Para Guardian by BiOptimizers

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Coronary heart disease (CHD). It is unclear if consuming black walnut as part of the diet can reduce the risk for CHD. Details: Epidemiological research has found that people who increase dietary consumption of nuts in general might have a lower risk of CHD and death due to coronary events. However, there is no available evidence showing that eating black walnut, specifically, reduces the risk of CHD (8478,13299). Still, in 2004, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming 1.5 ounces of walnuts per day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of CHD. The FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102335).
• Wound healing. Although there is interest in using topical black walnut hull and bark for wound healing, there is insufficient reliable information about the clinical effects of black walnut for this purpose. More evidence is needed to rate the effectiveness of black walnut for these uses.

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POSSIBLY EFFECTIVE

• Ventilator-associated pneumonia (VAP). Clove mouthwash might reduce the risk of acquiring pneumonia in patients on mechanical ventilation. Details: A large clinical trial in adults in the intensive care unit on mechanical ventilation shows that administration of a clove extract 6.66% mouthwash, 15 mL twice daily for 5 days, results in a 2-fold lower incidence of ventilator-associated pneumonia when compared with chlorhexidine mouthwash (112151).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alveolar osteitis. Although there has been interest in using topical clove for alveolar osteitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Anal fissures. It is unclear if topical clove oil is beneficial in patients with anal fissures. Details: Preliminary clinical research in patients with chronic anal fissures shows that applying clove oil 1% cream for 6 weeks heals fissures in 60% of patients by the 3-month follow-up, compared with only 12% of patients who used topical lidocaine 5% cream and stool softeners (43487).
• Cough. Although there has been interest in using oral clove for cough, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dental plaque. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a specific toothpaste (Sudantha, Link Natural Products Ltd.) containing a combination of clove, Acacia chundra Willd., malabar nut, bullet wood tree, black pepper, Indian beech, gall oak, Terminalia, and ginger twice daily for 12 weeks can reduce dental plaque, bleeding, and bacteria counts in the mouth when compared with placebo (43570). Other clinical research shows that administration of a mouth rinse containing clove, tea tree oil, and basil 10 mL twice daily for 21 days is as effective as a commercially available mouth rinse containing thymol, eucalyptol, menthol, and methyl salicylate in reducing dental plaque and gum inflammation (92160). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Diarrhea. Although there has been interest in using oral clove for diarrhea, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dyspepsia. Although there has been interest in using oral clove for dyspepsia, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Flatulence. Although there has been interest in using oral clove for flatulence, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Gingivitis. Although there has been interest in using topical clove for gingivitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Halitosis. Although there has been interest in using oral clove for halitosis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Hangover. It is unclear if oral clove flower extract is beneficial for reducing hangover severity. Details: Preliminary clinical research in a very small number of healthy males with a history of hangovers shows that taking a clove flower bud polyphenol extract 250 mg prior to drinking brandy (42.8% alcohol) decreases hangover severity scores by around 55% when compared with placebo (100597).
• Hyperhidrosis. It is unclear if topical clove oil is beneficial in patients with hyperhidrosis. Details: Preliminary clinical research in patients with hyperhidrosis of the palms shows that topical application of clove oil 45% in liposome base twice daily for 2 weeks improves hyperhidrosis severity and decreases the rate of sweating by around 34% when compared with a saline control (100596). The validity of these findings is limited by a lack of subject randomization.
• Impaired glucose tolerance (prediabetes). It is unclear if oral clove flower extract is beneficial in patients with prediabetes. Details: Preliminary clinical research in a very small number of patients with prediabetes shows that taking a polyphenolic extract from clove flower buds 250 mg daily for 30 days decreases pre-prandial plasma glucose by 14 mg/dL and postprandial plasma glucose by 40 mg/dL when compared to baseline (100595). The validity of these findings is limited by the very small size of the study and the lack of a control group.
• Mosquito repellent. Small clinical studies suggest that topical clove oil may repel mosquitos for up to 4-5 hours. Details: Preliminary clinical research shows that topical application of undiluted clove oil can repel 100% of mosquitoes for up to 4 hours (43427). Other preliminary research shows that topical application of gel containing clove oil 20% can repel 86% to 97% of mosquitoes for 5 hours (43411).
• Nausea and vomiting. Although there has been interest in using oral clove for nausea and vomiting, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Oral mucositis. Although there has been interest in using topical clove for oral mucositis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Pain (acute). It is unclear if topical clove is beneficial in patients with acute pain. Details: Preliminary clinical research shows that topical application of a gel containing ground cloves, applied as 4 grams of gel for 5 minutes prior to dental anesthesia injection, can reduce needle stick pain when compared with placebo. The effect of the clove gel on pain seems to be comparable to benzocaine 20% gel (43448).
• Premature ejaculation. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that administration of a multi-ingredient cream preparation (SS Cream) containing clove flower, Panax ginseng root, Angelica root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, Asiasari root, cinnamon bark, and toad venom to the glans penis, one hour prior to intercourse and washed off immediately before intercourse, increases ejaculatory latency time by over 4-fold when compared with placebo in adults with premature ejaculation (2537). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Pruritus. There is limited evidence on the topical use of clove oil in patients with chronic pruritus. Details: Preliminary clinical research in patients with chronic pruritus shows that applying clove oil 10% in petroleum jelly to the skin twice daily for 2 weeks reduces the daily duration of itching by 48 minutes and improves symptom severity and disability scores when compared with placebo (96950). More evidence is needed to rate clove for these uses.

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POSSIBLY EFFECTIVE

• Hypercholesterolemia. Small clinical trials show that consuming English walnuts as part of a low-fat diet seems to lower cholesterol. Total cholesterol and lipoproteins are decreased when English walnuts are substituted for other fatty foods and constitute up to 20% of the calories in the diet. When English walnuts are added to a low fat diet, total cholesterol may be decreased by 4% to 12% and low-density lipoprotein (LDL) may be decreased by 8% to 16% (6431,8476,8477). Substituting English walnuts for other dietary fats as part of a diet containing 30% fat seems to improve high-density lipoprotein (HDL) cholesterol-to-total cholesterol ratios in patients with type 2 diabetes. However, there is no effect on levels of low-density lipoprotein (LDL) cholesterol when compared with a 30% fat diet without English walnuts (13300).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Coronary heart disease (CHD). Epidemiological research has found that people who increase dietary consumption of nuts in general might have a lower risk of CHD and death due to coronary events. However, there is no available evidence showing that eating English walnut, specifically, reduces the risk of CHD (8478,13299). In 2004, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming 1.5 ounces of walnuts per day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of CHD. The FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102335).
• Diabetes. Data from preliminary clinical research on the effects of English walnuts in people with type 2 diabetes are conflicting. Some clinical research shows that taking English walnut leaf extract 100 mg twice daily for 3 months decreases fasting blood glucose by about 13% when compared with placebo (97750). In contrast, other clinical research shows that taking English walnut leaf extract 100 mg once daily for one week and then twice daily for 7 weeks has no effect on fasting blood glucose levels (97749). In a meta-analysis of 4 studies involving a total of 195 patients, taking English walnut leaf extracts orally, 200-750 mg daily for 8 to 12 weeks, reduces fasting blood glucose by a mean of about 18 mg/dL and increases fasting insulin levels by a mean of about 2 units/L, but does not alter post-prandial glucose levels (113406). The majority of studies do not show a significant effect on glycated hemoglobin (HbA1c), but the meta-analysis shows a reduction when English walnut leaf extracts are taken for more than 8 weeks (97749,97750,113406). Substituting English walnuts for other dietary fats as part of a diet containing 30% fat seems to improve high-density lipoprotein (HDL) cholesterol-to-total cholesterol ratios in patients with type 2 diabetes. However, there is no effect on levels of low-density lipoprotein (LDL) cholesterol when compared with a 30% fat diet without English walnuts (13300). More evidence is needed to rate English walnut for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral European barberry fruit is beneficial for acne. Details: Preliminary clinical research in adolescents 12-17 years of age with moderate or severe acne shows that taking European barberry aqueous extract 200 mg three times daily for 4 weeks reduces acne severity and decreases the number of acne lesions when compared with placebo (94824).
• Bacterial vaginosis. It is unclear if topical European barberry is beneficial for bacterial vaginosis. Details: A small clinical study in adults with bacterial vaginosis shows that applying 5 grams of a cream containing European barberry 5% with metronidazole 0.75% vaginally nightly for 7 days modestly reduces infection recurrence rate over the following three weeks when compared with metronidazole cream alone (94826).
• Breast cancer. Although there is interest in using oral European barberry for breast cancer prevention, there is insufficient reliable information about the clinical effects of European barberry for this condition.
• Dental plaque. It is unclear if brushing the teeth with a gel containing European barberry is beneficial for dental plaque. Details: Preliminary clinical research in males 11-12 years of age shows that brushing with a European barberry extract gel containing berberine 1%, three times daily for 3 weeks reduces plaque index when compared with placebo. This effect was similar to that seen with a commercial antiplaque toothpaste (Colgate) (33695).
• Diabetes. It is unclear if oral European barberry is beneficial for diabetes. Details: A small clinical study in adults with type 2 diabetes shows that taking European barberry juice 200 mL daily for 8 weeks, in conjunction with standard treatment, reduces fasting blood glucose levels by 7.5%, compared with an increase of 20% in those receiving standard treatment alone. Patients taking European barberry also had improvements in body weight, systolic and diastolic blood pressure, and total cholesterol when compared with standard treatment alone (98575).
• Gingivitis. It is unclear if brushing the teeth with a gel containing European barberry is beneficial for gingivitis. Details: Preliminary clinical research in males 11-12 years of age shows that brushing with a European barberry extract gel containing berberine 1%, three times daily for 3 weeks, reduces gingival inflammation when compared with placebo. This effect was similar to that seen with a commercial antiplaque toothpaste (Colgate) (33695).
• Hyperlipidemia. It is unclear if oral European barberry is beneficial for hyperlipidemia. Details: Meta-analyses of five small clinical trials shows that taking European barberry decreases total cholesterol by 24 mg/dL, low-density lipoprotein (LDL) cholesterol by 14 mg/dL, and triglycerides by 29 mg/dL, without significantly affecting high-density lipoprotein (HDL) cholesterol, when compared with a control intervention (102055,105756). However, because the studies included in these analyses enrolled patients with diabetes, metabolic syndrome, or nonalcoholic fatty liver disease (NAFLD), the effects of European barberry on lipid levels in patients with hyperlipidemia are unclear.
• Opioid withdrawal. It is unclear if oral European barberry is beneficial for opioid withdrawal. Details: Clinical research in patients using methadone during opioid withdrawal shows that taking European barberry root extract 500 mg twice daily for 4 weeks reduces overall symptoms of withdrawal by a large amount, but does not improve depression, anxiety, stress, or sleep quality, when compared with placebo (108156). More evidence is needed to rate European barberry for these uses.

