared with deferoxamine alone (63212). This difference in outcome is likely due to the shorter duration of therapy. Silymarin also does not seem to affect total iron binding capacity or liver iron concentration in patients with beta-thalassemia (107375).
• Chemotherapy-induced acral erythema. It is unclear if topical milk thistle is beneficial in patients with acral erythema due to capecitabine. Details: Preliminary clinical research shows that applying a gel containing a milk thistle extract of silymarin 1% twice daily to the hands and feet, starting from the first day of chemotherapy and continuing for 9 weeks thereafter, prolongs the time to onset of acral erythema and decreases its severity when compared with placebo in patients with gastrointestinal cancer who are receiving capecitabine for the first time (95022).
• Chemotherapy-induced hepatotoxicity. Results of clinical studies are mixed over whether oral milk thistle prevents or improves chemotherapy-induced hepatotoxicity. Details: One small clinical study in children and adults up to age 21 with acute lymphoblastic leukemia (ALL) and elevated liver function tests (LFTs) shows that taking a specific product containing the milk thistle constituent silibinin (Siliphos, Thorne Research, Inc.) 80-320 mg (depending on patient weight) daily for 28 days concurrently with chemotherapy does not improve LFTs or bilirubin levels when compared with placebo (63218). Another small clinical study in patients with non-metastatic breast cancer receiving doxorubicin, cyclophosphamide, and paclitaxel shows that taking a specific milk thistle extract of silymarin (Livergol, Goldaru Pharmaceutical Company) 140 mg three times daily with meals for 4 weeks does not improve fatty liver grading or LFTs when compared with placebo (105795). Conversely, a large clinical study in children aged 5-14 with elevated liver enzymes and receiving chemotherapy for ALL shows that taking silymarin 70 mg capsules twice daily or 50 mg syrup three times daily for 9 months modestly improves aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels, but does not improve alkaline phosphatase or albumin levels (113144). Similarly, observational research in patients with a variety of solid tumors and elevated LFTs due to chemotherapy or targeted therapy suggests that taking silymarin 150-900 mg daily is associated with reduced or stabilized LFTs in over half of patients; however, doses above 300-450 mg daily don't seem to have much more benefit (111176). The interpretation of these results is limited by the lack of a comparator group.
• Chemotherapy-induced nephrotoxicity. It is unclear if oral milk thistle is beneficial for the prevention of cisplatin-induced nephrotoxicity. Details: A small clinical study shows that taking a milk thistle extract standardized to 70% to 80% silymarin (Liverherb, Amin Pharmaceutical Company) 140 mg orally three times daily with meals, starting 24-48 hours before cisplatin and continuing until the end of three 21-day cycles, does not prevent cisplatin-induced nephrotoxicity when compared with placebo (95025).
• Cirrhosis. It is unclear if oral milk thistle extracts of silymarin are beneficial for cirrhosis from various causes. Details: Preliminary clinical research shows that taking a milk thistle extract of silymarin 420 mg orally daily for up to 4 years might improve liver function tests and decrease mortality in people with cirrhosis due to a variety of causes (2616,63145,63278,63340). However, a meta-analysis of clinical research evaluating milk thistle studies for the treatment of various liver diseases shows that effect sizes are generally small or lack statistical significance (63161).
• Contrast induced nephropathy. It is unclear if oral milk thistle is beneficial for reducing the risk of nephropathy from contrast agents. Details: Population research in Taiwanese patients with liver cirrhosis has found that taking silymarin daily for at least 90 days during a one-year period does not reduce the risk of contrast-induced nephropathy during the following four or more years (98453).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral milk thistle is beneficial for COVID-19. Details: Preliminary clinical research in adults hospitalized with COVID-19 requiring non-invasive oxygen support shows that taking a specific milk thistle product (SinaLive, Exir Nano Sina Company), 70 mg orally three times daily for 2 weeks, does not improve time to symptom resolution, lung scores, or length of stay when compared with placebo (109504).
• Critical illness (trauma). It is unclear if oral milk thistle is beneficial in critically ill patients with trauma-induced liver injury. Details: One small clinical study in patients admitted to the intensive care unit (ICU) due to trauma-induced liver injury shows that taking a specific milk thistle extract (Livergol, Goldaru Pharmaceutical Company) containing silymarin 140 mg three times daily for 14 days reduces markers of liver injury, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), when compared with placebo (105793). Whether this milk thistle extract improves morbidity, mortality, or length of ICU stay in these patients is unclear.
• Diabetic nephropathy. It is unclear if oral milk thistle is beneficial for improving kidney function in patients with this condition. Details: Preliminary clinical research in type 2 diabetic patients with diabetic nephropathy shows that taking a milk thistle extract of silymarin 140 mg orally three times daily for 3 months, in combination with conventional treatment decreases the urine albumin to creatinine ratio when compared with placebo. However, serum creatinine and estimated glomerular filtration rate are not improved (63250).
• Dyspepsia. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A specific combination product containing milk thistle (Iberogast, Medical Futures, Inc.) seems to improve symptoms of dyspepsia. The combination includes milk thistle plus peppermint leaf, German chamomile, caraway, licorice, clown's mustard plant, celandine, angelica, and lemon balm (19532). A meta-analysis of clinical research using this combination product shows that taking 1 mL orally three times daily over a period of 4 weeks reduces severity of acid reflux, epigastric pain, cramping, nausea, and vomiting when compared with placebo (13089).
