HepaFem by Vitanica

POSSIBLY EFFECTIVE

• Athletic performance. Oral beet may improve athletic performance associated with aerobic activities. However, it is not clear who is most likely to benefit, for which type of competition it is most useful, or what dose or duration of use is most appropriate. Details: Several small clinical trials, most of which enrolled elite athletes, recreational athletes, and sedentary males, as well as meta-analyses of some of these and other studies, show that beet improves various measures of athletic performance, including ability, muscular endurance, power output, sprinting, and strength (93844,94464,94468,94469,100143,100150,100152,105761,113422). Clinical research also shows that drinking beetroot juice improves the use of oxygen during exercise testing in recreationally-trained athletes, especially with severe exercise testing (94460,94463,94467,100147,105762). Also, in obese adolescents, taking beetroot juice daily for 6 days increases the time to exhaustion from severe exercise, but does not improve moderate exercise (100145). Not all research shows that beet supplementation benefits athletic performance. Another meta-analysis of several small clinical studies, including some of the studies above, shows that taking beetroot does not improve performance in high-intensity or sprint interval training (111159). Additionally, the majority of research in elite athletes does not support the use of beetroot juice to decrease the time needed to complete a task, aid in some sort of graded exercise test, or improve the use of oxygen during exercise testing (94455,94458,94460,94461,94464,94465,94466,94469,94473,100142,100153,105763). The supposed lack of effect of beetroot juice in elite athletes might be related to the natural production of nitrates and nitrites in the body or the increased ability to use oxygen that comes from extensive training (94458,94463). Alternatively, any changes might be very small (<1%) and not identified with statistical comparisons, although even very small changes might be beneficial in competition (94464). The most commonly used doses in all studies, regardless of effect, have included an acute dose of beetroot juice 70-500 mL up to 3 hours prior to exercise (93844,94463,94464,94466,94467,94473,97726,100142,100143,105761)(105762,111159,113422) or chronic dosing of up to 500 mL daily for 3-6 days (94459,94464,94469,100145,100147,100153,111159,113422). Less commonly, beetroot juice 70-140 mL daily, betalain-rich concentrate 100 mg daily, or a beetroot-based nutritional gel 100 grams daily, have been taken for longer dosing schedules of 7-15 days (97720,100144,100148,100152,105763,113422). Benefits in elite athletes, most often related to time trials, are usually limited to studies using chronic dosing of 7-15 days, which is longer than the duration of 6 days used in the majority of studies (94473,97720,100144,100148). Brands of juice used in clinical trials have included Beet It Sport (James White Drinks Ltd.) (94455,94458,94465,100142,100143,100144,100148,105761,105763), Beet It Stamina Shot (James White Drinks Ltd.) (93844), Beet It (James White Drinks Ltd) (94457,94459,94460,94467,94469,97726,100145,100153,105762,111159), and Love Beets Beetroot Juice (Gs Fresh Ltd.) (94461,94462). Although plasma levels have not been analyzed in all studies, the majority of studies suggest that these doses are adequate to increase levels of nitrates or nitrites, which is thought to be essential for increasing athletic potential (93844,94455,94458,94459,94460,94465,94467,94469,94466,94473,97726). The evidence also suggests benefit in both normoxic and hypoxic environments (94465,100148,105763).
• Exercise-induced muscle soreness. Drinking beetroot juice 7-8 times over 48 hours after strenuous exercise may reduce exercise-induced muscle soreness, but evidence is conflicting. Details: Some clinical research shows drinking beetroot juice (Love Beets Beetroot Juice, Gs Fresh Ltd.) 125 mL or 250 mL seven times over 48 hours after strenuous box jumps improves muscle soreness when compared with placebo and sodium nitrite (96964,97722). Other small clinical studies show that drinking beetroot juice 50-250 mL as eight separate doses over 48 hours after strenuous exerciseimproves muscle soreness and reduces tissue edema when compared with placebo (94461,113424). However, drinking beetroot juice 250 mL as seven separate doses over 48 hours after running a marathon does not appear to reduce muscle soreness when compared with placebo (94462). A meta-analysis of 4 small studies, mostly in healthy or physically active males, shows that drinking beetroot juice improves the pressure pain threshold, which is a measure of muscle soreness, at 48- and 72-hours post-exercise when compared with a fruit-flavored drink. However, beetroot juice does not improve subjective muscle soreness scores (111160). The validity of the findings from this meta-analysis is limited by the heterogeneity of the beetroot juice regimens among the included studies. Further, these results should not be generalized to elite athletes.