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POSSIBLY EFFECTIVE

• Dysmenorrhea. Taking fennel oil or extract by mouth may reduce pain in patients with primary dysmenorrhea. This benefit may be similar to ibuprofen or mefenamic acid. Details: Two separate meta-analyses in patients with primary dysmenorrhea show that taking fennel oil or fennel extract for 1-6 menstrual cycles reduces dysmenorrhea pain when compared with placebo. Improvement in pain was similar when compared with ibuprofen or mefenamic acid. In the included studies, doses of fennel oil ranged from 3-30 drops every 4-8 hours, and doses of fennel extract ranged from 30-230 mg daily (104196,108972). However, most studies included in these meta-analyses were small and low-quality, and all studies were conducted in Iran. Higher quality studies in other geographic locations are needed to confirm these findings.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. Although there has been interest in using oral fennel for anxiety, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Bronchitis. Although there has been interest in using oral fennel for bronchitis, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Cancer. Although there has been interest in using oral fennel for cancer prevention, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Cholera. Although there has been interest in using oral fennel for cholera, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Colic. Small clinical studies suggest that oral fennel may reduce crying time in infants with colic. However, most research to date has evaluated fennel in combination with other ingredients. Details: A meta-analysis of three small clinical studies shows that giving fennel to infants with colic can reduce crying time by about 72 minutes daily when compared with placebo (97497). However, the studies included in this meta-analysis were at medium to high risk of bias, and the placebo response rate was high in all of the included studies. Additionally, two of the three studies evaluated combination products (16735,19715,49428). In the one study that used fennel alone, administering 5-20 mL of fennel seed oil 0.1% emulsion daily for one week led to colic relief in 65% of infants, compared with 24% of infants receiving placebo (49428). The other studies evaluated fennel in combination with lemon balm and German chamomile (ColiMil) or in combination with chamomile, vervain, licorice, and lemon balm (Calma-Bebi, Bonomelli). These combination products produced a response in 57% to 85% of infants, compared with 26% to 49% of infants receiving placebo (16735,19715).
• Constipation. Oral fennel has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small crossover trial in patients with constipation shows that drinking an herbal tea containing 3 grams of a combination of fennel, anise, elderberry, and senna daily for 5 days can decrease colonic transit time, increase the number of daily evacuations, and improve the perception of bowel function when compared with placebo (49494). Another small clinical study in elderly patients with constipation shows that drinking a specific tea (Smooth Move, Traditional Medicinals) containing fennel, senna, licorice, orange peel, cassia cinnamon, coriander, and ginger for 28 days can increase the number of bowel movements when compared to baseline (46196). The validity of this finding is limited by the lack of a comparator group. Additionally, a small clinical study in patients aged 60-65 years with functional constipation shows that taking a traditional Iranian combination product containing 5 grams each of fennel seed and rose flower, dissolved in water twice daily before meals for 4 weeks, improves constipation severity and stool consistency when compared with polyethylene glycol 10 grams. Improvements in constipation severity persisted in both groups 4 weeks after treatment completion (108973). However, polyethylene glycol is usually taken at a higher dose of 17 grams daily, limiting the validity of these findings.
• Cough. Although there has been interest in using oral fennel for cough, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Dementia. Although there has been interest in using oral fennel for dementia, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Diabetes. Although there has been interest in using oral fennel for diabetes, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Dyspepsia. Although there has been interest in using oral fennel for dyspepsia, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Flatulence. Although there has been interest in using oral fennel for flatulence, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Hirsutism. It is unclear if topical fennel is beneficial in patients with hirsutism. Details: A small clinical study in females with male pattern body hair due to unknown causes shows that applying a fennel 2% cream twice daily for 12 weeks can reduce hair diameter by approximately 19% when compared with placebo (49429).
• Insomnia. Although there has been interest in using oral fennel for insomnia, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Irritable bowel syndrome (IBS). Oral fennel has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in adults with either diarrhea- or constipation-predominant IBS shows that taking two capsules containing fennel essential oil 25 mg and curcumin 42 mg per capsule (CU-FEO, Alfa Wassermann S.p.A.) twice daily for 30 days improves overall ratings of abdominal pain, abdominal distention, and quality of life by 24% when compared with placebo (97422).
• Lactation. Although there has been interest in using oral fennel to stimulate breastmilk production, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Menopausal symptoms. Small clinical studies suggest that oral fennel oil or fennel seed powder may modestly improve menopausal symptoms. Details: One small clinical trial in adults with medium severity menopausal symptoms shows that taking fennel essential oil 60 mg daily for 8 weeks improves scores on the Menopause Rating Scale when compared with a sunflower oil placebo (97498). Another small clinical study in postmenopausal adults shows that taking fennel seed powder 2 grams daily for 8 weeks improves scores on the Kupperman Menopausal Index when compared with placebo (104198). Fennel has also been evaluated in combination with other ingredients. One small clinical study shows that taking a combination of fennel 120 mg, chamomile 1000 mg, and saffron 60 mg daily for 12 weeks reduces physical, psychological, and urogenital symptom scores on the Menopause Rating Scale when compared with placebo or lower doses of the combination (103628). Additionally, a moderate-sized clinical study in postmenopausal women conducted in Iran shows that taking combined fennel and valerian extract 500 mg twice daily for 8 weeks modestly improves self-reported scores for frequency and severity of hot flashes but does not improve sleep quality or duration of hot flashes when compared with placebo (112369). However, it is unclear if these benefits are due to fennel, other ingredients, or the combination.
• Nausea and vomiting. Although there has been interest in using oral fennel for nausea and vomiting, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Nocturnal enuresis. Although there has been interest in using oral fennel for nocturnal enuresis, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Osteoarthritis. It is unclear if oral fennel extract is beneficial in patients with knee osteoarthritis. Details: A small clinical trial in females with osteoarthritis of the knee shows that taking powdered fennel extract 800 mg daily for 2 weeks reduces pain and disability scores, but not stiffness, when compared with placebo (104199).
• Polycystic ovary syndrome (PCOS). It is unclear if oral fennel is beneficial in patients with PCOS. Details: A small clinical study in patients with PCOS shows that taking two fennel capsules, containing anethole 21-27 mg per capsule, daily along with a hypocaloric standard diet or a hypocaloric high-protein diet for 3 months does not reduce body weight or improve androgenic parameters such as testosterone levels, sex hormone-binding globulin levels, or free androgen index, when compared with these diets plus placebo (104197). Fennel has also been evaluated in combination with other ingredients. A clinical study in patients with oligomenorrhea due to PCOS shows that taking a traditional combination product (Aslagh) containing equivalent amounts of essential oils of fennel, wild carrot seeds, and Vitex agnus-castus fruit for 3 months, either alone or in combination with metformin, improves rates of menstrual bleeding and menstrual cyclicity similarly to metformin alone. All three groups experienced a significant improvement from baseline. Aslagh was taken as two, 500-mg capsules twice daily, except during menses; metformin was titrated over one week to a dose of 500 mg three times daily (108974). Additionally, a moderate-sized clinical study in patients with PCOS shows that taking fennel 60 mg and Elwendia persica 25 mg twice daily for 4 months modestly improves number of ovarian follicles and body mass index when compared with placebo; however, when compared to baseline, the combination also improves hirsutism scores and menstrual cycle duration and interval (112370). It is unclear if these effects are due to fennel, other ingredients, or the combination.
• Rheumatoid arthritis (RA). Although there has been interest in using oral fennel for RA, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Sexual desire. It is unclear if oral fennel is beneficial for improving sexual desire. Details: A small clinical study in postmenopausal adults shows that taking fennel seed powder 2 grams daily for 8 weeks does not improve scores on the Hurlbert Index of Sexual Desire when compared with placebo (104198).
• Sunburn. It is unclear if topical fennel emulsion is beneficial for preventing sunburn. Details: A small clinical study shows that applying a fennel 5% emulsion topically prior to ultraviolet (UV) exposure can reduce sunburn by 65% when compared with a control (49518).
• Upper respiratory tract infection (URTI). Although there has been interest in using oral fennel for upper respiratory tract infections, there is insufficient reliable information about the clinical effects of fennel for this purpose.
• Vaginal atrophy. It is unclear if intravaginal application of fennel cream is beneficial in patients with vaginal atrophy. Details: A small clinical study in postmenopausal adults shows that applying 5 grams of a fennel 5% cream to the vagina once daily for 8 weeks seems to reverse vaginal thinning, improve vaginal pH, and reduce symptoms of vaginal atrophy such as itching, dryness, and pain with intercourse when compared with placebo (92509). Patients in the fennel group also rated their sexual function to be improved when compared with those receiving placebo (97496). More evidence is needed to rate fennel for these uses.

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POSSIBLY EFFECTIVE

• Atherosclerosis. When used alone or in combination with other ingredients, oral garlic seems to slow the progression of atherosclerosis. Details: Taking low doses of garlic powder (Kwai, Lichtwer Pharma) 300 mg, administered as a single dose or three times daily for up to 4 years, seems to lessen age-related decreases in aortic elasticity (4797,51595). Additionally, taking a specific time-released garlic powder supplement (Allicor, INAT-Farma) 150 mg twice daily for 24 months seems to reduce the rate of atherosclerosis progression, as measured by carotid intima-media thickness, when compared with placebo in males with early evidence of carotid atherosclerosis (88394). Higher doses of 900 mg daily seem to slow development of atherosclerosis in both aortic and femoral arteries when used over a four-year period in females, but not in males (3315,4798). In patients with evidence of coronary artery calcium and a Framingham risk score of greater than 10%, taking aged garlic extract (Kyolic Reserve, Wakunaga) 1200 mg twice daily for 12 months reduces coronary artery calcium progression by 29% when compared with placebo (102670). A meta-analysis also found that garlic powder tablets and aged garlic extract may reduce coronary artery calcium scores when compared with placebo (110721). Some clinical research has investigated the use of garlic in combination with other ingredients. Taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunaga) containing aged garlic extract 250 mg plus vitamin B12 100 mcg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months significantly reduces coronary artery calcium progression and improves vascular function in patients with a Framingham risk score of 10% to 20% without coronary artery disease (88385). In addition, taking a combination product containing aged garlic extract 1200 mg and coenzyme Q10 120 mg daily for one year significantly improves vascular elasticity endothelial function in firefighters facing high degrees of occupational stress (44225).
• Diabetes. Most clinical research suggests that oral garlic, taken alone or in combination with metformin for at least 12 weeks, modestly reduces fasting blood glucose levels in patients with diabetes. It is unclear if garlic improves postprandial glucose levels or glycated hemoglobin (HbA1c). Details: A meta-analysis of results from seven clinical studies in adults with type 2 diabetes shows that taking garlic powder 600-1500 mg daily, garlic oil 8.2 mg daily, or aged garlic extract 1000 mg daily reduces fasting blood glucose levels by about 2 mg/dL when compared with control. The greatest benefit is seen for patients with hyperglycemia at baseline, for interventions lasting at least 12 weeks, and for formulations consisting of garlic powder (96004). Specific garlic formulations used in the reviewed studies have included garlic powder 300 mg 2-3 times daily as tablets (Kwai, Lichtwer Pharmaceuticals) or time-released tablets (Allicor, INAT-Farma) for 4-24 weeks, sometimes in combination with metformin or a sulfonylurea (51396,51463,96004). In one study, when used in combination with metformin, garlic reduced fasting blood glucose levels 70% more than when metformin was used alone (51463). The findings from these studies are in contrast with the results from older meta-analyses, which showed that garlic does not improve glycemic indices or lipid levels in patients with diabetes. Reasons for these discrepancies may relate to the fact that the older analyses included lower quality research (6465,6897). There is insufficient reliable information available to determine if garlic significantly improves postprandial glucose levels or HbA1c (96004). A small clinical trial shows that taking aged garlic extract (Kyolic, Wakunaga) 2400 mg daily for 12 months does not reduce left ventricular myocardial mass, a marker of poor cardiac outcomes, in patients with diabetes. However, this study may have been inadequately powered to detect a difference between groups (102671).
• Endometriosis. Oral garlic seems to improve pain in people with endometriosis. Details: A clinical study in patients with endometriosis shows that taking a tablet containing garlic powder 400 mg, providing allicin 1.1 mg, daily for 3 months along with standard care reduces overall pain scores from baseline by 72%, compared with an increase of 4% from baseline in patients receiving placebo along with standard care (106615).
• Hyperlipidemia. Most research shows that taking oral garlic for at least 8 weeks seems to modestly reduce total and low-density lipoprotein (LDL) cholesterol levels in patients with hyperlipidemia. However, evidence is conflicting on whether garlic improves high-density lipoprotein (HDL) cholesterol or triglyceride levels. Details: A robust meta-analysis on this topic suggests that, on average, garlic preparations reduce total cholesterol by 15 mg/dL and LDL cholesterol by 6 mg/dL when compared with placebo in patients with hyperlipidemia. These improvements appear to be more pronounced when garlic is taken for more than 8 weeks and in patients with total and LDL cholesterol levels that are at least borderline high before treatment. This same analysis shows no reduction in triglycerides and only a slight increase in HDL of 1.5 mg/dL with garlic treatment (88399). A more recent meta-analysis supports prior findings that taking garlic improves HDL, LDL, and apolipoprotein-A levels while having no impact on triglycerides level. The meta-analysis found that while garlic does not appear to reduce cholesterol in the general population, it may reduce total cholesterol when taken by patients with cardiovascular risk factors (110721). Another partially conflicting meta-analysis found that garlic powder reduces total cholesterol, LDL, and triglyceride levels, but has no impact on HDL levels (110720). The majority of available research supports these findings, but conflicting results exist (279,731,732,1873,1875,4782,4783,4784,4785,4786)(4787,4788,4789,4792,4793,4794,4795,4807,6457,6897)(51343,15295,15296,51422,51429,51469,51590,88399,107238)(107352,110721). Whether garlic is beneficial for treating hyperlipidemia may also depend on the specific formulation or product taken. Mixed results have been reported for a variety of specific garlic products, including garlic powder tablets (Kwai, Lichtwer Pharma) 600-900 mg daily in two or more divided doses for 6-16 weeks (279,731,4782,4783,4784,4785,4787,4789,4792,4793)(4795,4807), aged garlic extract (Kyolic, Wakunaga) 1000-7200 mg daily in divided doses for 4-6 months (1873,1875,15295), a garlic powder product (Garlex, Bosch Pharmaceuticals) 300 mg twice daily for 12 weeks (51343), aged back garlic extract (ABG+; PharmActive Biotech Products) 250 mg daily for 6 weeks (108607), and others (732,15295). Subgroup analyses from the most robust meta-analysis to date suggest that products containing aged garlic extract may be more effective for lowering total cholesterol than garlic powder preparations. If garlic powder preparations are used, total cholesterol levels seem to be lowered to a greater degree in patients taking enteric-coated garlic powder tablets. The opposite trend may be true for reducing LDL cholesterol. Garlic powder tablets seem to reduce LDL cholesterol levels while aged garlic extract does not. However, the few studies that did evaluate the effect of aged garlic extract on LDL cholesterol did so in patients with low baseline LDL cholesterol levels. There is limited evidence on the use of raw garlic or garlic oil products for treating hyperlipidemia (88399). Taking garlic 1200 mg with fish oil 3 grams daily for 4 weeks or garlic oil 500 mg with fish oil 700 mg daily for 60 days also appears to improve lipid parameters in some patients (4789,4790,51669). Garlic alone may be more effective than garlic plus fish oil for improving LDL cholesterol levels, but the combination may be useful in patients with elevated levels of total cholesterol, LDL cholesterol, and triglycerides (4789).
• Hypertension. Some clinical research suggests that oral garlic seems to modestly reduce blood pressure in hypertensive and normotensive patients. Details: One meta-analysis of clinical studies show that taking garlic can reduce systolic and diastolic blood pressure by about 5 mmHg and 3 mmHg, respectively, in patients with or without hypertension (16605,51414,96007). However, another meta-analysis found that taking garlic may not impact systolic or diastolic blood pressure in patients with coronary artery disease when compared with placebo (110721). When only patients with hypertension are considered, taking garlic can decrease systolic blood pressure by about 7-9 mmHg and diastolic blood pressure by about 4-6 mmHg. These results are limited by the fact that many of the included studies were of low to moderate quality and short duration (96007,96008,96014). Most clinical research appears to support these findings (278,279,1873,51442,88398). However, conflicting results exist (107238,110721). Some garlic formulations evaluated for hypertension have included a specific garlic powder formulation (Kwai, Lichtwer Pharma) 2400 mg as a single dose or 600 mg daily for 12 weeks and a specific aged garlic extract (Garlic High Potency Everyday Formula 112, Wakunaga/Wagner) 960 mg to 7.2 grams daily in up to three divided doses for up to 6 months (278,279,1873,51442,88398). Other doses used in the available research have included garlic tablets 300-1500 mg in divided doses daily for 24 weeks (88386) and garlic oil 500 mg plus fish oil 600 mg daily for 60 days (51669). Hypotensive effects of garlic have also been examined in population research. A large population study found that eating raw garlic at least twice daily is associated with a reduced likelihood of having prehypertension when compared with eating raw garlic three or fewer times per week. However, any significant relationship was eliminated after adjusting for dietary salt, making conclusions difficult (102677).
• Nonalcoholic fatty liver disease (NAFLD). Oral garlic seems to reduce the severity of hepatic steatosis in patients with NAFLD. Details: A meta-analysis including 4 studies with 186 patients with NAFLD found that taking 800-1600 mg of garlic powder daily may reduce aspartate aminotransferase (AST) and alanine transaminase (ALT) and lower the probability of hepatic steatosis by 2.75 times when compared with placebo (110720). Clinical research in patients with NAFLD shows that taking garlic powder reduces the severity of steatosis in 51% to 62% of patients, compared to 16% to 26% of those taking placebo (102681,103470). Doses of garlic included a specific powder (Amin Pharmaceutical Company) 800 mg twice daily for 12 weeks or an enteric-coated powder 400 mg twice daily for 15 weeks (102681,103479). There was also an improvement in most liver enzymes, other than alkaline phosphatase, and the level of low-density lipoprotein (LDL) cholesterol when compared with placebo (102681). In addition, population research shows a 7% reduction in odds of developing NAFLD with each 1 gram of raw garlic per 1000 kcal consumed. However, this association was not observed in females (102673). NAFLD is strongly and independently associated with an increased risk for prehypertension and hypertension. A clinical study in adults with NAFLD and stable diet- or antihypertensive-controlled blood pressure shows that taking an enteric-coated tablet containing garlic powder 400 mg (Amin Pharmaceuticals), providing allicin 1.5 mg, twice daily for 15 weeks reduces systolic blood pressure, diastolic blood pressure, and mean arterial pressure by 8, 3, and 6 mmHg, respectively, when compared with placebo. High-sensitivity C-reactive protein is also reduced by 16% when compared with placebo (106614).
• Periodontitis. Oral aged garlic extract seems to improve some measures of gum health in people with mild to moderate periodontitis. Details: Clinical research in otherwise healthy patients with mild to moderate periodontitis shows that taking a specific aged garlic extract (Kyolic, Wakunaga) orally 1200 mg twice daily for 18 months improves probing pocket depth, but not gingival recession, when compared with placebo (105760). The validity of these findings is limited by the lack of an intention to treat analysis.

