A.Vogel Liver Gallbladder Tablets by Bioforce

POSSIBLY EFFECTIVE

• Dyspepsia. Oral artichoke leaf extract may improve symptoms in patients with functional dyspepsia or dyspepsia associated with biliary disease. Details: Several clinical trials in patients with functional dyspepsia or dyspepsia associated with biliary disease show that taking artichoke leaf extract can reduce symptoms such as nausea, vomiting, flatulence, and abdominal pain. Improvement seems to occur after 2 to 8 weeks of treatment (2056,11429,12208). The validity of some of this evidence is limited by a small sample size (2056) or lack of a control group (11429). However, a higher-quality clinical trial in patients with mild dyspepsia shows that taking artichoke leaf extract 640 mg three times daily for 6 weeks improves overall symptom and quality of life scores. Specifically, patient ratings for flatulence, feelings of fullness, and early satiety were reduced when compared with placebo. Further, for every 12 patients treated with this extract over placebo, one additional patient reported markedly or completely improved symptoms (12208). Some studies have used a specific extract called ALE LI 220 (Hepar-SL forte, Serturner Arzneimittel GmbH) at doses ranging from 320-640 mg three times daily for up to 8 weeks (2056,12208). Another study has used a different artichoke leaf extract (Cynara SL, Lichtwer Pharma) at a dose of 320-640 mg daily for 2 months (11429). Some clinical research has also assessed artichoke extract in combination with ginger extract. Results show that taking 2 capsules of a specific product containing artichoke leaf extract 100 mg and ginger extract 20 mg (ProDigest, Indena) daily for 4 weeks markedly or completely improves symptoms such as nausea, fullness, pain, and bloating in about 1.5-fold more patients with functional dyspepsia when compared with placebo (91474).
• Hyperlipidemia. Most research shows that oral artichoke lowers cholesterol and triglyceride levels in patients with hyperlipidemia. However, frozen artichoke juice does not appear to have these effects. Details: Multiple meta-analyses and clinical studies in patients who are either healthy or have hyperlipidemia, nonalcoholic fatty liver disease, or pre-obesity show that taking artichoke leaf extract or concentrated artichoke juice capsules daily for 4-24 weeks reduces total cholesterol by 13-18 mg/dL, low-density lipoprotein (LDL) cholesterol by 15-17 mg/dL, and triglycerides by 9-18 mg/dL, but does not increase high-density lipoprotein (HDL) cholesterol, when compared with placebo (104132,108713,111560,111564). While the five studies including non-hyperlipidemic patients in one of these analyses reported mixed results, all four of the studies evaluating artichoke leaf extract in patients with hyperlipidemia showed significant reductions in total cholesterol and LDL cholesterol when compared with placebo (104132). Additionally, a dose-response analysis suggests that baseline cholesterol levels are a stronger predictor of benefit than dose and treatment duration (108713). The validity of these findings is limited due to the high heterogeneity of studies included in meta-analyses. Another clinical study in patients with mild hypercholesterolemia shows that taking artichoke extract 250 mg twice daily for 8 weeks decreases LDL cholesterol by about 11% and increases HDL cholesterol by about 10% when compared with placebo (91478). Other formulations have also been evaluated, including cynarin, a constituent of artichoke, and artichoke juice. Some older, small clinical studies suggest that taking cynarin 20 mg three times daily for 2-7 months reduces total cholesterol and triglyceride levels when compared to baseline in patients with hypercholesterolemia and/or hypertriglyceridemia (52222,52223,52236). However, cynarin does not appear to reduce cholesterol levels in patients with familial type II hyperlipoproteinemia (1424). In patients with hyperlipidemia, consuming frozen artichoke juice 20-30 mL daily for 6-12 weeks does not appear to reduce total or LDL cholesterol levels and may even increase triglyceride levels (52216,52234). Artichoke leaf extract has also been evaluated in combination with other ingredients. Clinical research shows that taking a product containing red yeast rice extract, artichoke leaf extract, and other ingredients (Limicol, Laboratoire Lescuyer) 3 or 6 tablets daily for 4-16 weeks decreases LDL cholesterol by 14% to 21% in patients with hyperlipidemia. However, the red yeast in this product contains monacolin K (lovastatin), which likely contributed to the cholesterol-lowering effect (89451,89452,89454). Another specific product (Vazguard; Indena SpA), containing artichoke leaf extract (Indena SpA) 100 mg and bergamot phytosome 600 mg, has also shown benefit in patients with mild hypercholesterolemia when taken twice daily for 2 months (108712). However, it is unclear if this effect is due to artichoke leaf, bergamot, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Biliary disorders. Although there has been interest in using oral artichoke for various biliary disorders, including for the treatment of cholestasis or prevention of gallstones, there is insufficient reliable information about the clinical effects of artichoke for these conditions.