POSSIBLY INEFFECTIVE

• Chronic obstructive pulmonary disease (COPD). Drinking beetroot juice for up to 14 days may not improve exercise capacity in patients with COPD. Details: A meta-analysis of eight small clinical trials in patients with COPD shows that taking nitrate-rich beetroot juice does not improve most measures of exercise capacity, including the 6-minute walk test, cycling ergometry endurance time, and maximum rate of oxygen consumption (VO2 max), when compared with placebo. Additionally, beetroot juice did not reduce blood pressure or heart rate. However, the analysis did show a significant improvement in scores on the Borg Rating of Perceived Exhaustion scale with beetroot juice over placebo. Nitrate-rich beetroot juice doses ranged from 70-140 mL daily for up to 14 days (104200).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cognitive function. It is unclear if drinking beetroot juice is beneficial for cognitive function. Details: A small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days improves the time to complete part B of the trail making test, which is a test of cognitive function, but not part A, when compared with controls (111158). However, the duration and size of this study limits its validity. Further, it is unclear whether any improvement is clinically significant. The effect of acute beet administration on cognitive function has also been studied. A very small clinical study in healthy adults shows that taking beet extract (RedNite, Enovate Biolife) chewable tablets 3 grams 90 minutes prior to neuropsychological testing improves immediate and delayed memory capacity, frontal lobe function, and lexical flexibility but does not improve working memory, information processing speed, or subjective reports of memory performance when compared with placebo (113427).
• Coronary heart disease (CHD). It is unclear if oral beetroot extract is beneficial in patients with CHD. Details: A small clinical trial in patients with CHD shows that taking red beetroot extract 500 mg, containing around 25 mg betalains, twice daily for 2 weeks reduces total cholesterol and low-density lipoprotein (LDL) cholesterol by 15 mg/dL and reduces triglycerides by 8 mg/dL when compared to baseline. Slight improvements in blood pressure and blood glucose were also reported, but these changes were not clinically significant (103883). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear whether beetroot can reduce the risk of cardiovascular events in patients with CHD.
• Dyslipidemia. It is unclear if oral beetroot is beneficial in patients with dyslipidemia. Details: A meta-analysis of small clinical studies in healthy individuals or patients with dyslipidemia, cardiovascular disease, or overweight or obesity, shows that consuming beetroot juice or leaves does not improve levels of triglycerides or total, low-density lipoprotein, or high-density lipoprotein cholesterol when compared with controls (111163). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the enrolled patients and beetroot regimens.
• Exercise-induced muscle damage. It is unclear if oral beetroot juice improves recovery from muscle damage after exercise. Details: A meta-analysis of 4 small clinical studies in healthy or physically active individuals, most of which enrolled males only, shows that drinking beetroot juice improves measures of muscle recovery at 72 hours post-exercise when compared with a fruit-flavored drink. However, beetroot juice does not consistently improve recovery at earlier time points post-exercise, nor does it reduce levels of creatine kinase or markers of inflammation (i.e., interleukin-6, interleukin-8, c-reactive protein, or tumor necrosis factor-alpha) (111160). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the beetroot juice regimens among the included studies, which usually varied from 210-250 mg of nitrate in 7-11 servings over 3-7 days. Further, these results should not be generalized to elite athletes. Another very small clinical study in semi-professional female athletes shows that ingesting beetroot juice 50 mL 8 times over 48 hours after exercise-induced muscle damage enhances the recovery of some functional parameters such as muscle endurance but not others such as flexibility and vertical jump performance when compared with placebo (113424).
• Hypertension. Oral beet may slightly reduce blood pressure in healthy individuals, but it is unclear if it is beneficial in patients with hypertension. Details: Meta-analyses of small studies show the potential for a minor reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in healthy adults taking beetroot juice (94470,97718,97728). The average reduction in SBP and DBP with beetroot juice consumption is about 4 mmHg and 1 mmHg, respectively, which is greater than the effect seen with consuming blackcurrant juice or nitrate-depleted beetroot juice. The most benefit is seen when beetroot juice is taken for at least 2 weeks or at doses of 500 mL daily (97728). The effect of acute beet supplementation on blood pressure is conflicting. A small clinical study in healthy adults shows that drinking beet juice (Beet It, James White Company) 140 mL two hours prior to cardiovascular measurements reduces resting SBP by about 4 mmHg but does not improve resting or post-exercise DBP, central blood pressure, or arterial stiffness nor does it improve post-exercise SBP when compared with placebo. Subgroup analysis suggests