• Endometriosis. It is unclear if oral milk thistle is beneficial in patients with endometriosis. Details: Preliminary clinical research in females with ovarian endometrioma shows that taking a specific silymarin product (Goldaru Pharma) 140 mg twice daily for 12 weeks moderately improves pain scores, but not other sexual function scores, when compared with placebo (110486). However, some researchers have also recommended to avoid using milk thistle in estrogen-sensitive conditions, such as endometriosis, due to its estrogenic effects (93025,93026).
• Hepatitis. Small clinical studies suggest that oral milk thistle extracts of silymarin may improve hepatitis symptoms. It is unclear whether these products can improve liver function in these patients. Details: In people with hepatitis due to a variety of causes, taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 140 mg orally three times daily for 4 weeks reduces symptoms such as jaundice, dark urine, and scleral icterus, but does not improve liver function tests (LFTs) (63210,63317). However, some improvements in LFTs are seen with a silybin-phosphatidylcholine complex (Silipide, Inverni della Beffa Research and Development Laboratories) taken as 160-360 mg orally daily for 2 weeks to 3 months (63320,63321). However, there are methodological problems with these latter studies.
• Hepatitis B. Small clinical studies suggest that oral milk thistle extracts may improve liver function in people with hepatitis B, although it is unclear if these products can improve disease-related complications. Details: Preliminary clinical studies suggest that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 140 mg orally three times daily for 28 days to one year, or a silybin-phosphatidylcholine complex (Silipide, Inverni della Beffa Research and Development Laboratories) 240 mg orally twice daily for 7 days, improves liver function tests (LFTs) and liver histology (7356,63263,63299). However, another study shows that taking a milk thistle extract of silymarin 140 mg orally three times daily for 5-25 days has no effect of LFTs (63288). A meta-analysis of clinical research and a review conclude that any clinical effect of milk thistle in people with viral hepatitis is very limited and results suggest that it lacks a significant effect on mortality, liver disease complications, or liver histology (17228,63192).
• Hepatitis C. Small clinical studies suggest that oral milk thistle extracts may improve liver function but do not seem to reduce hepatitis C virus (HCV) RNA levels. Details: Preliminary clinical studies show that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 140 mg orally three times daily for 3-12 months, or a silybin-phosphatidylcholine complex (Silipide, Inverni della Beffa Research and Development Laboratories) 240 mg orally twice daily for 7 days, improves liver function tests (LFTs) and liver histology (7356,63299). However, other studies report that taking silymarin 125-140 mg three times daily for up to one year, 166 mg twice daily for 3 months, or 400 mg daily for 8 weeks does not improve serum HCV RNA levels, anti-HCV antibody levels, LFTs, or hepatomegaly (13170,63208,63247,63288,108658). Also, taking higher doses of silymarin, up to 700 mg three times daily for 6 months, does not have a significant effect on serum HCV RNA levels or LFTs when compared with placebo (63251). A meta-analysis of clinical research and a review conclude that any clinical effect of milk thistle in people with viral hepatitis is limited and most results show that milk thistle lacks a significant effect on mortality, liver disease complications, or liver histology (17228,63192,88156). Preliminary clinical research in adults with HCV-related advanced chronic liver disease shows that taking a specific milk thistle combination product containing silybinphospholipid complex 303 mg, vitamin D 10 mcg, and vitamin E 15 mg (Realsil 100 D, Ibi Lorenzini), twice daily for 12 months, improves liver stiffness scores, but not liver fibrosis scores, when compared with control (108659). It is unclear if this effect is due to milk thistle, other ingredients, or the combination.
• Hypercholesterolemia. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of three clinical trials in adults with hypercholesterolemia shows that taking a specific combination product (Berberol, PharmExtracta) containing milk thistle extract 105 mg and tree turmeric extract 588 mg twice daily for 3 months, along with diet and exercise, reduces levels of low-density lipoprotein (LDL) cholesterol by an average of 34 mg/dL when compared with diet and exercise alone. There was no effect on high-density lipoprotein (HDL) cholesterol or triglyceride levels (101158). The studies included in this meta-analysis are generally of low quality, lasted for no more than 12 months, and sometimes include patients with statin intolerance (95019,96140,101158). It is unclear if the effects of this product are due to milk thistle extract, tree turmeric extract, or the combination. Other clinical research shows that taking a similar product (Berberol K, PharmExtracta) containing milk thistle extract 105 mg, tree turmeric extract of berberine 500 mg, and monacolin K and KA 10 mg, taken once daily for 3 months along with diet and exercise, reduces levels of LDL cholesterol by about 28% when compared with diet and exercise alone in patients with hypercholesterolemia (97625). It is possible that any benefit of this product is due to the monacolin content.
• Hyperlipoproteinemia. It is unclear if oral milk thistle is beneficial in patients with hyperlipoproteinemia secondary to liver disease. Details: One very small crossover study shows that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 420 mg orally daily for 7 months does not significantly improve cholesterol levels in patients with hyperlipoproteinemia secondary to liver disease when compared with placebo (63255).
• Hypoxic liver injury. It is unclear if oral milk thistle is beneficial for reducing liver injury in patients with hypoxia. Details: Preliminary clinical research in patients presenting to the emergency department with hypoxia shows that taking a milk thistle extract of silymarin 280 mg every 8 hours for 3 days reduces markers of liver injury, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), when compared with placebo (103871).