POSSIBLY INEFFECTIVE

• Gastric cancer. Oral garlic does not seem to prevent gastric cancer. Details: Clinical research evaluating the effects of taking aged garlic extract for 7 years failed to show a reduced risk of developing gastric cancer up to 22 years later (14447,51470,102016), although there was a reduction in mortality associated with gastric cancer in subjects followed for 12-22 years (5-15 years after stopping the garlic extract) (102016). Also, a prospective, case-control study of 123,484 adults over a 30-year review period suggests that garlic intake, whether obtained from the diet or via supplementation, is not associated with a reduction in the rate of gastric cancer occurrence (97034). However, some research disagrees. One prospective population study suggests that a 1 kg/year increased increment in garlic intake is associated with a 17% reduced risk in gastric cancer incidence over 22 years. Also, consuming at least 3.25 kg yearly is associated with at least a 12% reduced risk when compared with consuming less than 2 kg each year. A sub-analysis suggests that this potential benefit is associated with garlic stalks, rather than garlic bulbs (111764). Meta-analyses of population research, as well as small population studies, have suggested 23% to 51% lower odds of developing gastric cancer with increased dietary garlic intake when compared with never eating garlic (3320,4775,4776,51209,51460,96005,108604). However, these studies have limited external validity.
• Helicobacter pylori. Oral garlic does not seem to be beneficial for Helicobacter pylori eradication. Details: Despite some promising initial laboratory research suggesting activity against Helicobacter pylori, garlic cloves, powder, or oil does not seem to have any beneficial effect when used to treat patients infected with Helicobacter pylori (3322,4761,4762,4763,4765,4774,97034).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral garlic for allergic rhinitis (hay fever), there is insufficient reliable information about the clinical effects of garlic for this condition.
• Alopecia areata. Topical garlic may increase hair growth by a small amount. Details: Preliminary clinical research in adults with alopecia areata shows that applying garlic 5% gel four times daily for 3 months, in addition to topical corticosteroid use, increases hair growth by 18% when compared with placebo plus topical corticosteroid (51386).
• Asthma. Although there has been interest in using oral garlic for asthma, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Athletic performance. It is unclear if oral garlic is beneficial for athletic performance. Details: Preliminary clinical research shows that taking a single dose of garlic 900 mg prior to exercise increases endurance when compared with placebo in young athletes (51623). A small preliminary clinical trial shows that taking garlic extract 1000 mg daily for 4 weeks does not reduce the time to cycle 40 km when compared to placebo (111765).
• Benign prostatic hyperplasia (BPH). It is unclear if oral garlic is beneficial for BPH. Details: In patients with BPH, preliminary clinical research shows that taking aqueous garlic extract 1 mg/kg daily for one month decreases prostate mass and urinary frequency and improves symptom scores and urinary flow rates when compared to baseline (10374). The validity of these findings is limited by the lack of a comparator group.
• Bladder cancer. Although there has been interest in using oral garlic for bladder cancer, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Breast cancer. It is unclear if oral garlic prevents breast cancer. Details: The relationship between garlic intake and risk of breast cancer is unclear. Overall, population research suggests that taking garlic does not seem to decrease the risk of breast cancer. However, when garlic and onions are examined together, there is some evidence of an association with a decreased risk of breast cancer (4779,102674). More research is needed.
• Bronchitis. Although there has been interest in using oral garlic for bronchitis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Cardiovascular disease (CVD). It is unclear if oral garlic is beneficial for reducing CVD risk factors in adults with hypercholesterolemia. Details: A clinical crossover study in adults with moderate hypercholesterolemia shows that taking a specific product (ABG+; PharmActive Biotech Products) containing aged black garlic extract 250 mg, standardized to provide S-allyl-L-cysteine 1.25 mg, daily for 6 weeks does not improve blood pressure, glucose or cholesterol levels, or anthropometric measures when compared with placebo. A subgroup analysis in males with elevated diastolic blood pressure at baseline shows that taking this product reduces diastolic blood pressure by 5-mmHg when compared with placebo (108607). It is unclear if garlic is beneficial in patients with existing CVD.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral garlic for CFS, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Colorectal cancer. It is unclear if oral garlic prevents colorectal cancer. Details: Several individual population studies have found that higher dietary intake of garlic is associated with a reduced risk of colorectal cancer (3320,4770,4771,4772). However, results from meta-analyses of population research are mixed (96003,102669). Reasons for the discrepancy seem to relate to the type of population study conducted. A meta-analysis of case-control studies supports a preventative effect of garlic. However, this is not supported when cohort studies are analyzed separately (102669). Case-control studies are prone to recall and selection bias, and some do not account for confounding factors associated with colorectal cancer (96003). Two separate meta-analyses of observational research conducted in various countries have found that consumption of garlic and other allium-containing vegetables (onions, leeks, chives and scallions) is associated with a reduced risk of colorectal cancer; however, subgroup analyses suggest improvement is greatest in studies conducted in Asian countries, modest in those conducted in North America, and absent in those conducted in Europe (108604,108605). The reasons for these differing findings are unclear but may be related to regional differences in dietary habits, such as the use of raw or cooked garlic. Few studies have examined the effects of garlic supplements. While a single preliminary clinical study in patients with confirmed colorectal adenomas shows that taking high-dose aged garlic extract 2.4 mL daily for 12 months reduces the risk of developing new adenomas by 29% when compared with a lower dose of 0.16 mL daily (51320), other studies do not support the use of garlic supplements for this purpose (4773,96003).
• Common cold. Oral garlic might reduce the frequency of the common cold when used prophylactically. Details: Preliminary clinical research shows that taking one capsule of garlic daily for 12 weeks during the winter months reduces the number of self-reported colds by approximately 63% when compared with placebo. The duration of symptoms was also reduced by approximately one day (10787). Also, a small clinical trial in older patients living in residential care shows that 12% of those taking one capsule daily of a combination of garlic and onion powder (Aliocare, Domca Sau, Spain) for 36 weeks had one or more common cold episodes compared with 45% of those taking placebo. Each capsule provided 14 mg garlic powder (111768).
• Corns. It is unclear if topical garlic is beneficial for corns. Details: Preliminary clinical research in a small number of patients with corns shows that applying a lipid soluble garlic extract topically to corns on the feet twice daily for 10-20 days results in improvement in most patients when compared with baseline (15030). The validity of this finding is limited by the lack of a comparator group.
• Coronary heart disease (CHD). It is unclear if oral garlic is beneficial for CHD. Details: A meta-analysis of preliminary clinical research in adults with CHD shows that taking garlic orally 800-2000 mg daily for 2-48 weeks reduces total cholesterol levels by an average of 16 mg/dL when compared with placebo. Taking garlic did not affect other cholesterol levels; however, the study may have been inadequately powered to detect a difference between groups. The validity of this study is limited by inclusion of patients with and without dyslipidemia at baseline (107238).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral garlic is beneficial for COVID-19. Details: Clinical research in non-critically ill patients hospitalized with COVID-19 shows that taking garlic extract (Gallecina, Samisaz Pharmaceutical Company, Iran) 90 mg every 8 hours for 5 days or until discharge modestly reduces the proportion of patients requiring supplemental oxygen for at least 1 day when compared with placebo. However, there was no overall effect on clinical status, intensive care admission, or discharge prior to day 6. All patients also took remdesivir (111766). A small preliminary clinical study in patients hospitalized with mild to moderate symptoms of COVID-19 shows that taking garlic essential oil orally 50 mg twice daily before breakfast and dinner for 10 days, in addition to standard COVID-19 treatment, reduces the median duration of fever from 5 to 4 days, cough from 7 to 5 days, and weakness from 9 to 7 days when compared with standard treatment alone. The median time to a negative COVID-19 test decreased from 8 to 7 days (109530). The validity of this study is limited by incomplete randomization, the lack of a placebo comparator, and the exclusion of people with severe symptoms.
• Cystic fibrosis. It is unclear if oral garlic is beneficial for cystic fibrosis. Details: Preliminary clinical research shows that taking garlic oil macerate 625 mg daily for 8 weeks does not improve pulmonary function, symptom scores, or the need for antibiotic therapy when compared with placebo in children with cystic fibrosis and chronic pulmonary infection (51438).
• Dental hypersensitivity. Although there has been interest in using oral garlic for dental hypersensitivity, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Denture stomatitis. It is unclear if topical garlic as a mouthwash is beneficial for denture stomatitis. Details: Preliminary clinical research in patients with oral denture stomatitis shows that using a garlic mouthwash 40 mg/mL three times daily for 4 weeks improves redness when compared to baseline. When compared with nystatin, garlic has a lesser degree of recovery, but better patient satisfaction (51466).
• Diabetic retinopathy. It is unclear if oral garlic is beneficial for diabetic retinopathy. Details: Preliminary research in patients with diabetic retinopathy and macular edema, treated with intravitreal bevacizumab and laser photocoagulation, shows that taking garlic powder 1 gram orally daily for 4 weeks improves the best-corrected visual acuity by 0.18 logMAR (logarithm of the minimum angle of resolution), compared with 0.06 for placebo. It also decreases intraocular pressure by 1 mmHg, compared with 0.3 mmHg for placebo (109529).
• Diarrhea. Although there has been interest in using oral garlic for various types of diarrhea, including travelers' diarrhea and dysentery, there is insufficient reliable information about the clinical effects of garlic for these conditions.
• Dysmenorrhea. Although there has been interest in using oral garlic for dysmenorrhea, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Esophageal cancer. It is unclear if oral garlic prevents esophageal cancer. Details: Observational research regarding the use of garlic in preventing esophageal cancer is conflicting. Some evidence suggests that raw garlic consumption does not prevent the development of esophageal cancer (51508). However, other population research suggests that weekly garlic consumption decreases the risk of developing esophageal cancer (51209).
• Exercise-induced muscle soreness. It is unclear if oral garlic is beneficial for exercise-induced muscle soreness. Details: Preliminary clinical research shows that taking allicin, a constituent of garlic, 80 mg daily for 14 days can reduce subjective assessments of exercise-induced muscle soreness in athletes when compared with placebo (51404).
• Fatigue. Although there has been interest in using oral garlic for fatigue, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Familial hypercholesterolemia. Oral garlic does not seem to improve blood lipid levels in children with familial hypercholesterolemia. Details: In children with familial hypercholesterolemia, a small clinical trial shows that taking garlic powdered extract, standardized based on alliin content, does not improve levels of total cholesterol, low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein (a), apolipoprotein B-100, homocysteine, fibrinogen, or blood pressure (4796).
• Fibrocystic breast disease. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product (Karinat, INAT-Farma), containing garlic powder 150 mg, beta-carotene 2.5 mg, alpha-tocopherol 5 mg, and ascorbic acid 30 mg twice daily for 6 months reduces the severity of breast pain, premenstrual syndrome, and menstruation pain, and can cause regression of palpable symptoms of breast fibromatosis (51317). It is unclear if these effects are due to garlic, other ingredients, or the combination.
• Gastritis. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with gastritis shows that taking a specific combination product (Karinat, INAT-Farma), containing garlic 150 mg, beta-carotene 2.5 mg, alpha-tocopherol 5 mg, and ascorbic acid 30 mg twice daily for 6 months improves digestion, inhibits H. pylori infection, and reduces the risk of precancerous lesion formation when compared with placebo (51308). It is unclear if these effects are due to garlic, other ingredients, or the combination.
• Gout. Although there has been interest in using oral garlic for gout, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Hepatitis. It is unclear if oral garlic is beneficial for hepatitis. Details: Preliminary clinical research shows that taking 3-6 capsules of a product containing garlic oil 50 mg and diphenyl-dimethyl-dicarboxylate 25 mg per capsule daily for 6 weeks improves liver function enzyme levels when compared with placebo in patients with chronic hepatitis (51478). The effects of garlic alone have not been determined.
• Hepatopulmonary syndrome. It is unclear if oral garlic is beneficial for hepatopulmonary syndrome. Details: Preliminary clinical research shows that garlic oil (Garlic Pearls, Ranbaxy, India) 1-2 grams/m² daily in two divided doses for 9-18 months may improve oxygen levels and remission rates when compared with placebo in patients with hepatopulmonary syndrome (51439).
• Influenza. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in older patients living in residential care shows that 12% of those taking one capsule daily of a combination of garlic and onion powder (Aliocare, Domca Sau, Spain) for 36 weeks had one or more influenza-like episodes compared with 36% of those taking placebo. Each capsule provided 14 mg garlic powder (111768).
• Lead toxicity. It is unclear if oral garlic is beneficial for lead toxicity. Details: Preliminary clinical research shows that taking garlic powder 400 mg three times daily for 4 weeks reduces blood lead concentration when compared with baseline, but not when compared to treatment with D-penicillamine, in patients with mild to moderate lead poisoning (51467).
• Lung cancer. It is unclear if oral garlic prevents lung cancer. Details: Some population research suggests that eating raw garlic is associated with a reduced odds of developing lung cancer. However, other research suggests that eating garlic or taking garlic supplements is not associated with a reduced risk of lung cancer (4778,103482). Reasons for the discrepancy possibly relate to the type of garlic consumed.
• Metabolic syndrome. Meta-analyses of small studies suggest that oral garlic may improve some metabolic parameters in patients with metabolic syndrome and other metabolic disorders. Details: Two meta-analyses of several small clinical studies in adults with metabolic syndrome or metabolic disorders including hyperlipidemia, hypertension, nonalcoholic fatty liver disease, obesity, and type 2 diabetes show that taking various forms of garlic improves triglycerides, total cholesterol, low-density lipoprotein cholesterol, diastolic blood pressure , measures of insulin resistance, and waist circumference when compared with control. However, the meta-analyses reach conflicting conclusions on whether garlic is beneficial for body mass index, high-density lipoprotein cholesterol, fasting blood glucose, or systolic blood pressure when compared with control. Garlic forms studied in the meta-analyses include raw garlic 5000-20,000 mg, aged garlic extract 240-6000 mg, garlic powder tablets 188-6000 mg, and garlic derivative ajoene 2.34 mg, taken daily for 4 to 36 weeks (113617,113619).
• Mosquito repellent. It is unclear if oral garlic is beneficial as a mosquito repellent. Details: Preliminary clinical research shows that taking a single dose of garlic orally does not seem to effectively repel mosquitos (51322). The effect of long-term garlic administration is unclear.
• Multiple myeloma. It is unclear if oral garlic prevents multiple myeloma. Details: A case-control study comparing a small population of adults with and without multiple myeloma has found that increased intake of garlic in the diet may be associated with a decreased risk of developing multiple myeloma (51476).
• Muscle strength. It is unclear if oral garlic is beneficial for muscle strength. Details: Population research has found that increased consumption of raw garlic is associated with increased hand grip strength in healthy adults. Females consuming raw garlic 2-3 times per week were 23% less likely to have low handgrip strength, defined as being below the 20th percentile, when compared to those who almost never eat garlic. In males, the odds of having low handgrip strength were 34% lower. Eating any raw garlic, even less than once per week, was associated with an increased likelihood for having high grip strength (102678).
• Obesity. It is unclear if oral garlic is beneficial for obesity. Details: Clinical research shows that taking garlic powder (Amin Pharmaceutical Company) 1600 mg daily for 12 weeks does not reduce body weight or body mass index when compared with placebo in overweight or obese patients with nonalcoholic fatty liver disease (NAFLD), although there is a small effect on waist circumference (102681). One small clinical study evaluating garlic in combination with multiple other ingredients shows that the combination (Prograde Metabolism) modestly improves body weight, fat mass, and waist and hip circumference when compared with placebo. The other ingredients include raspberry ketone, caffeine, capsicum extract, ginger root extract, bitter orange fruit, L-theanine, and black pepper fruit (40802). However, it is unclear if this benefit is due to garlic, other ingredients, or the combination.
• Onychomycosis. Although there has been interest in using topical garlic for onychomycosis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Oropharyngeal candidiasis. It is unclear if oral garlic is beneficial for oropharyngeal candidiasis. Details: Preliminary clinical research in patients with oral candidiasis shows that applying a topical garlic paste four times daily for 14 days to affected areas can increase the rate of complete eradication of oral lesions by 23% when compared with clotrimazole solution (51330).
• Osteoarthritis. It is unclear if oral garlic is beneficial for osteoarthritis. Details: Preliminary clinical research in overweight and obese females with knee osteoarthritis shows that taking garlic tablets (Nature Made) 500 mg twice daily for 12 weeks modestly reduces pain scores by an additional 15% when compared with placebo (98813).
• Otitis media. Although there has been interest in using topical garlic for otitis media, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Peripheral arterial disease (PAD). Oral garlic seems to improve pain-free walking distance by a small amount in patients with PAD. However, it does not seem to improve blood pressure. Details: In patients with stage II peripheral arterial occlusive disease, a small clinical trial shows that taking garlic (Kwai) 400 mg twice daily for 12 weeks improves pain-free walking distance by about 15 meters. There was no effect on blood pressure or ankle or brachial pressures (4801).
• Polycystic ovary syndrome (PCOS). It is unclear if oral garlic is beneficial for PCOS. Details: Preliminary clinical research in adults with PCOS shows that taking garlic orally 800 mg daily for 8 weeks reduces low-density lipoprotein (LDL) cholesterol levels by approximately 8% when compared with placebo. Taking garlic did not affect other cholesterol levels; however, the study may have been inadequately powered to detect a difference between groups. Garlic supplementation also modestly reduces body mass index (BMI) and waist circumference in this population. However, there was no change in hip circumference (107238,111763).
• Pre-eclampsia. It is unclear if oral garlic prevents pre-eclampsia during the third trimester. Details: Preliminary clinical research shows that taking a specific garlic extract (Garlet, Cosar Pharmaceutical Company) 800 mg daily during the third trimester of pregnancy does not reduce the risk of developing pre-eclampsia in high-risk patients with first-time pregnancies (9201,51626).
• Premenstrual syndrome (PMS). It is unclear if oral garlic is beneficial for PMS. Details: Preliminary clinical research in adult students with moderate to severe PMS shows that taking a specific garlic supplement (Allium-S, Dineh Pharmaceutical Company) orally 400 mg daily, standardized to contain 1.1 mg allicin, for 3 menstrual cycles improves PMS symptom scores 1.4 times more than placebo. After taking garlic for 3 cycles, 91% of students improved to mild PMS, compared with only 36% in the placebo group (107239).
• Prostate cancer. Observational research on the relationship between garlic intake and prostate cancer risk is conflicting. It is unclear if garlic supplements are beneficial in patients with prostate cancer. Details: Observational research in Chinese males shows that those who eat garlic 2.14 grams/day (about one clove) seem to have a 50% lower risk of developing prostate cancer (9876). Also, a pooled analysis of epidemiological research suggests that garlic consumption may be associated with a 23% decreased odds of developing prostate cancer (88410). A case-control study has also found that garlic, consumed at least twice weekly, may reduce the risk for prostate cancer when compared with lower consumption (4777). However, other population research suggests that garlic consumption has no effect on prostate cancer risk in Iranian males (51454). One very small clinical study in patients with prostate cancer shows that taking garlic extract 1 mg/kg daily for one month might improve prostate specific antigen (PSA) levels, urinary flow, and urinary frequency when compared with baseline (10374). The validity of these findings is limited by the small study size and lack of a comparator group.
• Rheumatoid arthritis (RA). Oral garlic seems to reduce pain by a small amount in patients with RA. Details: Clinical research in females with RA shows that taking dried garlic (Garcin; Goldaru Co.) 500 mg twice daily, providing allicin 5 mg, for 8 weeks reduces pain after activity and improves functional ability by a small amount when compared with placebo. Fatigue and pain were reduced by approximately 13% and tender joint count was reduced by 47% (102680,103481). The long-term effect of garlic supplementation is unclear.
• Scleroderma. It is unclear if oral garlic is beneficial for scleroderma. Details: Clinical research shows that taking garlic 900 mg daily for 7 days does not have an effect on vasomotor function when compared with placebo in females with scleroderma (51374).
• Stress. Although there has been interest in using oral garlic for stress, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tick repellent. It is unclear if oral garlic is beneficial as a tick repellent. Details: Preliminary clinical research shows that taking garlic 1200 mg daily for 8 weeks reduces the number of tick bites when compared with placebo (3318). However, the effect of garlic when compared with commercially available tick repellents is unknown (8027).
• Tinea capitis. Although there has been interest in using topical garlic for tinea capitis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tinea corporis. It is unclear if topical garlic is beneficial for tinea corporis. Details: Applying a gel containing 0.6% ajoene, a constituent of garlic, twice daily for one week seems to be as effective as terbinafine 1% cream for tinea corporis (4767).
• Tinea cruris. It is unclear if topical garlic is beneficial for tinea cruris. Details: Applying a gel containing 0.6% ajoene, a constituent of garlic, twice daily for one week seems to be as effective as terbinafine 1% cream for tinea cruris (4767).
• Tinea pedis. It is unclear if topical garlic is beneficial for tinea pedis. Details: Applying a gel containing 1% ajoene, a constituent of garlic, twice daily seems to be more effective than 0.6% ajoene gel, and seems to be as effective as 1% terbinafine (Lamisil) for tinea pedis infections. Sixty days after completing one week of treatment, mycological cure occurred in 100% of patients using 1% ajoene, 72% of patients using 0.6% ajoene , and 94% of those using 1% terbinafine (8019). Additional research suggests that 0.4% ajoene gel twice daily has a 7-day cure rate of around 80% (4766).
• Trichomoniasis. Although there has been interest in using oral garlic for trichomoniasis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tuberculosis. Although there has been interest in using oral garlic for tuberculosis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Unstable angina. It is unclear if intravenous garlic is beneficial for unstable angina. Details: Preliminary clinical research in patients with unstable angina shows that giving garlicin, 60 mg by intravenous infusion daily for 10 days improves symptoms by 7% when compared with intravenous nitroglycerin (51244).
• Urinary tract infections (UTIs). Although there has been interest in using oral garlic for UTIs, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Vaginal candidiasis. It is unclear if oral or topical garlic is beneficial for vaginal candidiasis. Details: One small clinical study in asymptomatic patients with culture-positive candida infections shows that taking garlic (Garlicin, Nature's Way) 1050 mg (3 tablets) twice daily for 14 days does not improve vaginal symptoms, candida colony counts, or cases of vaginal candidiasis when compared with placebo (88405). Another small clinical study shows that application of a vaginal cream containing garlic and thyme nightly for 7 nights is as effective as clotrimazole vaginal cream for treating vaginal candidiasis (88387). However, it is unclear if this effect is due to garlic, thyme, or the combination.
• Warts. It is unclear if topical garlic is beneficial for warts. Details: Preliminary clinical research shows that applying a specific lipid-soluble garlic extract topically to warts on the hands twice daily results in wart resolution within 1-2 weeks. An aqueous garlic extract applied twice daily also seems to provide modest improvement, but only after 30-40 days of treatment (15030). The validity of these findings is limited by the lack of a comparator group.
• Wound healing. It is unclear if topical garlic is beneficial for wound healing. Details: Based on patient and physician evaluations, preliminary clinical research shows that applying an ointment containing fresh garlic in petroleum jelly twice daily for 2 weeks results in 80% of surgical wounds healing at a faster rate than those treated with petroleum jelly. Most patients also indicated that the wound treated with garlic experienced less discomfort (102676). More evidence is needed to rate garlic for these uses.