that the reductions in resting SBP were only observed in males, not females (113423). Another small clinical study shows that consuming beet 100 grams baked into bread modestly decreases DBP over a 6-hour period when compared with white bread (97725). It is possible that genetics might play a role in the magnitude of effect seen with beetroot consumption. Adults with a specific gene polymorphism, eNOS Glu298Asp, experienced a greater reduction in DBP after consuming beet-containing bread (97724). Despite positive findings in studies of healthy individuals, research on the use of beetroot juice in patients with hypertension is unclear. A small clinical study in adults with hypertension who were taking antihypertensive medications shows that drinking nitrate-rich beetroot juice (Beet it; James White Drinks Ltd.) 70 mL twice daily for one week does not lower blood pressure when compared with nitrate-depleted beetroot juice (94457). Also, in patients with mild to moderate hypertension, clinical research shows that taking a combination of beetroot powder (Sensient) 300 mg, olive leaf extract 1000 mg, and green coffee bean extract 200 mg daily for 6 weeks does not lower blood pressure when compared with placebo (97723). However, some evidence suggests that at least part of the blood pressure lowering effects of beet might be independent of nitrate (97728). Furthermore, some research suggests that identifying effects on blood pressure might be dependent on the method of measurement, including clinic resting measurements, 24-hour monitoring, or morning/evening home resting measurements (97729).
• Hypertriglyceridemia. It is unclear if oral beet is beneficial in patients with hypertriglyceridemia. Details: A small clinical study in overweight or obese individuals with dyslipidemia shows that taking freeze-dried beet leaf 2.8 grams daily for 4 weeks in addition to nutritional guidance does not lower triglyceride levels when compared with nutritional guidance alone (100146). Beet has also been evaluated in combination with other ingredients. A small clinical trial in patients at risk for heart disease shows that a specific combination of beet and hawthorn berry (Neo40-Daily, Neogenis Labs), taken twice daily for 30 days, can modestly reduce blood triglyceride levels when compared to baseline (18222). It is unclear if these findings are due to beet, hawthorn berry, or the combination.
• Liver disease. Although there has been interest in using oral beet for liver disease, there is insufficient reliable information about the clinical effects of beet for this purpose.
• Muscle strength. It is unclear if oral beetroot juice is beneficial for muscle strength. Details: A meta-analysis of 18 clinical studies in healthy males shows that taking beetroot juice or beetroot gel 2-3 hours before exercise improves muscular strength when compared with placebo. Subgroup analysis suggests that beetroot-based supplements improve muscular strength in a fatigued but not resting state (113422). A small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days improves handgrip strength by approximately 18% compared with 4% in controls (111158). However, it is unclear whether any improvement is clinically significant.
• Obesity. It is unclear if oral beet leaf or beetroot juice is beneficial for weight loss. Details: A small clinical study in patients with overweight or obesity and dyslipidemia shows that taking freeze-dried beet leaf 2.8 grams daily for 4 weeks in addition to nutritional guidance does not reduce body weight or body mass index (BMI) when compared with nutritional guidance alone (100146). Similarly, a small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days does not improve weight loss when compared with controls (111158). However, the size and duration of this study may have been inadequate to detect differences between groups.
• Pregnancy-induced hypertension. It is unclear if oral beetroot juice is beneficial in patients with pregnancy-induced hypertension. Details: A small clinical trial in pregnant patients with hypertension who are at approximately 22-35 weeks gestation shows that taking beetroot juice (James White Drinks Ltd) 70 mL daily for 8 days does not reduce blood pressure when compared with a nitrate-depleted beetroot juice (100151). However, the study was small and designed to investigate the feasibility of using beetroot juice in this population.
• Pulmonary hypertension. It is unclear if oral beetroot juice is beneficial in patients with pulmonary hypertension. Details: A small clinical study shows that taking beetroot juice (Beet-It Sport; James White Drinks Ltd) 70 mL twice daily for 7 days does not improve right ventricular systolic function when compared with nitrate-depleted beetroot juice in patients with pulmonary hypertension (100149). However, this study was small and not adequately powered to detect differences between groups.
• Raynaud syndrome. It is unclear if oral beetroot juice is beneficial in patients with Raynaud syndrome. Details: A small clinical study in patients with Raynaud syndrome undergoing cold sensitivity tests shows that drinking beetroot juice (Beet-It, James White Drinks Ltd) 70 mL daily for 13 days, followed by 140 mL prior to testing, does not reduce pain in the hands or feet, but might improve thermal comfort in the feet, when compared to baseline (103884). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate beet for these uses.