• Diabetes. Several small clinical studies suggest that oral artichoke extract may slightly reduce fasting blood glucose, but may not improve glycated hemoglobin (HbA1c) or other measures of glycemic control, in patients with diabetes. Details: A meta-analysis of 9 small clinical trials shows that taking artichoke leaf extract for 8-12 weeks reduces fasting blood glucose by around 5 mg/dL, but does not improve HbA1c, insulin levels, or markers of insulin resistance, when compared with placebo (105768). The generalizability of these findings to patients with diabetes is limited; only 2 of the 9 studies specifically enrolled patients with diabetes. The other studies included patients who were overweight or with liver disease, hyperlipidemia, or metabolic syndrome. In contrast, a post-hoc analysis of clinical research in overweight adults at risk for developing diabetes shows that taking a specific artichoke leaf product (Altilix, Bionap S.r.l.) 50 mg daily for 6 months reduces HbA1c by around 0.9% and improves measures of insulin resistance and beta-cell function when compared with placebo (111564).
• Hangover. It is unclear if oral artichoke extract is beneficial for the prevention of hangover. Details: A small clinical study in healthy adults shows that taking artichoke extract 960 mg immediately before and after alcohol consumption does not prevent alcohol-induced hangover when compared with placebo (11774).
• Hepatitis C. It is unclear if oral artichoke is beneficial in patients with hepatitis C. Details: One small clinical study in patients with chronic hepatitis C shows that taking artichoke leaf extract 3200 mg daily for 12 weeks does not normalize liver enzyme levels or reduce viral load when compared to baseline. Although symptoms such as fatigue, abdominal discomfort, and joint problems appear to improve in the first 4 weeks, the improvement is not maintained over 12 weeks (91475). However, another small clinical study shows that drinking a tea infusion of wild artichoke three times daily for 3 months normalizes liver enzymes and serum virus levels in 12 of 15 patients with hepatitis C (97717). The validity of these findings is limited by the lack of a control group.
• Hypertension. Analyses of small clinical studies suggest that oral artichoke may slightly reduce blood pressure in patients with hypertension; however, individual study results are conflicting, and the improvements in blood pressure may not be clinically significant. Details: Evidence regarding an association between artichoke consumption and hypertension is conflicting (91477,104133,105767,111561). Two meta-analyses include many of the same studies yet reach contradictory conclusions. One meta-analysis of 8 small clinical trials shows that taking artichoke leaf extract, powder, or juice for 8-12 weeks does not reduce systolic blood pressure (SBP) or diastolic blood pressure (DBP). However, subgroup analysis in patients with documented hypertension shows that artichoke reduces SBP by around 3 mmHg and DBP by around 2 mmHg when compared with placebo (105767). In contrast, another meta-analysis of 7 small clinical trials shows that taking artichoke 50-2700 mg daily for 4-12 weeks reduces SBP by about 2 mmHg and DBP by about 1.5 mmHg. Subgroup analysis shows that the greatest reductions in SBP and DBP occur in doses of 500 mg daily or less, at durations longer than 8 weeks, and in patients under 50 years old (111561). Discrepancies between the results of the meta-analyses with overlapping studies may be due to the former meta-analysis including artichoke supplementation in combination with other ingredients, while the latter meta-analysis focused on artichoke supplementation alone.