• Infertility. It is unclear if oral milk thistle is beneficial for patients undergoing in vitro fertilization. Details: Preliminary clinical research shows that taking a milk thistle extract of silymarin 70 mg orally three times daily in combination with human chorionic gonadotropin (HCG) lowers the proportion of early and total apoptosis of follicle cells during in vitro fertilization due to male infertility. However, it does not have an effect on the number of oocytes retrieved or the thickness of the endometrium when compared with HCG plus placebo (63227).
• Lactation. It is unclear if oral milk thistle is beneficial for increasing milk production. Details: A small clinical study shows that taking a milk thistle extract standardized to 60% silymarin (BIO-C, Milte Italia S.r.l.) 240 mg twice daily for 4 weeks does not increase milk production when compared with placebo in mothers of preterm newborns (95027).
• Melasma. It is unclear if topical milk thistle is beneficial in patients with melasma. Details: Preliminary clinical research in adults with melasma shows that applying silymarin 1.4% cream twice daily for 3 months moderately improves melasma appearance scores when compared to baseline. These improvements were similar to hydroquinone cream 2% (110489). One small clinical trial in females with melasma shows that application of silymarin 1.4% cream twice daily to the affected area for 3 months is as effective for improving melasma area and severity as a specific type of laser therapy (low fluence Q switched ND:YAG 1064 nm) (105791).
• Menopausal symptoms. It is unclear if oral milk thistle reduces menopausal symptoms such as hot flashes. Details: One small clinical study in postmenopausal patients shows that taking milk thistle fruit extract 200 mg, containing 80% silymarin, twice daily for 8 weeks seems to reduce the number and severity of daily hot flashes and overall climacteric symptoms when compared with taking placebo (105053). This finding is limited by incomplete reporting and potentially inadequate blinding. Other preliminary clinical research has evaluated milk thistle in combination with black cohosh, dong quai, red clover, American ginseng, and chasteberry (Phyto-Female, SupHerb), with some evidence of benefit for reducing hot flashes and night sweats. (19552).
• Metabolic syndrome. Oral silymarin, a constituent of milk thistle, seems to improve some of the laboratory abnormalities associated with metabolic syndrome. Details: A meta-analysis of 11 low-quality clinical trials in adults with metabolic syndrome, conducted in Asia and Africa, shows that silymarin, 140-2100 mg daily for 45 days to 12 months, modestly reduces fasting blood glucose, glycated hemoglobin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, and increases high-density lipoprotein cholesterol levels, when compared with placebo (107374).
• Multiple sclerosis (MS). Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with MS shows that taking a supplement containing a milk thistle extract of silymarin 150 mg in combination with ferulic acid, gamma-oryzanol, and apigenin twice daily for 3-24 months may stabilize clinical symptoms of MS when compared to baseline (63223). It is unclear if this effect is due to milk thistle, other ingredients, or the combination.
• Nonalcoholic fatty liver disease (NAFLD). Small clinical studies suggest that oral milk thistle extracts of silymarin may slightly improve markers of liver function patients with NAFLD. Details: Two meta-analyses of small clinical trials in patients with NAFLD show that taking milk thistle products containing a total of silymarin 140-2100 mg daily, either alone or in combination with other ingredients, for 8-48 weeks reduces aspartate aminotransferase (AST) by 7 IU/L and alanine aminotransferase (ALT) by 9-15 IU/L, but does not affect weight or lipid levels, when compared with control (97622,105051). However, these changes in liver enzymes may not be clinically impactful and some experts note that serum AST levels do not reliably reflect the spectrum of liver histology in patients with NAFLD (98130). Preliminary clinical research in adults with NAFLD and a body-mass index (BMI) of at least 35 kg/m2 shows that taking milk thistle extract 140 mg 4 times daily for 8 weeks, in addition to lifestyle modifications, reduces BMI by approximately 1 kg/m² when compared with placebo with lifestyle modifications (108657). However, another small clinical trial in adults with NAFLD and a BMI of at least 40 kg/m2 shows that taking a specific silymarin product (Livergol, Goldaru Pharmaceuticals) 140 mg three times daily for 4 weeks did not reduce BMI or improve liver enzymes, such as AST and ALT, when compared with placebo (110484). One small clinical study in patients with NAFLD shows that taking a specific combination product (Eurosil 85, MEDAS SL) containing milk thistle extract standardized to silymarin 540 mg and vitamin E 36 mg daily for 3 months, in addition to following a low-calorie diet, does not appear to improve NAFLD-Fibrosis score or fatty liver index (FLI) when compared with following a low-calorie diet alone (96261).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral milk thistle is beneficial in patients with NASH. Details: Clinical research in patients with NASH shows that taking a milk thistle extract of silymarin 700 mg three times daily for 48 weeks improves fibrosis in more patients when compared with placebo (96107). However, there is no significant between-group difference in global histological improvement with this product (96107) or with a specific silymarin product (Legalon, Rottapharm Madaus, Mylan) 420 or 700 mg three times daily for 48-50 weeks (101150).
• Obsessive-compulsive disorder (OCD). It is unclear if oral milk thistle is beneficial in patients with OCD. Details: Preliminary clinical research shows that taking milk thistle leaf extract 200 mg orally three times daily for 8 weeks has a limited effect on OCD symptom scores when compared to baseline, but does not provide any benefit over fluoxetine 10 mg three times daily (63219).
• Parkinson disease. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a supplement containing a milk thistle extract of silymarin 150 mg in combination with ferulic acid, gamma-oryzanol, and apigenin orally twice daily for 3 months to 24 months may stabilize clinical symptoms in patients with Parkinson disease when compared to baseline (63223). It is unclear if this effect is due to milk thistle, other ingredients, or the combination.