(Read more about BEET)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using topical burdock for acne, there is insufficient reliable information about the clinical effects of burdock for this purpose.
• Aging skin. It is unclear if topical burdock is beneficial for reducing wrinkles. Details: A very small study in females aged 39-65 years shows that applying an emulsion containing burdock fruit extract 1.2% to the face twice daily for 4 weeks slightly reduces skin wrinkles around the eyes when compared with placebo (37420).
• Atopic dermatitis (eczema). Although there is interest in using topical burdock for eczema, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Breast cancer. Oral burdock root has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Population research in breast cancer patients has found that using a specific product containing burdock root, sheep sorrel, slippery elm bark, and Indian rhubarb (Essiac, Resperin Canada Limited) is not associated with improved quality of life when compared with no intervention (37419).
• Common cold. Although there is interest in using oral burdock for symptoms of the common cold, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Diabetes. Although there is interest in using oral burdock for diabetes, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Diverticulitis. It is unclear if oral burdock is beneficial in patients with diverticulitis. Details: A small open-label clinical study in patients with colonic diverticulitis shows that taking burdock tea (Ajikan, Co., Ltd.) providing 1.5 grams three times daily for a median of 26 months is associated with an acute diverticulitis recurrence rate of 11%, compared with 32% of those not taking burdock tea. Furthermore, the recurrence-free duration was increased by about 14 months. However, taking burdock tea for a median of 16 months does not prevent colonic diverticular bleeding recurrence (102696).
• Dry skin. Although there is interest in using topical burdock for dry skin, there is insufficient reliable information about the clinical effects of burdock for this purpose.
• Gout. Although there is interest in using oral burdock for gout, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Hepatitis. Although there is interest in using oral burdock for hepatitis, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Metabolic syndrome. It is unclear if oral burdock is beneficial in patients with metabolic syndrome. Details: A very small clinical study in patients with metabolic syndrome shows that drinking burdock extract 100 mL three times daily after meals for 16 weeks does not reduce body weight, abdominal fat, blood pressure, lipid levels, or glucose when compared with baseline or control (105667).
• Obesity. Although there is interest in using oral burdock for obesity, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Urinary tract infections (UTIs). Although there is interest in using oral burdock for UTI, there is insufficient reliable information about the clinical effects of burdock for this condition.
• Vaginitis. Topical burdock has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in adults and children with vaginitis has found that applying a specific solution containing burdock, chamomile, and aloe (Zelesse, ITF Research Pharma S.L.U., Alcobendas) to the vaginal area once or twice daily for 5-20 days is associated with moderate improvements in symptoms such as pruritus, erythema, and discharge when compared with baseline (102695,102697). The validity of this finding is limited by its observational nature and the lack of a control group. More evidence is needed to rate burdock for these uses.