• Irritable bowel syndrome (IBS). It is unclear if oral artichoke leaf extract is beneficial in patients with IBS. Details: Some observational research in patients with IBS has found that taking a specific artichoke leaf extract (Hepar-SL forte, Serturner Arzneimittel GmbH) 640 mg three times daily for 6 weeks is associated with reductions in abdominal pain, cramping, bloating, flatulence, and constipation when compared to baseline (2562). Also, a small clinical study in patients with IBS shows that taking a different specific artichoke leaf extract (Cynara SL, Lichtwer Pharma) 320-640 mg daily for 2 months reduces the incidence of IBS symptoms in patients with dyspepsia by about 26% when compared to baseline. Patients taking this extract also had improved quality of life (15204). The validity of these findings is limited by the lack of a control group.
• Metabolic syndrome. It is unclear if oral artichoke leaf extract is beneficial in patients with metabolic syndrome. Details: A small clinical trial in patients with metabolic syndrome shows that taking artichoke leaf extract 1800 mg daily for 12 weeks does not improve fasting blood glucose, insulin resistance, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or blood pressure when compared with placebo. However, taking artichoke extract does reduce triglycerides by around 27 mg/dL when compared with placebo (100935).
• Nausea and vomiting. Although there has been interest in using oral artichoke for nausea and vomiting, there is insufficient reliable information about the clinical effects of artichoke for this purpose.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral artichoke leaf extract is beneficial in patients with NAFLD. Details: Meta-analyses of 12 clinical studies in adults with a variety of metabolic disorders, including NAFLD, show that taking artichoke 50-2700 mg daily for 4-24 weeks reduces alanine aminotransferase (ALT) and aspartate aminotransferase (AST) when compared with placebo (111560,111563). These effects are greater for ALT in trials lasting 8 weeks or longer and for AST at doses over 500 mg daily (111563). The validity of these findings is limited by significant heterogeneity among the included studies. A small clinical trial in patients with NAFLD shows that taking a specific artichoke leaf extract (Cynarol, Niak Pharmaceuticals), standardized to contain cynarin 2%, as 200 mg three times daily for 2 months improves NAFLD severity, reduces liver size, and increases hepatic vein flow when compared with placebo. The severity of NAFLD improved in 82% of patients taking artichoke, compared with 5% taking placebo. NAFLD severity did not worsen in any patients taking artichoke, compared with 27.5% of those taking placebo. Serum levels of liver transaminases, total bilirubin, and lipids were also improved with artichoke when compared with placebo (100934). However, the validity of these findings is limited by inappropriate randomization, the use of a per-protocol analysis, and significant differences between groups at baseline. Artichoke leaf extract has also been evaluated in combination with conventional therapies. A clinical trial shows that taking metformin 500 mg twice daily and/or vitamin E 400 IU once daily along with a specific artichoke leaf extract (Tishoke; Goldaru Company) 400 mg twice daily, providing 40 mg chlorogenic acid daily, for 12 weeks improves NAFLD severity and reduces liver size when compared with baseline. However, these improvements were similar to those seen in patients taking metformin with vitamin E. After 12 weeks, the number of patients with no fat accumulation (steatosis grade 0) increased by 23% in the artichoke and metformin group, 17% in the artichoke and vitamin E group, and 10% in the metformin and vitamin E group (108714)
• Obesity. A meta-analysis of several small clinical studies suggests that oral artichoke extract may slightly reduce waist circumference, but not body weight or body mass index (BMI), in patients who are overweight or obese. Details: A meta-analysis of 10 small clinical trials shows that taking artichoke leaf extract, powder, or juice for 8-12 weeks reduces waist circumference by 1.11 cm, but does not improve body weight or BMI, when compared with placebo (105766). The generalizability of these findings to patients who are overweight or obese is limited by the fact that only 3 of the 10 trials specifically enrolled patients because they were overweight. Other studies evaluated patients with liver disease, metabolic syndrome, diabetes, hyperlipidemia, or hypertension. In contrast, a post-hoc analysis of clinical research in adults with overweight shows that taking an artichoke leaf supplement (Altilix, Bionap S.r.l.) 150 mg daily for 6 months reduces body weight by around 2.3 kg but does not improve waist circumference when compared with placebo (111564).
• Osteoarthritis. Although there has been interest in using oral artichoke for osteoarthritis, there is insufficient reliable information about the clinical effects of artichoke for this purpose. More evidence is needed to rate artichoke for these uses.