• Postpartum complications. It is unclear if topical milk thistle is beneficial in postpartum patients with an episiotomy. Details: Preliminary clinical research in postpartum patients shows that applying milk thistle 3% in Eucerin ointment twice daily to the suture site for 10 days reduces episiotomy pain and improves the healing rate when compared with placebo. The milk thistle product was prepared with an ethanolic extract of the seeds to provide 1.53% silybin (107373).
• Prostate cancer. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with a history of prostate cancer who have had radiotherapy or radical prostatectomy shows that taking a dietary supplement containing a milk thistle extract of silymarin 160 mg, soy isoflavones (Novasoy, ADM) 62.5 mg, lycopene (Lyc-O-Mato, LycoRed Natural Products Industries, Ltd.) 15 mg, vitamins, minerals, and antioxidants orally daily for 10 weeks increases the time it takes for prostate-specific antigen (PSA) levels to double by 2.6-fold when compared with placebo (60361).
• Radiation dermatitis. It is unclear if topical milk thistle is beneficial in patients with dermatitis due to radiation. Details: Preliminary clinical research in females with breast cancer undergoing radiotherapy shows that applying a specific topical product containing a milk thistle extract of silymarin (Leviaderm, Madaus GmbH) significantly reduces the incidence of radiation dermatitis and prolongs the time to the onset of radiation dermatitis when compared with applying a panthenol-containing cream (63239).
• Radiation mucositis. It is unclear if oral milk thistle is beneficial for preventing or treating mucositis due to radiation. Details: One small clinical study in patients with head and neck cancer receiving radiotherapy for the first time shows that taking a specific product containing a milk thistle extract of silymarin (Livergol, Goldaru Pharmaceutical Company), 140 mg three times daily starting from the first day of radiotherapy and continuing for 6 weeks thereafter, reduces the severity and prolongs the time to onset of radiation-induced mucositis when compared with placebo (95021).
• Toxin-induced liver damage. Most small clinical studies suggest that oral milk thistle extracts or constituents may reduce liver injury in people exposed to some, but not all, toxins and medications known to cause liver damage. Details: Taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 420 mg orally daily for up to one month improves liver function tests (LFTs) in people with abnormal LFTs due to chronic occupational exposure to paints or organic solvents such as toluene or xylene (2614,63280). Milk thistle extract has also shown some benefit for reducing drug-induced liver injury (DILI). In patients on isotretinoin therapy for acne, taking a specific milk thistle extract containing silymarin (Livergol, Goldaru Pharmaceutical Company) 140 mg daily for 30 days improves LFTs when compared with placebo (102852). A small clinical study in patients with relapsing-remitting multiple sclerosis who were initiating therapy with fingolimod shows that taking a specific milk thistle extract (Livergol, Goldaru Pharmaceutical Company) containing silymarin 140 mg daily for 6 months prevents fingolimod-induced LFT elevations when compared with placebo (105794). In patients receiving treatment for tuberculosis with rifampin, isoniazid, pyrazinamide, ethambutol, and streptomycin, taking the milk thistle constituent silibinin 70 mg orally three times daily for 6-12 months reduces the rate of liver toxicity to 14% compared with 53% in patients taking glucuronolactone 200 mg orally three times daily (63224). Additionally, in patients receiving standard treatment for tuberculosis with isoniazid, rifampicin, pyrazinamide, and ethambutol, taking a milk thistle extract of silymarin 140 mg orally three times daily for 4 weeks decreases the risk of DILI by 28% when compared with placebo. About 1 in every 4 patients who take silymarin for 4 weeks would avoid DILI (95024). A small clinical study in Iran, also in adults receiving standard treatment for tuberculosis, shows that taking a milk thistle extract of silymarin 150 mg twice daily for 2 weeks modestly improves LFTs when compared with control. None of the 16 patients in the silymarin group developed DILI compared with 2 of 21 patients in the control group; however, this finding was not statistically significant (112230). The interpretation of these findings is limited by the short study duration. However, taking a milk thistle extract of silymarin 420 mg orally daily for 3 months does not seem to prevent liver toxicity associated with tacrine (Cognex) therapy in people with Alzheimer disease (63140). Other research in people with elevated LFTs due to long-term therapy with phenothiazine or butyrophenone antipsychotic medications shows that taking silymarin 800 mg orally daily for 3 months also does not improve LFTs when compared with placebo (63344). A retrospective study in patients with DILI of various offending agents has also found that taking a milk thistle extract, containing a median of 450 mg silybin daily for 24 days is associated with 1.7-2.8 times higher likelihood of LFT normalization when compared with control (110485).
• Trichotillomania. It is unclear if oral milk thistle is beneficial in patients with this condition. Details: Preliminary clinical research in patients 12-65 years of age shows that taking milk thistle 150 mg twice daily for 2 weeks, and then 300 mg twice daily for 4 weeks, does not improve symptoms of trichotillomania when compared with placebo (99426).
• Ulcerative colitis. It is unclear if oral milk thistle is beneficial in patients with this condition. Details: Preliminary clinical research in patients 16-75 years of age shows that taking a specific milk thistle extract of silymarin (Livergol, Goldaru Pharmaceutical Company) 140 mg daily for 6 months, in conjunction with standard medications, decreases disease activity and helps maintain remission when compared with placebo in patients with ulcerative colitis (95029).
• Vitiligo. It is unclear if oral milk thistle reduces the severity of this condition. Details: Preliminary clinical research in a small number of patients with vitiligo shows that taking a specific milk thistle extract containing silymarin (Livergol, Goldaru Pharmaceutical Company) 140 mg twice daily along with phototherapy for 3 months does not improve the severity of vitiligo when compared with phototherapy plus placebo (102851). More evidence is needed to rate milk thistle for these uses.