(Read more about BURDOCK)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Constipation. Although there has been interest in using oral dandelion for constipation, there is insufficient reliable information about the clinical effects of dandelion for this purpose.
• Dyspepsia. Although there has been interest in using oral dandelion for dyspepsia, there is insufficient reliable information about the clinical effects of dandelion for this purpose.
• Flatulence. Although there has been interest in using oral dandelion for flatulence, there is insufficient reliable information about the clinical effects of dandelion for this purpose.
• Heart failure. Although there has been interest in using oral dandelion for its diuretic effects in patients with heart failure, there is insufficient reliable information about the clinical effects of dandelion for this purpose.
• Joint pain. Although there has been interest in using oral or topical dandelion for joint pain, there is insufficient reliable information about the clinical effects of dandelion for this purpose.
• Postoperative pain. It is unclear if topical dandelion is beneficial in patients with pain after jaw surgery. Details: A small clinical study in patients undergoing maxillofacial surgery shows that topical application of dandelion combined with borneol one time on the day of surgery and twice daily on the first and second days after surgery for 30 minutes does not reduce maxillofacial pain when compared with cold compresses or either ingredient alone (112484). The validity of this finding is limited by concurrent use of opioid analgesic and nonsteroidal anti-inflammatory medications.
• Postoperative swelling. It is unclear if topical dandelion is beneficial in patients with swelling after jaw surgery. Details: A small clinical study in patients who underwent maxillofacial surgery shows that topical application of dandelion combined with borneol one time on the day of surgery and twice daily on the first and second days after surgery for 30 minutes modestly reduces facial swelling and improves mouth opening abilities when compared with cold compresses or borneol alone (112484). It is unclear whether this effect is due to dandelion, borneol, or the combination.
• Tonsillitis. It is unclear if oral dandelion is beneficial in patients with tonsillitis. Details: One small clinical study in patients with acute purulent tonsillitis shows that eating soup containing dandelion (pugongying soup) daily for 3 days along with benzylpenicillin sodium 640,000 units daily improves recovery when compared with placebo plus benzylpenicillin sodium. Recovery rates were 36% with the dandelion-containing soup compared to 10% with placebo (18292).
• Urinary tract infections (UTIs). Oral dandelion has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with recurrent UTIs shows that taking a specific combination of dandelion root and uva ursi leaf extracts three times daily for 1 month reduces the risk of UTI recurrence when compared with placebo at 12-month's follow-up. For every 5 patients treated with this combination over placebo, one additional UTI was prevented (1932). In this combination, uva ursi is used for its antibacterial properties and dandelion is used to increase urination. However, this combination is not recommended for extended use because uva ursi may be unsafe when used long-term. Another small clinical study in premenopausal females with acute, uncomplicated lower UTIs shows that taking a combination product containing dandelion extract 50 mg, D-mannose, prebiotics, arabinogalactan, and astragalus root extract twice daily for five days, along with phenazopyridine and alkylating agents as conventional therapy, improves UTI symptoms and bacteriuria when compared with placebo plus conventional therapy (111757). It is unclear if these effects are due to dandelion, other ingredients, or the combination. More evidence is needed to rate dandelion for these uses.

(Read more about DANDELION)

There is insufficient reliable information available about the effectiveness of fringetree.

(Read more about FRINGETREE)

POSSIBLY EFFECTIVE

• Dyspepsia. A specific combination product containing greater celandine (Iberogast, Medical Futures, Inc) seems to improve symptoms of dyspepsia. The combination includes greater celandine plus peppermint leaf, German chamomile, caraway, licorice, clown's mustard plant, lemon balm, angelica, and milk thistle (7049,12724). A meta-analysis of studies using this combination product suggests that taking 1 mL orally three times daily over a period of 4-weeks significantly reduces severity of acid reflux, epigastric pain, cramping, nausea and vomiting compared to placebo (13089).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Preliminary clinical research suggests that injecting a specific semi-synthetic derivative of the greater celandine constituent chelidonine (Ukrain; not available in North America) intravenously helps improve survival of some patients with colorectal, bladder, pancreatic, lung, or breast cancer. However, poor study design makes it difficult to draw conclusions about the efficacy of Ukrain for cancer (13409,53460,53472,53473,53497,53498). Also, some researchers suggest that doses sufficiently high to shrink tumors might be too toxic for clinical use (13412). In addition to assessing Ukrain, some research has assessed the effects of a greater celandine decoction in cancer patients. Some preliminary clinical research suggests that taking 30 mL of an oral solution containing greater celandine twice daily for 2 weeks might have antitumor effects in patients with esophageal squamous cell carcinoma. Each dose of solution was equivalent to 30 grams of rough herbs (53512). More evidence is needed to rate greater celandine for these uses.

(Read more about GREATER CELANDINE)

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.

(Read more about MILK THISTLE)

LIKELY SAFE ...when used in amounts commonly found in foods.

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes, short term. Beetroot juice has been safely used in clinical trials in doses of up to 500 mL daily for up to 7 days and a beetroot-based nutritional gel has been used safely in doses of up to 100 grams daily for 8 days (94461,94462,94464,100149,100152,100153).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of beets used medicinally during pregnancy and breast-feeding.

(Read more about BEET)

LIKELY SAFE ...when used in amounts commonly found in foods (12659,12660). Burdock root is commonly eaten as a vegetable (37422,92153,92154)

POSSIBLY SAFE ...when used topically, short-term. An emulsion containing burdock fruit extract 1.2% has been safely applied to the face twice daily for 4 weeks (37420). There is insufficient reliable information available about the safety of burdock when used orally in supplemental doses.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about BURDOCK)

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

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (12). There is insufficient reliable information available about the safety of dandelion when used topically.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using amounts greater than those in foods.