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POSSIBLY INEFFECTIVE

• Urine drug tests. Drinking water with goldenseal or adding goldenseal tea to urine does not appear to cause a false negative urine drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, or tetrahydrocannabinol (THC). Details: Goldenseal is often promoted to mask illicit drugs in the urine, but drinking one gallon of water with goldenseal or adding goldenseal tea to urine samples does not seem to cause a false negative immunoassay (EMIT and TDx) for cocaine, amphetamines, barbiturates, benzodiazepines, or opiates. It also does not produce a false negative for Microgenics CEDIA DAU assays for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, or THC (260,261,52599). Although adding goldenseal tea to urine samples at 15 grams per liter may produce a false-negative EMIT reading for the presence of THC, the adulteration is obvious due to a brownish color in the urine (52599). Some people also claim that goldenseal can cause a false positive on a drug screen. However, goldenseal does not seem to cause false positives for the fluorescent polarization immunoassay (FPIA) or thin-layer chromatography (TLC) assays for amphetamines, opiates, cocaine, methadone, or their metabolites (2590).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical goldenseal for acne, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral goldenseal for allergic rhinitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Anorexia nervosa. Although there has been interest in using oral goldenseal for anorexia nervosa, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Atopic dermatitis (eczema). Although there has been interest in using topical goldenseal for atopic dermatitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral goldenseal for CFS, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Conjunctivitis. Although there has been interest in using goldenseal as an eye drop for conjunctivitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Dandruff. Although there has been interest in using topical goldenseal for dandruff, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Flatulence. Although there has been interest in using oral goldenseal for flatulence, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Gastritis. Although there has been interest in using oral goldenseal for gastritis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Gingivitis. Although there has been interest in using goldenseal as a mouthwash for gingivitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Hemorrhoids. Although there has been interest in using oral goldenseal for hemorrhoids, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Herpes labialis (cold sores). Although there has been interest in using topical goldenseal for herpes labialis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Menorrhagia. Although there has been interest in using oral goldenseal for menorrhagia, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Otitis media. Although there has been interest in using goldenseal as an ear drop for otitis media, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Peptic ulcers. Although there has been interest in using oral goldenseal for peptic ulcers, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Respiratory tract infections. Although there has been interest in using oral goldenseal for various respiratory tract infections, including influenza, pneumonia, rhinosinusitis, and the common cold, there is insufficient reliable information about the clinical effects of goldenseal for these conditions.
• Tinnitus. Although there has been interest in using goldenseal as an ear drop for tinnitus, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Urinary tract infections (UTIs). Although there has been interest in using oral goldenseal for UTIs, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Uveitis. Although there has been interest in using goldenseal as an eye drop for uveitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Vaginitis. Although there has been interest in using oral goldenseal for vaginitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
• Wound healing. Although there has been interest in using topical goldenseal for wound healing, there is insufficient reliable information about the clinical effects of goldenseal for this purpose. There is insufficient reliable information available about the effectiveness of goldenseal for its other uses.