(Read more about MILK THISTLE)

POSSIBLY EFFECTIVE

• Sexual dysfunction. Oral tribulus seems to improve sexual experience in females with hypoactive sexual desire disorder (HSDD) or sexual dysfunction. Some research also shows that oral tribulus improves sexual function in males. Details: Clinical research in premenopausal and postmenopausal patients with HSDD shows that taking tribulus 250 mg three times daily (Androsten, Herbarium) for 3 months improves overall satisfaction and lubrication, as well as pain, desire, sexual arousal, and ability to reach orgasm, when compared with placebo (92027,97331,97332). Other preliminary clinical research in females with HSDD shows that taking tribulus extract 7.5 mg daily for 4 weeks improves sexual desire, arousal, satisfaction, orgasm, pain, and lubrication when compared with placebo (92022). A nonblinded clinical study comparing tribulus dosing regimens shows that taking oral tribulus 280 mg, either once daily or in three divided daily doses, for 90 days results in similar improvements in sexual dysfunction, regardless of menopausal status. However, neither dosing schedule increases clitoral blood flow when compared with baseline (108551). Tribulus has also been studied in males. One clinical study in males with erectile dysfunction, with or without HSDD, shows that taking tribulus (Tribestan, Sopharma AD) 500 mg three times daily for 3 months improves sexual desire and intercourse satisfaction when compared with placebo (97330).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral tribulus does not seem to improve athletic performance. Details: Small clinical studies in athletes show that taking tribulus orally, alone or in combination with other ingredients such as androstenedione, most often as 450-770 mg daily for 5-8 weeks, does not seem to enhance body composition or exercise performance when compared with placebo or a control group (7514,13255,92029,108552).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral tribulus is beneficial for angina. Details: Preliminary clinical research shows that taking a tribulus extract orally might reduce symptoms of angina when compared with a control (3931).
• Atopic dermatitis (eczema). Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some preliminary clinical research shows that taking tribulus orally in combination with 9 other herbs (Zemaphyte) daily for 8 weeks reduces redness and skin lesions in adults and children with nonexudative atopic dermatitis (12627,12628). However, other research shows no effect (12630). It is unclear if these effects are due to tribulus, the other ingredients, or the combination.
• Bacterial vaginosis. Topical tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with bacterial vaginosis shows that using a specific vaginal suppository (Forzajeh) containing tribulus, myrtle, fennel, and tamarind daily for 1 week is as effective as metronidazole vaginal suppository for improving vaginal discharge volume and odor, pelvic pain, cervical inflammation, and vaginal pH (100339). It is unclear if these effects are due to tribulus, the other ingredients, or the combination.
• Benign prostatic hyperplasia (BPH). Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with BPH shows that taking a combination supplement (Prostalyn, East India Pharmaceutical Works Ltd.) containing tribulus 600 mg and curry leaf (Murraya koenigii) 600 mg twice daily for 12 weeks improves prostate symptoms when compared to baseline, with no difference when compared to tamsulosin 400 mcg daily. This supplement also seems to reduce prostate volume by around 2 mL (92033).
• Cancer. Although there is interest in using oral tribulus for cancer, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral tribulus for CFS, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Diabetes. It is unclear if oral tribulus is beneficial for diabetes. Details: Preliminary clinical research in females with type 2 diabetes who are taking oral hypoglycemic agents shows that taking tribulus extract powder 500 mg twice daily for 3 months modestly reduces fasting glucose and postprandial glucose levels, but not glycated hemoglobin, when compared with placebo. However, the validity of these findings is limited by the difference in diabetes severity between groups at baseline (97327).
• Erectile dysfunction (ED). It is unclear if oral tribulus is beneficial for ED. Research is conflicting. Details: Clinical research in patients with ED shows that taking tribulus (Tribestan, Sopharma AD) 500 mg three times daily for 3 months does not provide a clinically beneficial improvement in erectile function when compared with placebo (97330). Other clinical research shows that taking tribulus 400 mg twice daily for 30 days does not improve erectile function when compared with placebo (92031). However, one preliminary clinical study in patients with partial androgen deficiency shows that taking tribulus 250 mg three times daily for 3 months improves erectile function when compared to baseline (92028). Tribulus has also been studied in combination with other ingredients. Preliminary clinical research shows that taking a combination supplement (Tradamix TX1000, Tradapharma Sagl) containing tribulus 450 mg, brown algae 300 mg, and chitosan 250 mg twice daily for 3 months improves sexual satisfaction, desire, ejaculation function, and sexual quality of life when compared with placebo in patients with mild-to-moderate ED (92030). It is unclear if these effects are due to tribulus, the other ingredients, or the combination.
• Exercise-induced muscle damage. It is unclear if oral tribulus is beneficial for exercise-induced muscle damage. Details: Clinical research in a small number of healthy, untrained males shows that taking tribulus 500 mg daily for 2 weeks prior to performing resistance exercise reduces markers of muscle damage, including creatine phosphokinase (CPK) and lactate dehydrogenase (LDH), but does not reduce levels of the inflammatory markers interleukin-6 (IL-6) or C-reactive protein (CRP), when compared with placebo (103236). However, another small clinical study in male CrossFit athletes shows that taking tribulus 770 mg capsules (Quamtrax Pharmaceuticals) daily for 42 days does not reduce CPK but does improve CRP and oxidant status when compared with placebo (111747). However, it is unclear whether any improvements are clinically significant. A very small crossover clinical study in trained male athletes shows that taking 20 mg/kg/day of tribulus in 3 divided doses 30 minutes before meals with 500 mL of water for 4 weeks does not reduce muscle soreness after intensive aerobic exercise when compared with placebo (111746).
• Gonorrhea. Although there is interest in using oral tribulus for gonorrhea, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Hypercholesterolemia. Although there is interest in using oral tribulus for hypercholesterolemia, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Hypertension. It is unclear if oral tribulus can lower blood pressure. Details: In patients with pre-hypertension, clinical research shows that taking powdered tribulus fruit 2 grams three times daily for 2 months reduces systolic and diastolic blood pressure by 6 and 5 mmHg, respectively, when compared with placebo (105245). It is unclear what effect Tribulus may have in patients with diagnosed hypertension.
• Kidney stones (nephrolithiasis). Although there is interest in using oral tribulus for kidney stones, there is insufficient reliable information about the clinical effects of tribulus for this purpose.
• Male infertility. It is unclear if oral tribulus is beneficial for male infertility; the available research is conflicting. Details: Case series suggest that taking a specific tribulus product (Tribestan, Sopharma) 250 mg three times daily for 30 days improves ejaculate volume, sperm concentration, and sperm motility in patients with infertility due to oligoasthenozoospermia (78865), and improves libido and erections in patients with primary hypogonadism (78868). Conversely, a small clinical study in patients with oligozoospermia shows that taking tribulus granules 6 grams daily for 60 days does not improve sperm count when compared with placebo (92032). In patients with idiopathic infertility, taking tribulus 250 mg three times daily for 3 months does not increase sperm concentration, sperm motility, serum testosterone levels, or luteinizing hormone levels (97328). The difference in these findings might be due to the small study sizes, as well as the variable etiology of infertility.
• Menopausal symptoms. Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination product containing tribulus 40 mg, ginger, saffron, and Ceylon cinnamon (Aphrodit, Goldaru Company) twice daily for 4 weeks improves mental and physical symptoms during menopause, but not genitourinary symptoms, when compared with placebo (97326). It is not clear if this effect is due to tribulus, the other ingredients, or the combination.
• Osteoporosis. Although there is interest in using oral tribulus for osteoporosis, there is insufficient reliable information about the clinical effects of tribulus for this condition.
• Polycystic ovary syndrome (PCOS). Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that taking tribulus extract (Tribulus forte, Mediherb, Integra Healthcare Ltd) 245 mg daily along with other ingredients and lifestyle modification during the follicular phase of the menstrual cycle for 3 months improves some symptoms of PCOS, including a 33% reduction in oligomenorrhea or amenorrhea and a 43-day reduction in the duration between menstrual cycles, when compared with lifestyle modification alone. Taking tribulus with other ingredients also improves quality of life by about 30% and reduces body mass index by 1 kg/m2 when compared with placebo. Although the conception rate increased 4-fold in patients taking the combination product, the live birth rate was similar to those taking placebo. (97216). It is unclear if these effects are due to tribulus, the other ingredients, or the combination.
• Premature ejaculation. Oral tribulus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination product containing tribulus, 5-HTP, winter savory, and chanca piedra (EiacuMev, Farmaceutica Mev) daily for 3 months improves time to ejaculation by 30 seconds and reduces symptoms related to premature ejaculation when compared to control (97016). More evidence is needed to rate tribulus for these uses.