(Read more about DANDELION)

There is insufficient reliable information available about the safety of fringetree.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about FRINGETREE)

POSSIBLY UNSAFE ...when used orally. Greater celandine has been implicated in dozens of cases of liver damage, primarily in European countries including Germany (363,13410,16839,41412,53502,53504,53506,53507,53510). There is insufficient reliable information available about the safety of greater celandine when used topically or when derivatives of greater celandine constituents are used intravenously.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about GREATER CELANDINE)

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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CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, beet might decrease the levels and clinical effects of CYP1A2 substrates.  Details In vitro research suggests that beet induces CYP1A2 enzymes (111404).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, beet might increase the levels of CYP3A4 substrates.  Details In vitro research suggests that betanin, the major pigment in beet, competitively inhibits CYP3A4 in a dose-dependent manner similarly to strong CYP3A4 inhibitor ketoconazole (113425).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking burdock with anticoagulant or antiplatelet drugs might increase the risk of bleeding.  Details In vitro research shows that lignans from burdock reduce rabbit platelet aggregation by inhibiting platelet activating factor (12619). This interaction has not been reported in humans.

(Read more about BURDOCK)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking dandelion root along with anticoagulant or antiplatelet drugs might increase the risk of bruising and bleeding.  Details In vitro research suggests that dandelion root inhibits platelet aggregation (18291).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dandelion might increase the risk for hypoglycemia when used with antidiabetes drugs.  Details Laboratory research suggests that dandelion extract may have moderate alpha-glucosidase inhibitor activity and might also increase insulin secretion (13474,90926). Also, in a case report, a 58-year-old woman with type 2 diabetes who was being treated with insulin developed hypoglycemia 2 weeks after beginning to eat salads containing dandelion (46960).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dandelion might increase levels of drugs metabolized by CYP1A2.  Details Laboratory research suggests that dandelion might inhibit CYP1A2 (12734). So far, this interaction has not been reported in humans. However, until more is known, watch for an increase in the levels of drugs metabolized by CYP1A2 in patients taking dandelion.

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dandelion might increase the clearance of drugs that are UDP-glucuronosyltransferase substrates.  Details There is some preliminary evidence that dandelion might induce UDP-glucuronosyltransferase, a phase II enzyme (12734).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, through diuretic effects, dandelion might reduce excretion and increase levels of lithium.  Details Animal research suggests that dandelion has diuretic properties (13475). As diuretics can increase serum lithium levels, the dose of lithium might need to be decreased when taken with dandelion.

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dandelion might increase the risk of hyperkalemia when taken with potassium-sparing diuretics.  Details Dandelion contains significant amounts of potassium (13465).

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, dandelion might lower fluoroquinolone levels.  Details Animal research shows that dandelion reduces absorption of ciprofloxacin and can lower levels by 73% (13477). However, this effect has not been reported in humans.

(Read more about DANDELION)

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CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Research in vitro shows that chelidonine, a constituent of greater celandine, inhibits cytochrome P450 2D6 (CYP2D6) enzyme activity (99455). Theoretically, greater celandine might increase levels of drugs metabolized by CYP2D6.  Details Some drugs metabolized by CYP2D6 include amitriptyline (Elavil), clozapine (Clozaril), codeine, desipramine (Norpramin), donepezil (Aricept), fentanyl (Duragesic), flecainide (Tambocor), fluoxetine (Prozac), meperidine (Demerol), methadone (Dolophine), metoprolol (Lopressor, Toprol XL), olanzapine (Zyprexa), ondansetron (Zofran), tramadol (Ultram), trazodone (Desyrel), and many others.

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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).

(Read more about MILK THISTLE)

General ...Orally, beet seems to be well tolerated when used for medicinal purposes, short term.
Most Common Adverse Effects:
Orally: Red stools and red urine.
Serious Adverse Effects (Rare):
Orally: Hypocalcemia and kidney damage when ingested in large amounts.

Endocrine ...Theoretically, ingestion of large quantities of beets could lead to hypocalcemia because of the oxaluric acid content (18).