(Read more about GOLDENSEAL)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical grapefruit oil for acne, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Asthma. It is unclear if oral grapefruit is beneficial in patients with asthma. Details: There is some evidence that consumption of vitamin C-rich citrus fruits, including grapefruit and others, might improve lung function in people with asthma. Intake of citrus fruits 1-2 times weekly has produced this benefit in some studies (6049,6055,6056). However, other studies have shown no benefit (6057,6058).
• Atherosclerosis. Although there has been interest in using oral grapefruit to treat or prevent atherosclerosis, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Atopic dermatitis (eczema). It is unclear if oral grapefruit seed extract is beneficial in patients with atopic dermatitis. Details: One small, uncontrolled clinical study in patients with atopic dermatitis shows that taking a specific grapefruit seed extract product (ParaMicrocidin, Allergy Research Group) 150 mg three times daily for one month can decrease complaints of constipation, flatulence, and abdominal discomfort, possibly due to changes in intestinal microflora (5866). The validity of these findings is limited by a lack of control group.
• Depression. Although there has been interest in using inhaled grapefruit oil as aromatherapy for depression, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Gingivitis. Although there has been interest in using topical grapefruit oil as a rinse for gingivitis, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Headache. Although there has been interest in using inhaled grapefruit oil as aromatherapy for headache, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Hypercholesterolemia. It is unclear if oral grapefruit is beneficial in patients with hypercholesterolemia. Details: One small clinical study in patients with hypercholesterolemia shows that taking capsules containing grapefruit pectin 5 grams three times daily for 16 weeks decreases total cholesterol by 8% and the ratio of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol by 10% when compared to baseline (2216). The validity of these findings is limited by the lack of a comparator group.
• Hypertriglyceridemia. It is unclear if oral grapefruit is beneficial in patients with hypertriglyceridemia. Details: One small clinical study in patients with hypertriglyceridemia that is not well controlled on statin therapy shows that consuming one red or white grapefruit daily for 30 days reduces total cholesterol by 8% to 15.5% and low-density lipoprotein (LDL) cholesterol by 11% to 20% when compared with placebo. In addition, consuming one red, but not one white, grapefruit daily reduces triglyceride levels by 17% when compared with placebo in these patients (53352).
• Intestinal parasite infection. Although there has been interest in using oral grapefruit seed extract for intestinal parasite infections, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Lice. It is unclear if topical grapefruit extract is beneficial in children with head lice. Details: One small clinical study in children aged 2-9 years with head lice shows that applying 50 mL of a specific shampoo containing grapefruit extract (Licatack shampoo) to the hair for 10-20 minutes and then rinsing with water and combing can eliminate adult lice. Applying a second application after 10 days seems to help remove any remaining nits (91417). The validity of these findings is limited by a lack of control group.
• Obesity. While some small studies suggest that oral grapefruit extract, taken in combination with other citrus extracts, may modestly improve weight loss, the effect of oral grapefruit alone is unclear. Details: One small clinical study in obese adults shows that consuming one and a half fresh grapefruits daily for 12 weeks reduces body weight by 1.3 kg when compared with placebo. Also, although drinking 8 ounces of grapefruit juice or taking grapefruit capsules three times daily for 12 weeks did not improve body weight when compared with placebo in the overall study population, a sub-group analysis of obese adults with metabolic syndrome shows that taking grapefruit capsules or drinking grapefruit juice increases weight loss and improves insulin resistance when compared with placebo (53353). Grapefruit has also been evaluated in combination with other citrus ingredients. Two clinical studies shows that taking a specific combination product (Sinetrol, Fytexia) containing sweet orange, blood orange, and grapefruit extracts for 12 weeks can decrease body weight, body fat percentage, and body mass index (BMI) in otherwise healthy overweight adults (95517,95518). In one study, taking this supplement as 450 mg twice daily for 12 weeks reduced body weight by 1 kg and body fat percentage by 6.5% when compared with placebo. Hip circumference, waist circumference, and blood glucose were also reduced when compared with placebo (95518). In another study, taking this same supplement as 700 mg twice daily for 12 weeks reduced body weight by 5.6 kg, body fat percentage by 5%, and BMI by 2% when compared to baseline. Patients taking placebo experienced no significant improvements from baseline (95517). It is not clear if these effects are due to grapefruit extract, other ingredients, or the combination.
• Pharyngitis. Although there has been interest in using topical grapefruit oil as a gargle for pharyngitis, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Psoriasis. Although there has been interest in using oral grapefruit for psoriasis, there is insufficient reliable information about the clinical effects of grapefruit for this purpose.
• Stress. Although there has been interest in using inhaled grapefruit oil as aromatherapy for stress, there is insufficient reliable information about the clinical effects of grapefruit oil for this purpose.
• Upper respiratory tract infection (URTI). Although there has been interest in using grapefruit oil as aromatherapy for various upper respiratory tract infections, including influenza and the common cold, there is insufficient reliable information about the clinical effects of grapefruit oil for these conditions.
• Vaginal candidiasis. Although there has been interest in using oral and topical grapefruit seed extract for vaginal candidiasis, there is insufficient reliable information about the clinical effects of grapefruit seed extract for this purpose. More evidence is needed to rate grapefruit for these uses.

(Read more about GRAPEFRUIT)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

(Read more about LIPASE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. In patients with deep wrinkles, preliminary clinical research shows that taking zinc citrate 50 mg and phytase 3,000 units daily for four days prior to a botulinum toxin treatment increases the patient-reported duration of botulinum toxin effects by approximately 25%, compared with no improvement in patients taking zinc gluconate 10 mg or placebo. The efficacy of botulinum treatment was also improved (101913). Whether this reported benefit is due to the dose or form of zinc, citrate, phytase, the combination, or other factors, is unclear (101913,101914).
• Blepharospasm. In patients with blepharospasm, preliminary clinical research shows that taking zinc citrate 50 mg and phytase 3,000 units daily for four days prior to a botulinum toxin treatment increases the patient-reported duration of botulinum toxin effects by approximately 25%, compared with no improvement in patients taking zinc gluconate 10 mg or placebo. The efficacy of botulinum treatment was also improved (101913). Whether this reported benefit is due to the dose or form of zinc, citrate, phytase, the combination, or other factors, is unclear (101913,101914).
• Child growth. Clinical research in infants consuming a corn-based diet shows that taking a fat- and micronutrient-based food supplement containing phytase, docosahexaenoic acid (DHA), arachidonic acid, and lysine increases linear growth at age 8 and 10 months and improves locomotor development when compared with not taking this supplement. In contrast, a similar fat- and micronutrient-based supplement without phytase, DHA, arachidonic acid, and lysine does not improve these indices when compared with not taking a supplement. The phytase-containing supplement did not affect linear growth, weight for age, or hand-eye coordination at 12 months (101902). These reported benefits to child growth are likely to be due to the combination of provided essential and non-essential nutrients. Any role of phytase is expected to be minimal.
• Iron deficiency anemia. Taking phytase with a meal containing phytate and iron increases iron absorption (101903,101904,101906). However, the effect of phytase specifically for the treatment of iron deficiency anemia remains unclear (101902). Phytase is sometimes added to the diet to increase the absorption of iron from food. In a small study of women, some with iron deficiency anemia, incubating wheat as a source of phytase with a traditional grain high in phytate increased iron absorption from the meal to 8.3% from 2.6% (101904). Also, adding microbial phytase to whole wheat rolls containing phytate increases iron absorption from a meal by approximately 82% when compared with rolls without added phytase (101906). In another small study, the addition of a microbial phytase to a single corn meal with added micronutrients increases iron absorption and incorporation into red blood cells after 14 days by 1.85-fold when compared with the meal without added phytase (101903). However, consuming white wheat rolls with added wheat bran as a source of phytase does not increase iron absorption from the meal when compared to consuming rolls with added wheat bran with deactivated phytase (101906). The use of phytase as treatment for iron deficiency, with or without anemia, has rarely been investigated. However, clinical research in infants consuming a corn-based diet shows that taking a fat- and micronutrient-based food supplement containing phytase, docosahexaenoic acid (DHA), arachidonic acid, and lysine for 6 months does not seem to be more effective for reducing anemia than taking the food supplement without phytase (101902).
• Zinc deficiency. Preliminary clinical research shows that adding phytase 20.5 units to a millet-based porridge with added zinc immediately prior to consumption increases zinc absorption by approximately 68% in children aged 12-24 months (101911). Some of these children had low plasma levels of zinc at baseline. However, the use of phytase specifically for the treatment of zinc deficiency has not been investigated. More evidence is needed to rate phytase for these uses.

(Read more about PHYTASE)

Proteolytic enzymes represent a wide group of enzymes that are used alone or in combination. See specific monographs for effectiveness information.

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

POSSIBLY EFFECTIVE

• Benign prostatic hyperplasia (BPH). Taking oral pumpkin seed or pumpkin seed oil may improve symptoms of BPH. Details: One study in patients with BPH shows that taking pumpkin seed 5 grams twice daily for 12 months may be more effective for controlling symptoms than pumpkin seed extract 1000 mg twice daily (92383). A specific pumpkin seed extract (Prosta Pink Forte) 1-2 capsules daily for 12 weeks has also been used (11231). Some preliminary clinical research also suggests that taking pumpkin seed oil (Prostafit, EuRho Vital) two tablets daily for 6 months may be as effective as the medication prazosin (92382). Pumpkin seed oil has also been compared with tamsulosin. A clinical study comparing pumpkin seed oil 360 mg twice daily to tamsulosin 0.4 mg once nightly for 3 months shows that both treatment groups report improvements in BPH symptoms and quality of life when compared with baseline, although improvement appears greater in the tamsulosin group, specifically when measured at 1 month and 3 months. In the pumpkin seed oil group, adverse effects were reported in 0% of patients, compared with 15% of patients taking tamsulosin (107842). The validity of this study is limited due to the short duration of treatment. Pumpkin seed oil or extracts have also been studied in combination with saw palmetto (6777), with saw palmetto, nettle root, and lemon extracts plus beta carotene (5093), and with saw palmetto, small flowered willow herb, lycopene, and pygeum (92379).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Oral pumpkin seed oil might improve hair regrowth in males with mild to moderate hair loss. Details: Clinical research in males with mild to moderate hair loss shows that taking pumpkin seed oil (Octa Sabal Plus, Dreamplus Co. Ltd.) 400 mg daily in divided doses for 24 weeks increases hair count by 30% when compared with placebo. Self-rated improvement and satisfaction scores were 62% and 52% with pumpkin seed oil and placebo, respectively (92378). Clinical research in patients with female pattern hair loss shows that applying 1 mL of pumpkin seed oil to the scalp daily for 30 days improves hair regrowth similarly to minoxidil 5% foam, 1 mL daily (104974).
• Interstitial cystitis. Although there is interest in using oral pumpkin for interstitial cystitis, there is insufficient reliable information about the clinical effects of pumpkin for this condition.
• Intestinal parasite infection. Although there is interest in using oral pumpkin for intestinal parasite infection, there is insufficient reliable information about the clinical effects of pumpkin for this condition.
• Overactive bladder. Oral pumpkin seed oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with overactive bladder shows that taking a specific combination product (Granu Fink femina, Omega Pharma) containing pumpkin seed oil 227 mg, sweet sumac bark extract 56 mg, and hops cone extract 18 mg three times daily for 12 weeks decreases the frequency of urination and leakage and improves quality of life when compared to baseline (103253). The validity of these findings is limited by the lack of a control group. Additionally, it is unclear if these findings are due to pumpkin seed oil, other ingredients, or the combination.
• Urinary tract infections (UTIs). Although there is interest in using oral pumpkin for UTIs, there is insufficient reliable information about the clinical effects of pumpkin for this condition. More evidence is needed to rate pumpkin for these uses.

(Read more about PUMPKIN)