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LIKELY SAFE ...when used orally and appropriately. A specific milk thistle extract standardized to contain 70% to 80% silymarin (Legalon, Madaus GmbH) has been safely used in doses up to 420 mg daily for up to 4 years (2613,2614,2616,7355,63210,63212,63278,63280,63299,63340)(88154,97626,105792). Higher doses of up to 2100 mg daily have been safely used for up to 48 weeks (63251,96107,101150). Another specific milk thistle extract of silymarin (Livergol, Goldaru Pharmaceutical Company) has been safely used at doses of 140 mg daily for up to 6 months and doses of 420 mg daily for up to 6 weeks (95021,95029,102851,102852,105793,105794,105795). Some isolated milk thistle constituents also appear to be safe. Silibinin (Siliphos, Thorne Research) has been used safely in doses up to 320 mg daily for 28 days (63218). Some combination products containing milk thistle and other ingredients also appear to be safe. A silybin-phosphatidylcholine complex (Silipide, Inverni della Beffa Research and Development Laboratories) has been safely used in doses of 480 mg daily for 7 days (7356) and 240 mg daily for 3 months (63320). Tree turmeric and milk thistle capsules (Berberol, PharmExtracta) standardized to contain 60% to 80% silybin have been safely used twice daily for up to 12 months (95019,96140,96141,96142,97624,101158).

POSSIBLY SAFE ...when used topically and appropriately, short-term. A milk thistle extract cream standardized to silymarin 0.25% (Leviaderm, Madaus GmbH) has been used safely throughout a course of radiotherapy (63239). Another milk thistle extract cream containing silymarin 1.4% has been used with apparent safety twice daily for 3 months (105791,110489). A cream containing milk thistle fruit extract 25% has been used with apparent safety twice daily for up to 12 weeks (111175). A milk thistle extract gel containing silymarin 1% has been used with apparent safety twice daily for 9 weeks (95022). There is insufficient reliable information available about the safety of intravenous formulations of milk thistle or its constituents.

PREGNANCY AND LACTATION:
While research in an animal model shows that taking milk thistle during pregnancy and lactation does not adversely impact infant development (102850), there is insufficient reliable information available about its safety during pregnancy or lactation in humans; avoid using.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A milk thistle extract 140 mg three times daily has been used with apparent safety for up to 9 months (88154,98452). A specific product containing the milk thistle constituent silybin (Siliphos, Thorne Research Inc.) has been used with apparent safety in doses up to 320 mg daily for up to 4 weeks in children one year of age and older (63218).