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POSSIBLY EFFECTIVE

• Diabetes. Oral milk thistle extracts of silymarin seem to improve glycemic control in patients with diabetes. 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). Additionally, a meta-analysis of 22 clinical studies in healthy adults and adults with diabetes or other medical conditions shows that taking milk thistle reduces fasting blood glucose by around 22 mg/dL, reduces glycated hemoglobin by 0.85%, and reduces fasting insulin by 3.8 mU/mL when compared with placebo or control (113987). 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 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 suggests 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 is associated with moderate improvements in 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. Topical milk thistle has also been evaluated in combination with other ingredients. A small open-label study conducted in Korea 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). A similar open-label study conducted in Brazil in adults with acne shows that applying a serum with this same combination and concentration of ingredients once daily for 12 weeks improves investigator's global assessment of acne severity, global lesion count, inflammatory and non-inflammatory lesions, post-inflammatory hyperpigmentation, skin clarity, skin tone evenness, and overall skin appearance and reduces skin surface oil when compared to baseline. Additionally, an open-label study conducted in the US and Germany in adults with acne shows that applying this same serum daily for 4 weeks in addition to prescription topical acne medications reduces investigator-assessed erythema, dryness, and scaling when compared to baseline (113985). In the aforementioned studies, it is unclear if these effects are due to milk thistle, other ingredients, or the combination. The validity of the studies is also limited by the lack of a comparator group.
• 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. It is unclear if oral milk thistle is beneficial in patients with Alzheimer disease. Details: A small, single-blind clinical study in patients with Alzheimer disease shows that taking milk thistle 450 mg daily for 3 months improves scores on the Mini Mental State Exam when compared with placebo (113978). Other 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).
• Chemotherapy-induced peripheral neuropathy. It is unclear if oral milk thistle is beneficial for chemotherapy-induced peripheral neuropathy. Details: A small clinical study in adults with cancer receiving cisplatin chemotherapy shows that taking a specific product (Livergol, Goldaru) containing milk thistle 140 mg three times daily for 3 months improves overall symptoms of chemotherapy-induced peripheral neuropathy when compared to baseline, but not when compared with placebo, with the possible exception of hyposthesia to touch and pins and needles sensation which had worsened only in the placebo group (113979).
• 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). An observational study in adults with hepatitis B virus-related liver cirrhosis suggests that taking milk thistle 150 mg 2-3 times daily for at least 30 days in combination with anti-viral therapy is associated with lower mortality and liver transplantation rates at 1- and 2-year follow up and greater improvement in international normalized ratio, model for end-stage liver disease score, and the Charlson comorbidity index at 1-year follow-up when compared with anti-viral therapy alone (113986).
• 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).
• Gambling disorder. It is unclear if oral milk thistle is beneficial for gambling disorder. Details: A small clinical study in adults with gambling disorder shows that taking milk thistle 150 mg twice daily for 2 weeks and then 300 mg daily for the next 6 weeks does not improve symptoms associated with gambling disorder, including gambling urges, thoughts, and behaviors, or improve symptoms of anxiety and depression when compared with placebo (113974). The interpretation of these results is limited by the small sample size and a strong placebo effect.
• 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 dysfunction-associated steatotic liver disease (MASLD). It is unclear if oral milk thistle is beneficial for MASLD. Details: A moderate-sized, open-label, non-controlled study in patients with MASLD shows that taking milk thistle standardized to silymarin 150 mg twice daily for 6 months does not improve liver stiffness or liver enzymes when compared with essential phospholipids. It is unclear if any changes in these outcomes are statistically significant when compared to baseline (114462). The validity of these findings is limited by the lack of a placebo group, lack of reporting of changes to diet and exercise, unclear statistical analysis and reporting, and the use of a per protocol analysis instead of intention-to-treat analysis. Also review milk thistle's effectiveness in nonalcoholic fatty liver disease (NAFLD), a similar condition.