POSSIBLY EFFECTIVE

• Menopausal symptoms. Oral rhubarb root extract seems to help improve symptoms of menopause. Details: Clinical research in perimenopausal and postmenopausal patients shows that taking a specific dry extract of rhubarb root (ERr 731, Estroease, Lupin Pharmaceuticals) 4 mg orally daily for 3-27 months improves symptoms of menopause by 46% to 83% compared to an improvement of less than 20% with placebo. About 83% of females taking the rhubarb extract report overall clinical improvement, with specific improvements in anxiety, hot flushes, sweating, sleep, mood, quality of life, fatigue, sexual problems, urinary tract problems, vaginal dryness, and joint and muscle issues (92294,92295,92296,92297,92298,108960).
• Pancreatitis. Oral or rectal rhubarb might improve symptoms and duration of hospital stay in individuals with acute pancreatitis. It is unclear if oral rhubarb helps to prevent pancreatitis in individuals undergoing endoscopic retrograde cholangiopancreatography (ERCP). Details: Meta-analyses of clinical research in adults with acute pancreatitis in China shows that administering rhubarb 10-90 grams daily via gastric tube or rectal enema for 3-14 days, in combination with somatostatin, octreotide, or ulinastatin, reduces the risk for complications such as sepsis or kidney failure by 45%, duration of abdominal pain by 1.3-2 days, and duration of hospital stay by 6.7-6.9 days when compared with taking these medications alone (97922,100964). However, the included studies were of low methodological quality. Additionally, somatostatin and octreotide are not recommended for the treatment of acute pancreatitis by the American College of Gastroenterology or the American Gastroenterological Association (101001,100965). A separate meta-analysis and individual clinical studies show that administering rhubarb 6-20 grams 1-3 times daily for 5-14 days, usually via nasojejunal tube with early enteral nutrition, reduces the duration of hospital stay and improves abdominal symptoms when compared with enteral nutrition alone (92301,103475). The meta-analysis shows that administering rhubarb reduces hospital stay by 4.5 days and intensive care unit stay by 2.8 days. The use of rhubarb also reduced the duration of severe abdominal pain, abdominal distention, and abnormal bowel sounds by 1-2 days. However, there was no effect on mortality rate, infection rate, or the incidence of multiple organ dysfunction (103475). Rhubarb has also been studied for the prevention of pancreatitis in patients undergoing a specific procedure called endoscopic retrograde cholangiopancreatography (ERCP). Preliminary clinical research in patients at high risk for post-ERCP complications shows that drinking a raw rhubarb solution after the procedure reduces the incidence of post-ERCP pancreatitis by 74% and post-ERCP hyperamylasemia by 81% when compared to standard care. However, this study was of low methodological quality, and the rhubarb solution preparation and dose were not reported (97920).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). It is unclear if oral rhubarb reduces ARDS. Details: A small clinical study in patients with ARDS shows that administering rhubarb leachate 10 grams in 30 mL water via nasogastric tube three times daily for 7 days, in addition to standard treatment, modestly improves oxygenation and reduces indices of pulmonary vascular permeability when compared with standard treatment (97921).
• Appendicitis. Oral rhubarb has only been evaluated in combination with other ingredients for use in pediatric appendiceal abscess; its effect when used alone is unclear. Details: A large observational study in children 3-14 years old with appendiceal abscess also receiving intravenous antibiotics suggests that taking a rhubarb peony decoction twice daily for 7-14 days is associated with a higher clinical cure rate of 93% when compared with 81% in the control group, but does not improve length of stay, post-operative complications, or recurrence rate (112380). However, it is unclear if the effects are from rhubarb, other ingredients, or the combination.
• Canker sores. Topical rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small open-label clinical study in adults with mild canker sores shows that topical application of a specific combination product (Pyralvex Soluté, Laboratoires Norgine Pharma) containing rhubarb extract 5% and salicylic acid reduces the time to symptom resolution by about 3 days when compared to using a water control (97919).
• Chronic kidney disease (CKD). It is unclear if oral rhubarb prevents the progression of CKD or improves markers of kidney function. Details: A meta-analysis of results from two low-quality clinical studies shows that taking rhubarb 1-7.7 grams daily for up to 48 months as part of traditional Chinese medicine does not delay the onset of kidney failure when compared with standard treatment (92302). However, these results were calculated using regression analysis rather than long-term follow-up, which limits the validity of these findings. Another meta-analysis of clinical research shows that rhubarb may improve serum creatinine and blood urea nitrogen in patients with CKD when compared with no treatment (92302). However, rhubarb does not appear to improve blood urea nitrogen when compared with captopril (71329). The validity of the research to date is limited by the low to very low methodological quality of the studies and the high risk of bias. Additionally, all of the studies were conducted in China; it is unclear if these findings are applicable to other populations.
• Constipation. It is unclear if rhubarb is beneficial for constipation. Details: A small clinical study in middle-aged adults with constipation shows that taking rhubarb extract 12.5 mg or 25 mg based on rhein content (Gutisrheum, Laboratories Ortis) at bedtime for 1 month improves stool frequency and consistency when compared with placebo (112381). The validity of these findings is limited by patient-reported outcomes. A clinical study in patients with chronic constipation, defined as having a bowel movement no more than twice per week, shows that a specific combination product (Nucarb; Wilshire Laboratories Ltd) containing rhubarb extract 250 mg, activated charcoal 180 mg, calcium sennosides 50 mg, peppermint oil 0.5 mg, fennel oil 0.5 mg, and sulfur 50 mg, taken as two tablets at bedtime for one week, followed by 1 tablet at bedtime for 1 week, reduces passing gas, abdominal pain, and sensation of bloating by 81%, 73%, and 72% respectively, when compared with baseline. Sensation of straining, severity of constipation, and feeling of incomplete evacuation were reduced by 69%, 67%, and 54% respectively, when compared with baseline (108853). The validity of these findings is limited by the lack of a comparator group, and it is unclear whether the effects are due to rhubarb, the combination, or other ingredients.
• Dysmenorrhea. It is unclear if oral rhubarb reduces dysmenorrhea. Details: Preliminary clinical research in young adults with dysmenorrhea shows that taking rhubarb root and rhizome powder 2520 mg daily, beginning 2 days before menstruation and continuing for 5 days, repeated for three consecutive cycles, has similar efficacy to mefenamic acid 500 mg three times daily in reducing pain and improving quality of life. Those receiving either treatment experienced an overall improvement of greater than 80%, which is attributed to a reduction in pain, fatigue, headache, and gastrointestinal symptoms (92300).
• Gastrointestinal bleeding. It is unclear if spraying rhubarb powder with a gastroscope reduces gastrointestinal bleeding. Details: In patients with acute gastrointestinal bleeding, a meta-analysis of mainly preliminary clinical research shows that spraying rhubarb powder under a gastroscope has a small to moderate hemostatic effect over 24-72 hours when compared with norepinephrine. The risk of re-bleeding over 48 hours was also reduced by about 58% (103474).
• Herpes labialis (cold sores). Topical rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that applying a cream containing rhubarb and sage to cold sores is similarly effective to acyclovir (Zovirax) cream. Acyclovir cream heals lesions in about 6.3 days; the rhubarb and sage cream heals lesions in about 7.2 days (10437). It is not clear if these improvements are due to the treatments used or to the natural resolution of the cold sores. Additionally, it is unclear if the benefit is due to rhubarb, other ingredients, or the combination.
• Hypercholesterolemia. It is unclear if oral rhubarb helps to lower cholesterol levels. Details: A very small clinical study including 10 males with hypercholesterolemia shows that eating ground rhubarb stalk fiber 27 grams daily for 4 weeks reduces total cholesterol by 8% and low-density lipoprotein (LDL) cholesterol by 9%, but does not affect high-density lipoprotein (HDL) cholesterol levels, when compared to baseline (71363). The validity of these findings is limited by the very small study size and the lack of a comparator group.
• Malignant pleural effusions. Topical rhubarb powder has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients living in China with advanced malignant cancer and malignant pleural effusions shows that applying a combination product (Hehuang Company) containing rhubarb powder 100 grams and mirabilite 400 grams to the chest wall for 8 hours daily for 28 days as an adjunct to standard therapy leads to partial or complete reduction of effusion in 67% of participants, compared with 55% of those receiving placebo and standard therapy (105961).
• Nasopharyngeal cancer. Oral rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with nasopharyngeal carcinoma shows that taking a specific combination product (Shenlong) containing rhubarb and other herbs along with radiation therapy does not improve tumor remission or survival when compared to radiation therapy alone (71380).
• Nonalcoholic fatty liver disease (NAFLD). Oral rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with NAFLD shows that taking 3-5 tablets of a specific Chinese herbal medicine (Danning Pian) containing rhubarb, giant knotweed, dried green orange peel, and dried ripe orange peel three times daily for 3 month improves lipids, liver function, and clinical symptoms (71315). It is not clear if this effect is due to rhubarb, the other ingredients, or the combination.
• Obesity. It is unclear if oral rhubarb is beneficial for weight loss. Details: A small clinical study in overweight and obese females shows that taking rhubarb with ginger, astragalus, red sage, and turmeric does not reduce body weight when compared with placebo (20346).
• Organophosphorus pesticide poisoning. It is unclear if giving rhubarb by gastric tube, nasal feeding, or enema is beneficial for organophosphorus pesticide poisoning. Details: A meta-analysis of low-quality clinical research in patients with acute organophosphorus pesticide poisoning shows that taking crude rhubarb 9-120 grams daily via gastric tube, nasal feeding, or retention enema, in conjunction with standard treatment, decreases the incidence of intermediate syndrome by 78% and organ dysfunction syndrome by 66% when compared to standard treatment alone. Rhubarb also reduces the duration of hospital stay by 2.8 days, but with no change in mortality rate, when compared to standard treatment alone. Standard treatment in these studies included atropine, pralidoxime, ventilation, diuresis, other supportive measures, and/or mannitol (92303).
• Sepsis. It is unclear if oral rhubarb is beneficial for sepsis. Details: A meta-analysis of low-quality clinical research in patients with sepsis or systemic inflammatory response syndrome (SIRS) shows that taking rhubarb powder in conjunction with conventional therapy reduces the incidence of gastrointestinal dysfunction, but does not reduce mortality rate, when compared to conventional therapy alone (92305).
• Stroke. Oral rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of clinical research in patients with acute ischemic stroke shows that taking traditional Chinese medicine containing rhubarb root and rhizome in conjunction with traditional Western medicine for up to 30 days enhances overall clinical improvement by 27% when compared with traditional Western medicine alone. However, the validity of this outcome is limited by small sample size, the variability in the Chinese medicine formulas used, and the high risk for bias of the included studies (92299). More evidence is needed to rate rhubarb for these uses.

(Read more about RHUBARB)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Oral slippery elm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Retrospective population research has found that taking a specific product containing burdock root, Indian rhubarb, sheep sorrel, and slippery elm bark (Essiac, Resperin Canada Limited) does not improve quality of life in breast cancer patients and may have a negative effect on physical well-being (37419).
• Constipation. Although there has been interest in using oral slippery elm for constipation, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Cough. Although there has been interest in using lozenges containing slippery elm for cough, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Diarrhea. Although there has been interest in using oral slippery elm for diarrhea, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Inflammatory bowel disease (IBD). Although there has been interest in using oral slippery elm for IBD, including Crohn disease and ulcerative colitis, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Irritable bowel syndrome (IBS). Oral slippery elm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific formulation containing slippery elm inner bark, lactulose, oat bran, and licorice root can improve stool frequency by 20% and reduce abdominal pain and bloating in people with constipation-predominant IBS when compared to baseline. Also, taking a different formulation containing slippery elm inner bark, bilberry fruit, cinnamon quilts, and agrimony aerial parts can reduce abdominal pain, bloating, and flatulence in people with diarrhea-predominant IBS when compared to baseline, although stool frequency is increased in these individuals as well (35462). It is unclear if these findings are due to slippery elm, other ingredients, or the combination.
• Peptic ulcers. Although there has been interest in using oral slippery elm for peptic ulcers, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
• Pharyngitis. It is unclear if lozenges containing slippery elm are beneficial in patients with sore throat. Details: Slippery elm has demulcent properties and, when added to lozenges, may soothe sore throats (272,512,1740). However, clinical research is lacking. More evidence is needed to rate slippery elm for these uses.

(Read more about SLIPPERY ELM)

POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Oral turmeric seems to improve symptoms in people with allergic rhinitis. Details: A large clinical study in people with allergic rhinitis shows that taking a specific curcumin product (Organika Health Products) 500 mg daily for 2 months reduces nasal symptoms, including sneezing, itching, runny nose, and congestion, when compared with placebo (96138).
• Depression. Most research shows that oral curcumin, a constituent of turmeric, 1 gram daily improves symptoms of depression after 6 weeks when taken along with an antidepressant. However, it is unclear whether curcumin is beneficial when used for greater than 8 weeks. Details: Curcumin appears to be most beneficial for depression in middle aged patients compared to older patients, when taken for at least 6 weeks, and when used at a dose of at least 1 gram daily. In adults with major depressive disorder, a meta-analysis of data from six clinical studies, as well as individual studies not included in this analysis, show that taking curcumin 1 gram daily along with an antidepressant moderately improves depression symptoms when compared with placebo (96131,96139). Another meta-analysis of 10 studies shows symptom reductions in patients with major depression when combined with conventional antidepressants, but not when used alone in patients with milder depressive symptoms. However, the quality of the evidence is low (104971). When used alone, one clinical study shows that curcumin 1 gram daily for 6 weeks may be similarly effective to fluoxetine 20 mg daily. Taking both products together seems to be more effective than either product alone, increasing the response rate from 65% to 78% (89728). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that curcumin extract at doses of 500-1000 mg daily is provisionally recommended for monotherapy or adjunctive use in mild to moderate depression (110318).
• Dyspepsia. Oral turmeric may be modestly beneficial for some patients with dyspepsia. In patients with functional dyspepsia, small clinical studies show that oral curcumin, a constituent of turmeric, is similarly effective when compared with the proton-pump inhibitor omeprazole. Details: Clinical research shows that taking turmeric 500 mg four times daily for 7 days can relieve overall symptoms of dyspepsia in 64% more patients than taking placebo (11144). A small, unblinded clinical study in patients with a type of dyspepsia called postprandial distress syndrome shows that taking turmeric 250 mg or 500 mg orally three times daily after meals for 4 weeks is associated with reductions in symptom scores which are similar to those seen with simethicone 60 mg three times daily for 4 weeks. However, the recurrence rate upon stopping therapy was about 14% with simethicone, compared with 43% to 46% with turmeric (104963). In patients with functional dyspepsia, taking the constituent curcumin appears similarly effective when compared with omeprazole, but might not provide further symptom reduction in those also taking famotidine or omeprazole (106063,106801,111599). One small clinical study in Iran shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily in addition to famotidine 40 mg daily for 30 days is no more effective for reducing overall symptoms of dyspepsia, such as abdominal pain, heartburn, bloating, and nausea, when compared with famotidine alone (106063). Another small clinical study in Thailand shows that taking curcumin 500 mg four times daily for 4 weeks is similarly effective for reducing dyspepsia severity and improving satisfaction when compared with an unspecified dose of omeprazole and more effective when compared with placebo (106801). Similarly, a moderate-size clinical study in Thailand shows that taking curcumin 500 mg four times daily for 4 weeks is similarly effective for reducing dyspepsia severity when compared with omeprazole 20 mg daily. However, taking curcumin and omeprazole in combination did not provide further symptom reduction (111599). The validity of these results is limited by the high rate of study dropouts.
• Hyperlipidemia. Research is conflicting on whether oral turmeric, curcumin, or curcuminoids can reduce serum lipids. Any improvement in lipids is likely to be small. Reasons for the conflicting findings may relate to turmeric formulation, duration of treatment, and/or the baseline cholesterol status of the included patients. Details: Results from meta-analyses of clinical research show inconsistent and conflicting results. One large meta-analysis of over 50 clinical studies in healthy adults and those with a variety of conditions shows that supplementation with turmeric or curcumin 80-4000 mg daily for 4-24 weeks reduces total cholesterol by 4 mg/dL, low-density lipoprotein (LDL) cholesterol by 5 mg/dL, and triglycerides by 7 mg/dL and increases high-density lipoprotein (HDL) cholesterol by 2 mg/dL when compared with placebo (112119). Two other meta-analyses of 27 clinical studies agree that taking turmeric, curcumin, or curcuminoids moderately reduce triglyceride levels but suggest that turmeric does not improve total cholesterol when compared with placebo. However, the meta-analyses contradict one another on whether turmeric and its constituents reduce LDL cholesterol or increase HDL cholesterol. (96128,96135). Additionally, a third meta-analysis of 10 clinical trials shows that taking up to 2400 mg daily of curcumin or curcuminoids, from turmeric or isolated sources, for up to 12 weeks, does not significantly improve triglycerides, LDL cholesterol, HDL cholesterol, or total cholesterol (110220).
• Nonalcoholic fatty liver disease (NAFLD). Oral curcumin, a constituent of turmeric, seems to attenuate fat deposition and improve some metabolic parameters in adults with NAFLD. Details: Clinical research shows that taking curcumin daily reduces NAFLD severity in 30% to 79% of patients, compared to 5% to 27.5% of patients receiving placebo. Curcumin also reduces the quantity of additional fat deposition in the liver to 0% to 4.5%, compared to 17.5% to 26% in those taking placebo. Most research shows that taking curcumin also reduces liver enzyme levels, body mass index (BMI), blood glucose levels, glycated hemoglobin (HbA1c), and total cholesterol when compared with placebo. Although some clinical research shows that taking curcumin improves levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, a meta-analysis of clinical research shows that these lipid levels are not improved in patients with NAFLD, specifically (97430,97431,100258,102350,106062,107120,109279,111349). However, another meta-analysis of 14 small, heterogeneous clinical studies in adults with NAFLD, that included some of these studies, shows that taking various doses and forms of turmeric or curcumin modestly reduces liver enzyme levels, improves measures of insulin resistance, reduces waist circumference, and improves LDL, HDL, and triglyceride levels when compared with placebo (111348). A small clinical trial in patients with NAFLD given specific lifestyle recommendations shows that taking curcumin modestly reduces the frequency of metabolic syndrome and fatty liver but does not have beneficial effects on fatty liver-associated indices, adiposity, or the atherogenic index, when compared with placebo (109285). Findings for specific endpoints are mixed between individual studies and may depend on the formulation of curcumin used or the duration of treatment. These studies have used various doses and formulations. In one study, 500 mg of a dispersion formulation equivalent to 70 mg of curcumin daily for 8 weeks was used (97430). Also, 250 mg once daily or 500 mg twice daily of a specific phytosomal formulation (Meriva, Indena) containing curcumin and soy phosphatidylcholine in a 1:2 ratio and standardized to an overall curcuminoid content of 20% was taken for 8 weeks (97431,106062). Another study used 1 gram of powdered turmeric rhizome taken three times daily with meals for 12 weeks (102350). One study used a curcumin-piperine complex (Curcumin C3 complex 500 mg plus Bioperine 5 mg) daily for 8 weeks (107120). One study used curcumin (Arjuna Natural Extract) 500 mg three times daily for 12 weeks (109285). Despite positive results with curcumin in several small clinical studies of patients with NAFLD, there is some concern that curcumin might cause hepatotoxicity in rare cases, especially when highly bioavailable formulations are used in high doses (103633). There is also evidence that the risk for hepatotoxicity with curcumin may be increased in individuals with the HLAB*35:01 allele (109288). Curcumin-induced hepatotoxicity has not been reported in clinical trials of patients with NAFLD, and its potential mechanism is unclear. However, patients seeking to take curcumin for NAFLD should be advised to monitor for symptoms of hepatotoxicity, including abdominal pain, dark urine, fatigue, jaundice, nausea, and pruritus.
• Oral mucositis. Oral curcumin or curcumin-containing mouthwash seem to reduce the development of severe oral mucositis, as well as reduce the severity and pain of oral mucositis, associated with cancer treatment. Details: Clinical research in patients receiving radiotherapy following recent radical surgery for oral cancer shows that taking turmeric (BCM-95, Arjuna Natural Pvt. Ltd., India) during radiotherapy reduces the incidence of severe oral mucositis to 25% or 20% in those taking turmeric 500 mg two or three times daily, respectively, compared with 65% in those taking placebo. The incidences of severe oral pain, dysphagia, and dermatitis were also reduced by at least 50% (105398). A small clinical study in patients receiving chemotherapy with or without head and neck radiotherapy shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 7 weeks improves severity of oral mucositis at weeks 1, 4, and 7 and reduces pain at week 7 when compared with placebo. Effects were more pronounced in those with chemotherapy-induced oral mucositis than radiotherapy-induced oral mucositis (106800). In patients with head and neck cancer receiving radiotherapy, preliminary clinical research shows that swishing with 10 mL of turmeric solution (prepared by dissolving turmeric 400 mg in 80 mL of water) six times daily for 6 weeks delays mucositis and reduces the number of cases of intolerable mucositis by 49% when compared to swishing with 10 mL of povidone-iodine solution twice daily for 6 weeks (89726). Another small clinical study shows that swishing with 10 mL of nanoparticulate curcumin 0.1% mouthwash three times daily for 6 weeks is associated with a 50% lower risk of developing oral mucositis, and a delay of 2 weeks in the onset of mucositis, when compared with benzydamine 0.15% mouthwash (104969). A small clinical study in patients with mucositis due to head and neck radiotherapy shows that taking curcumin nanoparticles (SinaCurcumin, ExirNanoSina) 40 mg daily or using 10 mL of a curcumin 0.1% mouthwash three times daily for up to 21 days improves scores related to pain, burning, ulceration, and erythema when compared with placebo. Results with either oral or topical curcumin were similar (111350).
• Osteoarthritis. Some oral turmeric extracts and combination products containing turmeric seem to improve certain symptoms of knee osteoarthritis. However, it is unclear how turmeric compares to the use of non-steroidal anti-inflammatory drugs (NSAIDs). Details: Several meta-analyses of clinical studies show that turmeric extracts and/or curcuminoid products reduce knee pain and stiffness, improve physical function, and reduce the need for rescue medication when compared with placebo (104970,106792,109280,110222). However, a reduced effect was noted in patients with increasing age or body mass index (104790). The studies evaluated in these meta-analyses are heterogeneous, of low- to moderate-quality, and utilized a variety of products and/or dosing strategies (104970,106792,109280,110222). Small to moderate-sized clinical studies show that specific products (Meriva, Indena; Theracurmin, Theravalues Corp) containing curcumin 90-100 mg twice daily for up to 6 months, or specific turmeric extracts (Turmacin, Natural Remedies Pvt. Ltd.; Curcugen, DolCas Biotech, LLC) 500 mg twice daily for 6-12 weeks, reduce pain and analgesic use and improve functionality when compared with placebo (17953,80988,89721,97424,104148,107118). A specific turmeric extract (CuraMed, EuroPharma USA) 1500 mg daily for 12 weeks improves functionality, but not pain, when compared with placebo (96127). Also, a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina), 40 mg twice daily for 6 weeks, improves pain, stiffness, and physical activity scores and reduces intake of rescue acetaminophen by about 60% when compared with placebo (102349). However, not all turmeric products seem to be effective for improving symptoms of osteoarthritis. One small clinical study shows that taking a specific turmeric extract (B-Turmactive, PLAMECA S.A.) 500 mg daily for one week does not reduce knee pain when compared with placebo (104147). Also, a meta-analysis of clinical research shows that benefits are limited to bio-optimized forms of curcuminoids, and benefits related to pure extracts are lacking (110222). Turmeric has also been compared with conventional treatments for knee osteoarthritis in small meta-analyses, a network meta-analysis, and individual clinical studies. However, the evidence is mixed as to whether turmeric is as effective or more effective than NSAIDs, such as ibuprofen 400 mg taken 2-3 times daily, diclofenac 25-100 mg daily, or chondroprotective drugs (17952,89720,89722,106792,109280,110222,113607). A network meta-analysis comparing 6 interventions in adults with knee osteoarthritis suggests that curcumin monotherapy, curcumin with chondroprotective agents, or curcumin with NSAIDs improves scores related to pain, function, and stiffness while reducing the need for rescue medication and the incidence of adverse events (113607). Individual studies are heterogenous with respect to comparator medication and dosing schedule. Doses included a non-commercial turmeric extract 500 mg 3-4 times daily for 4-6 weeks (17952,89720) or turmeric extract 500 mg twice daily for 3 months (89722). Topical turmeric has also been evaluated. One clinical study shows that applying curcumin topically as a 5% ointment in Vaseline twice daily for 6 weeks reduces pain associated with knee osteoarthritis by a mean of about 11 on a 100-point visual analog scale when compared with placebo (104964). Another clinical study in patients with knee osteoarthritis shows that applying curcumin in a self-nano-emulsifying polyethylene glycol organogel 1.5 grams to the knee twice daily for 8 weeks reduces pain, stiffness, and difficulty with physical function scores by 72%, 62%, and 46%, respectively, when compared to baseline, with improvements superior to placebo for all outcomes (113357). Research also shows that taking specific combination products containing turmeric and other ingredients can improve pain and functionality in patients with osteoarthritis. These combination products have combined turmeric with chondroitin sulfate and glucosamine hydrochloride (CartiJoint Forte, Fidia Farmaceutici SpA); boswellic acid (Curamin, EuroPharma USA; Rhulief); Boswellia serrata (Rhulief); ashwagandha, Boswellia serrata, and zinc (Articulin-F, Eisen Pharmaceutical Co. Pvt. Ltd.); devil's claw and bromelain (AINAT, Laboratoire de Rhumatologie Appliquée); Boswellia serrata, guggul, and valerian (Phytoproflex, OPTM Healthcare); Boswellia serrata and terminalia (LI73014F2, Laila Nutraceuticals); ashwagandha, Boswellia serrata, and ginger (Artrex, Mendar); or extracts of ginger rhizome, devil's claw tuber, Boswellia serrata resin, and celery seed (Tregocel, Max Biocare) (19276,51950,81466,89717,89719,96127,97419,97421,97428,106078)(109280).
• Pruritus. Oral turmeric has been evaluated for the management of pruritus of various etiologies, with promising results. Details: Clinical research in patients with kidney failure shows that taking turmeric 500 mg orally three times daily for 8 weeks decreases symptoms of uremic pruritus by 1.9-fold when compared with placebo (89724). Also, a small clinical study in patients with sulfur mustard-induced chronic pruritus shows that taking a specific combination product (C3 Complex, Sami Labs LTD) containing curcumin 1 gram plus extract from black pepper or long pepper (Bioperine) daily for 4 weeks reduces pruritus severity and improves quality of life when compared with placebo (81120,81176).