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LIKELY UNSAFE ...when the spine-covered fruit is used orally. There have been reports of bilateral pneumothorax and bronchial polyp after oral consumption of the spine-covered fruit (818).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Animal research suggests that tribulus might adversely affect fetal development (12674); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking milk thistle with antidiabetes drugs may increase the risk of hypoglycemia.  Details Clinical research shows that milk thistle extract, alone or along with tree turmeric extract, can lower blood glucose levels and glycated hemoglobin (HbA1c) in patients with type 2 diabetes, including those already taking antidiabetes drugs (15102,63190,63314,63318,95019,96140,96141,97624,97626).

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might inhibit CYP2B6.  Details An in vitro study shows that silybin, a constituent of milk thistle, binds to and noncompetitively inhibits CYP2B6. Additionally, silybin might downregulate the expression of CYP2B6 by decreasing mRNA and protein levels (112229).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B It is unclear if milk thistle inhibits CYP2C9; research is conflicting.  Details In vitro research suggests that milk thistle might inhibit CYP2C9 (7089,17973,17976). However, contradictory clinical research shows that milk thistle extract does not inhibit CYP2C9 or significantly affect levels of the CYP2C9 substrate tolbutamide (13712,95026). Differences in results could be due to differences in dosages or formulations utilized (95026).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D It is unclear if milk thistle inhibits CYP3A4; research is conflicting.  Details While laboratory research shows conflicting results (7318,17973,17975,17976), pharmacokinetic research shows that taking milk thistle extract 420-1350 mg daily does not significantly affect the metabolism of the CYP3A4 substrates irinotecan, midazolam, or indinavir (8234,17974,93578,95026).

ESTROGENS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might interfere with estrogen therapy through competition for estrogen receptors.  Details Animal research suggests that a milk thistle extract of silymarin binds to estrogen receptor beta (93025,93026).

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might affect the clearance of drugs that undergo glucuronidation.  Details Laboratory research shows that milk thistle constituents inhibit uridine diphosphoglucuronosyl transferase (UGT), the major phase 2 enzyme that is responsible for glucuronidation (7318,17973). Theoretically, this could decrease the clearance and increase levels of glucuronidated drugs. Other laboratory research suggests that a milk thistle extract of silymarin might inhibit beta-glucuronidase (7354), although the significance of this effect is unclear.

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, milk thistle might interfere with statin therapy by decreasing the activity of organic anion transporting polypeptide 1B1 (OATB1B1) and inhibiting breast cancer resistance protein (BCRP).  Details Preliminary evidence suggests that a milk thistle extract of silymarin can decrease the activity of the OATP1B1, which transports HMG-CoA reductase inhibitors into the liver to their site of action. The silibinin component also inhibits BCRP, which transports statins from the liver into the bile for excretion. However, in a preliminary study in healthy males, silymarin 140 mg three times daily had no effect on the pharmacokinetics of a single 10 mg dose of rosuvastatin (16408).

INDINAVIR (Crixivan) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, milk thistle may induce cytochrome P450 3A4 (CYP3A4) enzymes and increase the metabolism of indinavir; however, results are conflicting.  Details One pharmacokinetic study shows that taking milk thistle (Standardized Milk Thistle, General Nutrition Corp.) 175 mg three times daily in combination with multiple doses of indinavir 800 mg every 8 hours decreases the mean trough levels of indinavir by 25% (8234). However, results from the same pharmacokinetic study show that milk thistle does not affect the overall exposure to indinavir (8234). Furthermore, two other pharmacokinetic studies show that taking specific milk thistle extract (Legalon, Rottapharm Madaus; Thisilyn, Nature's Way) 160-450 mg every 8 hours in combination with multiple doses of indinavir 800 mg every 8 hours does not reduce levels of indinavir (93578).

LEDIPASVIR Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might increase the levels and clinical effects of ledipasvir.  Details Animal research in rats shows that milk thistle increases the area under the curve (AUC) for ledipasvir and slows its elimination (109505).

MORPHINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of milk thistle with morphine might affect serum levels of morphine and either increase or decrease its effects.  Details Animal research shows that milk thistle reduces serum levels of morphine by up to 66% (101161). In contrast, laboratory research shows that milk thistle constituents inhibit uridine diphosphoglucuronosyl transferase (UGT), the major phase 2 enzyme that is responsible for glucuronidation (7318,17973). Theoretically, this could decrease the clearance and increase morphine levels. The effect of taking milk thistle on morphine metabolism in humans is not known.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, milk thistle might increase the absorption of P-glycoprotein substrates. However, this effect does not seem to be clinically significant.  Details Although in vitro research shows that milk thistle can inhibit P-glycoprotein activity (95019), clinical research does not agree. A small pharmacokinetic study in healthy volunteers shows that taking milk thistle (Enzymatic Therapy Inc.) 900 mg, standardized to 80% silymarin, in 3 divided doses daily for 14 days does not affect absorption of digoxin, a P-glycoprotein probe substrate (35825).

RALOXIFENE (Evista) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might decrease the clearance and increase levels of raloxifene.  Details Laboratory research suggests that the milk thistle constituents silibinin and silymarin inhibit the glucuronidation of raloxifene in the intestines (93024).

SIROLIMUS (Rapamune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Milk thistle might decrease the clearance of sirolimus.  Details Pharmacokinetic research shows that a milk thistle extract of silymarin decreases the apparent clearance of sirolimus in hepatically impaired renal transplant patients (19876). It is unclear if this interaction occurs in patients without hepatic impairment.