• 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: Four meta-analyses of up to 23 mostly 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 7-13 IU/L and alanine aminotransferase (ALT) by 9-17 IU/L when compared with control (97622,105051,113976,113982). 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). Metabolic indices have also been evaluated. A meta-analysis of up to 20 mostly small clinical studies in patients with NAFLD shows that taking milk thistle for up to 48 weeks slightly improves serum lipids when compared with control (113976). A small clinical study 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). A meta-analysis of 7 small clinical trials also shows there is little to no change in BMI associated with silymarin use in these patients (113976). 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), though a meta-analysis of 2 small clinical studies in patients with NAFLD shows that taking milk thistle for 12-24 weeks does reduce FLI when compared with control (113976). Also review milk thistle's effectiveness in metabolic dysfunction-associated steatotic liver disease (MASLD), a similar condition.
• 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). Pooling 1 of these clinical studies (96107) into a meta-analysis with another clinical trial that evaluated milk thistle in combination with phosphatidylcholine and vitamin E suggests an improvement in fibrosis by at least one stage when compared with placebo (113984). However, it is unclear if this effect is due to milk thistle, other ingredients, or the combination. Metabolic indices have also been evaluated. A meta-analysis of small clinical studies in patients with NASH or nonalcoholic fatty liver disease (NAFLD) shows that taking milk thistle reduces aspartate aminotransferase (AST) by about 13 IU/L, alanine aminotransferase (ALT) by about 17 IU/L, serum triglycerides by about 23 mg/dL and increases high-density lipoprotein cholesterol by about 2 mg/dL, but does not alter gamma-glutamyl transferase, total cholesterol, low-density lipoprotein cholesterol, body mass index, or insulin resistance when compared with control (113982). However, trials on NAFLD and NASH were not analyzed separately which limits the generalizability of these findings to patients with NASH specifically. The dose and duration of milk thistle treatment was also not described.
• Obesity. It is unclear if oral milk thistle is beneficial in patients with obesity. Details: A meta-analysis of 11 clinical studies in healthy adults and adults with various medical conditions shows that taking milk thistle does not reduce body weight or body mass index when compared with placebo or control (113987). A very small open-label study in adult females with obesity suggests that taking a specific milk thistle extract product (Neocholal-S, Italmex) 151.5 mg, containing silybin 45 mg, twice daily for 12 weeks does not reduce body weight but may reduce fasting blood glucose levels and insulin resistance when compared to baseline (113980). The validity of this study is limited by the lack of a comparator group and very small sample size.
• 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). Additionally, meta-analysis pooling this study (63239) with one other small clinical study also shows that applying a cream or gel containing milk thistle extract reduces the incidence radiation dermatitis when compared with control (113674).
• 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.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Artichoke has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Artichoke extract has been used with apparent safety at doses up to 3200 mg daily for up to 12 weeks (6282,15204,52235,91475,91478,100934). Artichoke leaf powder has been used with apparent safety at a dose of 1000 mg daily for up to 8 weeks (104133). Cynarin, a constituent in artichoke extract, has been used with apparent safety at daily doses of 750 mg daily for up to 3 months or 60 mg daily for up to 7 months (1423,1424,52222,52223,52236).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of artichoke when used in medicinal amounts during pregnancy or lactation; avoid amounts greater than those found in foods.