Gastrointestinal ...Orally, beet juice may cause red stools (94470,97726,100142,100145,105762). This red coloring of the stools is not harmful. Additionally, beet supplementation has been reported to cause black stools. In one case, a 79-year-old male on apixaban and clopidogrel presented with black stools, nausea, and vomiting after taking beet pills 2-3 days prior. The likelihood of upper gastrointestinal bleed was determined to be low based on factors such as normal vital signs and lack of severe anemia. The patient was diagnosed with beet-induced pseudo-hematochezia which was successfully treated with fluids and discontinuation of the beet supplement (113426).
Other less common gastrointestinal side effects include loose stools, constipation, and nausea (100149).

Genitourinary ...Orally, beet is known to produce red or pink urine (beeturia) in some people (32569,34134,94464,94470,97725,97726,100142,100145,100152,105762,113422). However, this red coloring of the urine is not harmful and dissipates after about 12 hours (113422).

Neurologic/CNS ...Orally, vivid dreams and worsening headaches have each occurred in one person in a clinical trial, although it is not clear if this is due to beet (97723).

Renal ...Theoretically, ingestion of large quantities of beets could lead to kidney damage due to its oxaluric acid content (18).

(Read more about BEET)

General ...Orally, burdock is well tolerated when consumed as a food. Although a thorough evaluation of safety outcomes is lacking, there has been long-standing historical use of burdock with few noted adverse effects.
Serious Adverse Effects (Rare):
All ROAs: Allergic reactions, including contact dermatitis and anaphylaxis.

Dermatologic ...Contact dermatitis has been reported secondary to burdock, especially after prolonged use of the root oil (37422). There are cases of allergic dermatitis secondary to using burdock plasters. Two males and a 14 year-old female developed erythematous and vesicular, pruritic, and exudative reactions in areas corresponding to the application of burdock root plasters (12667). Reactions occurred up to 7 days after initial use. Patch testing was positive for burdock sensitivity in all three patients and was nonreactive in matched controls.

Hematologic ...In one case report, a 38-year-old female developed immune-mediated thrombocytopenia after consuming a "cleansing" tea containing unknown amounts of burdock and yellow dock. The patient presented with bruising, mild weakness, and fatigue, which started 2-3 days after consuming the tea, and was found to have a platelet count of 5,000 per mcL. Symptoms resolved after platelet transfusion and treatment with oral dexamethasone (108971). It is unclear if these effects were caused by burdock, yellow dock, the combination, or other contributing factors.

Hepatic ...A case of idiosyncratic drug-induced liver disease (DILI) is reported in a 36-year-old female who presented with abdominal pain after 1 month of taking an herbal liver detox tea containing burdock and other ingredients. Remarkable laboratory values included elevated liver enzymes, alkaline phosphatase, and total bilirubin. The patient received a loading dose of N-acetylcysteine and was hospitalized for 12 days (112178). However, it is unclear if the adverse effect was due to burdock, other ingredients, or the combination.

Immunologic ...There is one case of anaphylactic shock secondary to eating boiled burdock. One hour after eating boiled burdock the patient presented with redness over the entire body and dyspnea. He was found to have low blood pressure and was treated with subcutaneous epinephrine 1 mg and intravenous lactated ringer's solution containing hydrocortisone 100 mg and dexamethasone 8 mg. The cause of anaphylactic shock was attributed to allergenicity to burdock based on positive skin prick test results. Previously, the patient had experienced urticaria after eating boiled burdock (12660).

Neurologic/CNS ...Anticholinergic reactions including dry mouth, dizziness, blurred vision, weakness, dilated pupils, inability to urinate, and bradycardia have been reported following the consumption of burdock products (12662,37421,37431,37434,37435). However, these anticholinergic reactions are believed result from contamination of burdock with belladonna alkaloids. Burdock itself does not contain atropine or other constituents that would be responsible for these reactions.

(Read more about BURDOCK)

General ...Orally, dandelion seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, heartburn, and stomach discomfort.
Topically: Dermatitis in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis in sensitive individuals.

Cardiovascular ...In one report, a 39-year-old obese woman developed palpitations and syncope after taking a weight loss supplement containing a combination of dandelion, bladderwrack, and boldo for 3 weeks. The patient was found to have prolonged QT-interval on ECG and frequent episodes of sustained polymorphic ventricular tachycardia (14321). It is not clear whether dandelion, another ingredient, or the combination of ingredients is responsible for this adverse effect. The product was not analyzed to determine the presence of any potential toxic contaminants.