SOFOSBUVIR (Solvaldi) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might decrease the levels and clinical effects of sofosbuvir.  Details Animal research in rats shows that milk thistle reduces the metabolism of sofosbuvir, as well as the hepatic uptake of its active metabolite (109505).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, the milk thistle constituent silibinin might increase tamoxifen levels and interfere with its conversion to an active metabolite.  Details Animal research suggests that the milk thistle constituent silibinin might increase plasma levels of tamoxifen and alter its conversion to an active metabolite. The mechanism appears to involve inhibition of pre-systemic metabolism of tamoxifen by cytochrome P450 (CYP) 2C9 and CYP3A4, and inhibition of P-glycoprotein-mediated efflux of tamoxifen into the intestine for excretion (17101). Whether this interaction occurs in humans is not known.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might increase the effects of warfarin.  Details In one case report, a man stabilized on warfarin experienced an increase in INR from 2.64 to 4.12 after taking a combination product containing milk thistle 200 mg daily, as well as dandelion, wild yam, niacinamide, and vitamin B12. Levels returned to normal after stopping the supplement (101159). Although a direct correlation between milk thistle and the change in INR cannot be confirmed, some in vitro research suggests that milk thistle might inhibit cytochrome P450 2C9 (CYP2C9), an enzyme involved in the metabolism of various drugs, including warfarin (7089,17973,17976).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Taking tribulus with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research shows that Tribulus can lower blood glucose levels in adults with type 2 diabetes who are taking antidiabetes medications (97327).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking tribulus with antihypertensive drugs might increase the risk of hypotension.  Details Animal research shows that tribulus can lower blood pressure by inhibiting angiotensin-converting enzyme (ACE) (12673). Tribulus has also demonstrated hypotensive effects in pre-hypertensive adults (105245).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, tribulus might increase the levels and clinical effects of lithium.  Details Tribulus is thought to have diuretic properties (12681). Due to these potential diuretic effects, tribulus might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

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General ...Orally, milk thistle is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal bloating, diarrhea, dyspepsia, flatulence, and nausea. However, these adverse effects do not typically occur at a greater frequency than with placebo.
Serious Adverse Effects (Rare):
Orally: Allergic reactions, including anaphylaxis, have been reported.

Dermatologic ...Orally, milk thistle may cause allergic reactions including urticaria, eczema, skin rash, and anaphylaxis in some people (6879,7355,8956,63210,63212,63238,63251,63315,63325,95029). Allergic reactions may be more likely to occur in patients sensitive to the Asteraceae/Compositae family (6879,8956). A case report describes a 49-year-old female who developed clinical, serologic, and immunopathologic features of bullous pemphigoid after taking milk thistle orally for 6 weeks. Symptoms resolved after treatment with prednisone and methotrexate (107376). Topically, milk thistle can cause erythema (110489).

Gastrointestinal ...Mild gastrointestinal symptoms have been reported, including nausea, vomiting, bloating, diarrhea, epigastric pain, abdominal colic or discomfort, dyspepsia, dysgeusia, flatulence, constipation, and loss of appetite (2616,6879,8956,13170,63140,63146,63160,63210,63218,63219)(63221,63244,63247,63250,63251,63320,63321,63323,63324,63325)(63327,63328,95024,95029,107374). There is one report of a 57-year-old female with sweating, nausea, colicky abdominal pain, diarrhea, vomiting, weakness, and collapse after ingesting milk thistle; symptoms subsided after 24-48 hours without medical treatment and recurred with re-challenge (63329).

Musculoskeletal ...In one clinical study three patients taking milk thistle 200 mg orally three times daily experienced tremor; the incidence of this adverse effect was similar for patients treated with fluoxetine 10 mg three times daily (63219).

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General ...Orally, tribulus seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Cases of liver and kidney injury, seizures, and chronic painful erection with impaired sexual function have been reported. Pneumothorax and bronchial polyp after consuming the spine-covered tribulus fruit have been reported.

Gastrointestinal ...Orally, tribulus can cause abdominal pain, cramping, nausea, vomiting, diarrhea, and constipation (92022,92027). However, in one study, the rates of these gastrointestinal complaints were similar for patients taking tribulus and those receiving placebo (92022).

Genitourinary ...In one case report, a patient taking two tribulus tablets (unknown dose) daily for 15 days presented to the local emergency department with a painful erection lasting 72 hours. The priapism was resolved with medical management; however, post-episode sexual function was impaired (92023).

Hepatic ...In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of tribulus water (92069).

Neurologic/CNS ...Orally, tribulus has been reported to cause general excitation and insomnia. These symptoms were reversed upon discontinuation of the drug or decreasing the dose (78867). In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of tribulus water (92069).

Pulmonary/Respiratory ...In one case report, a patient developed a bilateral pneumothorax after consuming the spine-covered fruit of tribulus (818). In another case report, a patient developed a polyp in the lobar bronchus of the right interior lobe due to the presence of a tribulus fruit spine (78852).

Renal ...In one case report, a patient drinking tribulus water 2 liters daily for two days presented with lower limb weakness, seizures, hepatitis, and acute kidney injury. The patient's condition improved after hemodialysis and discontinuation of the tribulus water (92069). In another case report, a healthy male taking one tribulus tablet (unknown dose) daily for a few months for bodybuilding purposes developed hyperbilirubinemia followed by acute kidney failure 2-3 weeks later. The patient was managed with intravenous fluids and a low-salt, low-protein diet (92025).

Other ...In one case report, gynecomastia was observed in a male weightlifter taking an herbal combination product containing tribulus. However, it is not clear if this adverse effect can be attributed to tribulus alone (78859).

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