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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 (95021,95029,102851,102852,105793,105794,105795,113979). 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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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, artichoke leaf extract may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details A meta-analysis of small clinical studies shows that taking artichoke leaf extract for 8-12 weeks can modestly reduce fasting plasma glucose when compared with placebo (105768).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, artichoke leaf extract may increase the risk of hypotension when taken with antihypertensive drugs.  Details A meta-analysis of small clinical studies in patients with hypertension shows that taking artichoke can reduce systolic blood pressure by around 3 mmHg and diastolic blood pressure by around 2 mmHg when compared with placebo (105767).

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, artichoke might increase serum levels of drugs metabolized by CYP2B6.  Details In vitro research shows that artichoke leaf extract inhibits CYP2B6 activity (97717). However, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, artichoke might increase serum levels of drugs metabolized by CYP2C19.  Details In vitro research shows that artichoke leaf extract inhibits CYP2C19 activity (97717). However, this interaction has not been reported in humans.

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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 (15102,63190,63314,63318,95019,96140,96141,97624,97626,113987).

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). Additionally, 3 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are CYP2C9 substrates, including imatinib and capecitabine (111644). 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). However, 8 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are CYP3A4 substrates, including gefitinib, sorafenib, doxorubicin, and vincristine (111644).

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, and animal research shows this increases the maximum plasma concentration of pitavastatin and pravastatin (113975). 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.

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Milk thistle may inhibit one form of OATP, OATP-B1, which could reduce the bioavailability and clinical effects of OATP-B1 substrates.  Details In vitro research shows that milk thistle inhibits OATP-B1. Two case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are OATP substrates, including sorafenib and methotrexate (111644). OATPs are expressed in the small intestine and liver and are responsible for the uptake of drugs and other compounds into the body. Inhibition of OATP may reduce the bioavailability of oral drugs that are substrates of OATP.

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 In vitro research shows that milk thistle can inhibit P-glycoprotein activity (95019,111644) and 1 case report from the World Health Organization (WHO) adverse drug reaction database describes increased abdominal pain in a patient taking milk thistle and the cancer medication vincristine, a P-glycoprotein substrate, though this patient was also taking methotrexate (111644). However, 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 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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General ...Orally, artichoke extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, flatulence, hunger, and nausea.
Topically: Contact dermatitis in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis to artichoke inulin has been reported in individuals sensitive to inulin.
Topically: Chest tightness, cough, and dyspnea after occupational exposure in sensitive individuals.

Dermatologic ...Artichoke can cause an allergic reaction in some patients. Patients sensitive to the Asteraceae/Compositae family may be at the greatest risk. Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs. Topically, allergic contact dermatitis can occur with the use of artichoke. This has been attributed to the constituent cynaropicrin (11,52206,52226,52230). Redness in the face (11774) and sweating (91475) have been reported rarely following oral use of artichoke extract.
Occupational or airborne exposure to artichoke may also cause allergic reactions. In one case, a 52-year-old male presented with severe spongiotic dermatitis in exposed areas that was recurrent over the past 8 years. A patch test confirmed allergies to artichokes and sesquiterpene lactones, a group of allergens from the Compositae family, and the patient confirmed occupational and airborne exposure to artichokes during the time of his symptoms. The patient improved considerably after treatment with dupilumab (111565).

Gastrointestinal ...Orally, artichoke extract might increase abdominal discomfort, flatulence, diarrhea, hunger, and nausea in some patients (2562,52238,91475). Abdominal pain and a bitter taste in the mouth were reported by a single person following oral use of a dietary supplement containing artichoke extract, as well as red yeast rice, pine bark extract, and garlic extract (89452). It is not clear if this adverse effect was due to artichoke, other ingredients, or the combination.
In one case report, the autopsy of an 84-year-old female revealed a colonic bezoar comprised of artichoke fiber and fragments. This bezoar caused complete intestinal obstruction, leading to fatal acute peritonitis. Although rare, patients who lack adequate teeth and/or who have a history of gastric surgery are at increased risk for fibrous bezoar formation (97716).

Pulmonary/Respiratory ...Following occupational exposure, allergic symptoms including dyspnea, cough, chest tightness, and asthma symptoms or exacerbation have been reported. The effects were attributed to sensitization to artichoke. Subsequent nasal challenge with artichoke extract caused reduced nasal patency in these patients (52210,52230).
Orally, severe anaphylactic shock in response to artichoke inulin as an ingredient in commercially available products has been reported (52217). Individuals with a noted sensitivity to artichokes should consume inulin with caution. While rare, individuals with a known inulin allergy should avoid artichoke and artichoke extract.

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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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