Dermatologic ...Topically, dandelion can cause contact dermatitis and erythema multiforme in sensitive individuals. Dandelion can cause an allergic reaction in individuals sensitive to the Asteraceae/Compositae family (13478,13481,42893,46945,46977). Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.

Endocrine ...In one report, a 56-year-old man with renal impairment developed hyperoxalaemia and peripheral gangrene after ingesting large amounts of dandelion tea (10 to 15 cups daily for 6 months). The adverse effect was attributed to the high oxalate content of dandelion tea (258 mcmol/L) and reduced renal oxalate clearance caused by renal impairment (90639). In another report, a 58-year-old woman with type 2 diabetes who was being treated with insulin developed hypoglycemic symptoms 2 weeks after beginning to eat salads containing dandelion (46960). The hypoglycemic effect was attributed to the potential alpha-glucosidase inhibitory activity of dandelion.

Gastrointestinal ...Gastrointestinal symptoms, including stomach discomfort, diarrhea, and heartburn, have been reported following oral use of dandelion (19146,36931). A case of intestinal blockage has been reported for a patient who ingested a large amount of dandelion greens three weeks after undergoing a stomach operation (46981). Also, a case of hemorrhagic cystitis has been reported for a 33-year-old woman who took a specific herbal product (Slim-Kombu, Balestra and Mech, Vicenza, Italy) containing 20 herbal extracts, including dandelion extract. Symptoms resolved after the patient discontinued using the product, and symptoms resumed when the patient began taking the supplement again four months later. While various ingredients in the supplement may have contributed to the symptoms, it is possible that dandelion extract may have contributed to the effect due to its diuretic, laxative, cholagogue, and antirheumatic properties (46959).

Other ...Orally, products containing dandelion pollen can cause allergic reactions, including anaphylaxis (13479,13480). Also, rhinoconjunctivitis and asthma have been reported after handling products such as bird feed containing dandelion and other herbs, with reported positive skin tests for dandelion hypersensitivity (46948). Dandelion pollen may cause pollinosis, such as allergic rhinitis and conjunctivitis (18065,46951,46964,46966,46972).

(Read more about DANDELION)

General ...Orally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

(Read more about FRINGETREE)

General ...Orally, greater celandine has been implicated in dozens of cases of liver damage (363,13410,16839,41412,53502,53504,53506,53507,53510). Greater celandine can also cause rash (13410). Greater celandine extract has caused a single case of hemolytic anemia (53508).
Topically, greater celandine can cause contact dermatitis (13411).
Intravenously, a derivative of the greater celandine constituent chelidonine (Ukrain) can cause gastrointestinal symptoms, increased body temperature, general burning sensations, and bleeding (13409,53460).

Dermatologic ...Orally, greater celandine can cause rash (13410). Topically, greater celandine can cause contact dermatitis (13411).

Gastrointestinal ...Intravenously, a derivative of the greater celandine constituent chelidonine (Ukrain) can cause gastrointestinal symptoms, including obstipation, nausea, and diarrhea (13409,53460).

Hematologic ...Orally, greater celandine extract has caused a single case of hemolytic anemia. This resulted in thrombocytopenia, destruction of liver cells, and kidney failure, requiring treatment (53508).
Intravenously, a derivative of the greater celandine constituent chelidonine (Ukrain) can cause bleeding (13409,53460).

Hepatic ...Orally, greater celandine has been implicated in dozens of cases of liver damage (363,13410,16839,41412,53502,53504,53506,53507,53510). The cause is unknown, but appears to be idiopathic. It seems to be independent of dose, and the amount of time before development of liver disease is generally long and variable (363,53506). The main symptom is usually jaundice (53506). Liver enzymes are elevated at least two-fold in all cases where measurements were completed (53506). Although other causes of liver toxicity cannot be ruled out in some cases, many reported cases of hepatotoxicity are probably or likely associated with the use of greater celandine. Recurrence of hepatitis with unintentional re-exposure has also been reported (53506,94282). Discontinuation of greater celandine usually results in a fairly rapid recovery although liver enzymes need months to return to normal (53506,94282). Death has occurred in one patient with hepatitis due to bleeding associated with colonic diverticulitis. Causality was described as possible, not probable, in this case (53506).

Neurologic/CNS ...Intravenously, a derivative of the greater celandine constituent chelidonine (Ukrain) can cause increased body temperature and general burning sensations (13409).

(Read more about GREATER CELANDINE)

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).

(Read more about MILK THISTLE)