POSSIBLY INEFFECTIVE

• Alzheimer disease. Neither oral turmeric nor its constituent curcumin appears to improve cognitive function or attenuate cognitive decline in adults with this condition. Details: A small clinical trial shows that taking the turmeric constituent, curcumin, 1-4 grams daily for 6 months does not improve mental state examination scores when compared with placebo (17096). Furthermore, a meta-analysis of this study and another small clinical study in patients with Alzheimer disease shows that the turmeric group experienced greater cognitive decline when compared with placebo (100261). While this research is limited by small study sizes and heterogeneous patient populations, the current evidence does not support the use of turmeric in patients with this condition.
• Peptic ulcers. Oral turmeric does not seem to improve the healing of peptic or gastric ulcers when compared with placebo or liquid antacids. Details: Some clinical research shows that taking turmeric 2 grams three times daily for 8 weeks does not improve the healing of peptic ulcers when compared with placebo in Vietnamese patients (81444). Also, taking powdered turmeric rhizome 250 mg four times daily for 6 weeks seems to be less effective than a liquid aluminum-magnesium-hydroxide antacid for promoting gastric ulcer healing (81284).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical turmeric for acne, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Age-related cognitive decline. Some small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve cognition in elderly patients experiencing cognitive decline. Details: A meta-analysis of three small clinical trials shows that curcumin modestly improves cognition in the elderly (100261). One of these clinical trials shows that taking a specific brand of curcumin (Theracurmin, Theravalues Corp.) 90 mg twice daily for 18 months improves long-term memory and attention when compared with placebo in middle-aged and older adults with or without mild cognitive impairment (96161).
• Amenorrhea. Although there has been interest in using oral turmeric for amenorrhea, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Ankylosing spondylitis. Although there has been interest in using oral turmeric for ankylosing spondylitis, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Aromatase inhibitor-induced arthralgia. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for aromatase inhibitor-induced arthralgia. Details: A small clinical trial in patients experiencing aromatase inhibitor-induced arthralgia shows that taking curcuminoids as a nanoemulsion (Curcumin C3 Complex, Sabinsa Corporation) 200 mg daily for 3 months does not improve grip strength or joint symptoms when compared with placebo (113345). However, this study may have been underpowered to detect a difference between groups.
• Asthma. Some small clinical studies suggest that oral turmeric, as an adjunct to conventional asthma treatment, does not improve lung function or symptoms in adults and children with asthma. Details: One small clinical study in adults with mild to moderate asthma shows that adjuvant therapy with turmeric as curcumin 500 mg twice daily for 30 days does not improve lung function based on FEV1, or improve symptoms such as dyspnea, wheezing, cough, or tightness, when compared to standard treatment alone (99349). A small clinical trial in children 7-18 years of age with moderate to severe asthma shows that adding turmeric 500-1000 mg (containing 20-40 mg curcuminoids) daily for 6 months to standard therapy does not improve overall asthma symptoms when compared with placebo and standard therapy, although it may decrease the frequency of nighttime awakenings and the use of rescue inhalers (99348). Due to their small sizes and high drop-out rates, these studies may have been underpowered to detect a difference between groups.
• Athletic performance. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for athletic performance. Details: Preliminary clinical research in middle-aged male long-distance runners shows that taking a turmeric extract providing 2 grams of curcumin 95% and piperine 5% daily for 6 weeks does not improve aerobic capacity when compared with placebo (109286).
• Benign prostatic hyperplasia (BPH). It is unclear if oral curcumin, a constituent of turmeric, is beneficial in BPH. Details: A clinical study in patients with BPH shows that taking curcumin 2250 mg once daily along with tamsulosin and finasteride for 6 months improves lower urinary tract symptoms related to storage, but not overall symptoms or symptoms related to voiding, by about 35%, compared with 25% in those receiving tamsulosin and finasteride alone. Periprostatic fat thickness, quality of life, and erectile function also were improved (106799).
• Beta-thalassemia. It is unclear if oral turmeric is beneficial for iron overload in patients with beta-thalassemia. Details: A small clinical study in patients with beta-thalassemia major and iron overload shows that taking turmeric extract containing curcumin 500 mg twice daily for 12 weeks modestly reduces non-transferrin bound iron (NTBI) by 0.6 micromol/L, but not hemoglobin, transferrin saturation, total iron binding capacity, ferritin, or hepcidin, when compared with placebo (99306). Another small clinical study in adult males with beta-thalassemia intermedia and iron overload shows that taking a higher dose of curcumin 500 mg three times daily for 12 weeks modestly reduces serum iron and ferritin turmeric levels and transferrin saturation when compared with placebo (108871).
• Bruises. Although there has been interest in using topical turmeric to alleviate bruising, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Cachexia. It is unclear if oral curcumin, a constituent of turmeric, is beneficial for cancer cachexia. Details: A small clinical trial in patients with cancer anorexia-cachexia syndrome shows that taking curcumin 800 mg twice daily for 8 weeks does not reduce weight loss or improve body composition or handgrip strength when compared with placebo (109283).
• Canker sores. Some preliminary research suggests that topical curcumin, a constituent of turmeric, is beneficial for minor canker sores. Details: Preliminary clinical research in young adults with minor canker sores shows that applying a 2% curcumin oral gel for 6 months reduces ulcer size, pain, and recurrence rate and increases healing rate similarly to 0.1% triamcinolone oral paste (104962). The validity of the study is limited by a lack of investigator blinding and the lack of an intention to treat analysis. Another small clinical study shows that applying a 1% curcumin nanomicelle gel (SinaCurcumin Pharmaceuticals) on lesions three times daily for one week is modestly more effective than applying a 2% curcumin gel for reducing pain and ulcer size (109282). The validity of this finding is limited by the lack of a non-curcumin comparator group.
• Carpal tunnel syndrome. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is unclear if topical curcumin, a constituent of turmeric, is beneficial for carpal tunnel syndrome. Details: A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing turmeric, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, and vitamins C, E, B1, B2, B6, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with control (111702). The validity of these effects is limited by a lack of blinding. The study may also be inadequately powered to detect a difference between groups. Additionally, it is unclear if the effects are due to turmeric, other ingredients, or the combination. Topical turmeric has also been investigated. A small clinical study in patients with mild to moderate carpal tunnel syndrome shows that applying a 1% curcuminoid gel (Sinanomin) to the wrists twice daily for 8 weeks modestly decreases symptom severity and improves function when compared with a placebo gel. However, there was no change in electrodiagnostic testing of the injury. All patients also used a night splint (113356).
• Chemotherapy-induced acral erythema. It is unclear if oral or topical turmeric reduces the risk for acral erythema from capecitabine. Details: A small clinical trial in adults with cancer shows that taking turmeric 4 grams daily for 6 weeks starting at the beginning of treatment with capecitabine does not reduce the incidence of acral erythema overall; however, it does seem to reduce acral erythema grade 2 or higher when compared with expected incidence rates (99309). Topical turmeric has also been evaluated. A clinical study in patients with colorectal, gastric, pancreatic, or breast cancer receiving capecitabine shows that applying a specific ointment (Alpha) standardized to contain curcumin extract 0.5% and henna extract 10% to the soles and palms twice daily, beginning on day 1 of chemotherapy and continued for 4 cycles, does not prevent acral erythema or improve World Health Organization severity scores when compared with placebo. A post-hoc analysis suggests that there may have been a trend toward delayed onset and progression; however, this study was not structured to assess these outcomes (108874).
• Chemotherapy-induced constipation. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced constipation. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks does not reduce symptoms of constipation when compared with placebo (107111).
• Chemotherapy-induced diarrhea. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced diarrhea. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks does not reduce symptoms of diarrhea when compared with placebo (107111).
• Chemotherapy-induced nausea and vomiting (CINV). It is unclear if oral curcumin reduces CINV. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks modestly reduces symptoms of nausea, but not vomiting, in the second and third months after the start of treatment when compared with placebo (107111).
• Chemotherapy-induced peripheral neuropathy. It is unclear if oral curcumin reduces symptoms of chemotherapy-induced peripheral neuropathy. Details: A small clinical study in patients with various forms of cancer receiving standard chemotherapy for that cancer type shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg twice daily for 9 weeks modestly reduces symptoms of chemotherapy-induced peripheral neuropathy over a three-month period when compared with placebo (107111).
• Chronic kidney disease (CKD). It is unclear if oral turmeric is beneficial for CKD. Details: A meta-analysis of four small clinical trials in patients with CKD related to diabetic nephropathy or lupus nephritis shows that taking curcumin or turmeric for 0.5-4 months moderately reduces proteinuria when compared with placebo (109276). Also, a small clinical trial in children and young adults ages 6-25 years with vascular dysfunction related to autosomal dominant polycystic disease (PKD) shows that curcumin powder 25 mg/kg daily for 12 months does not improve vascular function or kidney function when compared with placebo (107117).
• Colorectal adenoma. It is unclear if oral turmeric is beneficial for managing colorectal adenoma. Details: Preliminary clinical research in adults with familial adenomatous polyposis shows that taking curcumin 1500 mg twice daily for 12 months does not reduce the quantity or size of lower intestinal adenomatous polyps when compared with placebo (97427). A very small clinical trial in patients with familial adenomatous polyposis shows that taking 8 capsules daily of a turmeric extract, in a formulation also containing pepper fruit, spirulina, seaweed, and ginger root, for 6 months does not affect total polyp number or burden when compared with placebo. However, both number and burden were modestly reduced in the left colon. Each capsule provided curcuminoids 123.65 mg and turmerones 26.79 mg (110223).
• Colorectal cancer. It is unclear if oral turmeric is beneficial for the prevention or treatment of colorectal cancer. Details: A small clinical trial in patients undergoing chemotherapy following colorectal cancer surgery shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily for 8 weeks modestly improves some measures of quality of life when compared with placebo (107109). In addition, a small clinical study in people at high risk for colorectal cancer, such as those who smoke, shows that taking the turmeric constituent, curcumin, 4 grams daily for 30 days can reduce the number of precancerous rectal aberrant crypt foci (18204). It is not clear if this results in a reduced risk for colorectal cancer.
• Coronary artery bypass graft (CABG) surgery. One small study suggests that oral turmeric may reduce the risk for myocardial infarction after CABG surgery. Details: Preliminary clinical research shows that taking the turmeric constituent, curcuminoids, 4 grams daily in four divided doses, beginning 3 days prior to surgery and continuing for 5 days post-surgery, decreases the relative risk of myocardial infarction following CABG by approximately 56% when compared with placebo (81143).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral turmeric or its constituent, curcumin, is beneficial for reducing symptoms of COVID-19. Details: Small studies have evaluated curcumin as an adjunctive therapy in adults hospitalized with confirmed COVID-19. Patients in these studies also received treatments such as antimicrobials, anti-inflammatory medications, anticoagulants, antiretrovirals, and immunosuppressants (104966,105393,107119). One study shows that adding curcumin reduces the duration of shortness of breath by 6-9 days when compared with patients who received other treatments in combination with probiotics. However, there were no differences in the duration of other symptoms, including fever, cough, or sore throat. Subgroup analyses suggest that taking curcumin may improve oxygenation and reduce the need for supplemental oxygen or ventilation (105393). Another study shows that adding curcumin modestly reduces the time to resolution of COVID-19 symptoms, the length of supplemental oxygen use, and the likelihood for deterioration in the patients' condition when compared with patients who received other treatments alone (104966). A third study shows some benefit of curcumin on fever and cough when compared with baseline; however, it is unclear if any changes were significant when compared with placebo (107119). Doses of curcumin used in these studies include curcumin 525 mg with piperine 2.5 mg (C3 Complex, SamiDirect) twice daily, starting at admission and continuing for 14 days (105393), or a specific nanocurcumin product (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 2 weeks or 240 mg daily in divided doses for 7 days (104966,107119). Limitations of these studies include the small number of patients with severe symptoms, the large number of outcomes evaluated, the inconsistencies in other treatments used, the lack of clarity related to presentation of some results, and, in most cases, a lack of blinding. Turmeric has also been evaluated in adults in the outpatient setting with suspected or confirmed mild to moderate COVID-19. One small clinical study shows that taking curcumin (SinaCurcumin, ExirNanoSina) 80 mg twice daily for 14 days in addition to other COVID-19 treatments (mainly hydroxychloroquine and azithromycin) reduces the duration of cough, chills, myalgia, and smell and taste disturbance, but not dyspnea, fever, sore throat, or others, by 1-2 days when compared with placebo with other treatments (106802). The validity of this study is limited by the lack of confirmatory diagnosis at baseline and lack of consistency with other treatments, as well as the unclear reporting of symptom duration in relation to the initiation of treatment. Another small clinical study in outpatients confirmed to have COVID-19 shows that taking curcumin 1000 mg plus piperine 10 mg (Sami Labs Limited) daily for 14 days modestly improves weakness, but not cough, pain, headache, difficulty breathing, or biochemical indices, when compared with placebo (109278). Some research has also examined the effect of turmeric as part of a polyherbal combination. Clinical research in patients hospitalized for moderate COVID-19 symptoms shows that using an Ayurvedic formulation 1776 mg twice daily containing turmeric, ashwagandha, ginger, and Boswellia serrata (BV-4051) for 14 days modestly reduces the duration of illness and reduces the severity of fever, cough, and smell and taste dysfunction when compared to placebo. There was no beneficial effect on other symptoms, including nasal congestion, breathing difficulty, headache, and gastrointestinal symptoms. More than half of the patients were also treated with remdesivir which did not impact the majority of these findings (109899).
• Crohn disease. It is unclear if oral turmeric is beneficial for improving symptoms of active Crohn disease. Details: Some clinical research shows that taking the turmeric constituent, curcumin, 1.08 grams daily for one month, then 1.44 grams daily for one month, can reduce bowel movements, diarrhea, and abdominal pain when compared to baseline in patients with Crohn disease (79730). The validity of these findings is limited by the lack of a comparator group.
• Denture stomatitis. Topical turmeric may be beneficial for treating denture stomatitis. Details: A small clinical study in patients with denture stomatitis shows that applying topical curcumin gel (Curenext, Abbott Laboratories) three times daily for 2 weeks resolves denture stomatitis lesions similarly to clotrimazole ointment (106797).
• Diabetes. Low-quality clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve glycemic control in patients with diabetes. Details: A meta-analysis of small clinical trials in patients with diabetic kidney disease shows that curcumin reduces levels of fasting glucose by approximately 8.3 mg/dL when compared with placebo. Curcumin was used in doses of 66.3-1670 mg daily for 2-6 months (107114). Preliminary clinical research included in the analysis shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 12 weeks reduces fasting blood glucose by about 20 mg/dL (104149). Other meta-analyses of low- to moderate-quality clinical studies in patients with a variety of conditions including type 2 diabetes show that taking turmeric extract, curcumin, or curcuminoids for 4-36 weeks improves glycated hemoglobin (HbA1c) by 0.4-0.7% and reduces fasting glucose by approximately 13 mg/dL when compared with placebo or conventional treatment (106806,108877,113604). The validity of these findings is limited by the heterogeneity of the included studies and broad curcuminoid doses ranging from 46-1500 mg daily. Conversely, other meta-analyses in patients with type 2 diabetes show that curcumin does not reduce HbA1c or insulin levels when compared with placebo (104965,108877,113604).
• Diabetic foot ulcers. It is unclear if oral curcumin is beneficial in patients with diabetic foot ulcers. Details: Preliminary clinical research in patients with grade 3 diabetic foot ulcers shows that taking nanocurcumin 80 mg orally daily for 12 weeks does not improve glycated hemoglobin (HbA1c) or change the rate of ulcer healing when compared with placebo. Taking turmeric did result in modest decreases in fasting blood glucose, insulin levels, and insulin resistance (104972).
• Diabetic nephropathy. It is unclear if oral curcumin is beneficial in patients with diabetic nephropathy. Details: Meta-analyses of two to four small clinical trials in patients with diabetic kidney disease show that curcumin modestly improves serum levels of creatinine, total cholesterol, and fasting glucose, and reduces systolic blood pressure by 4 mmHg, when compared with placebo. However, there was no effect on diastolic blood pressure, proteinuria, or serum levels of other plasma lipids or blood urea nitrogen. Curcumin was used in doses of 66.3-1670 mg daily for 2-6 months (107114). One small study included in this analysis, which evaluated patients receiving hemodialysis, shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 12 weeks reduces fasting blood glucose by about 20 mg/dL when compared with placebo (104149).
• Dysmenorrhea. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in university students aged 18 to 24 in Iran with mild to severe primary dysmenorrhea and premenstrual syndrome (PMS) shows that taking a specific combination product containing curcumin 500 mg plus extract from black pepper 5 mg (C3 Complex, Sami Labs) daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation for 3 consecutive menstrual cycles, does not improve the severity of symptoms when compared with placebo (106805). Conversely, a small clinical study in adults with moderately painful dysmenorrhea shows that taking a single dose of a combination product containing turmeric, Boswellia serrata, and sesame (Rhuleave-K, Arjuna Natural Private Ltd.) 1000 mg at the start of menstruation relieves menstrual cramp pain and reduces pain intensity for up to 6 hours when compared with placebo (112806). However, it is unclear if these effects are due to turmeric, other ingredients, or the combinations.
• Endometriosis. It is unclear if oral turmeric is beneficial for reducing pain due to endometriosis. Details: A small clinical study in adults with endometriosis shows that taking the turmeric constituent, curcumin, 500 mg twice daily for 8 weeks does not affect pain associated with endometriosis or quality of life when compared with placebo (113603).
• Erythema. Although there has been interest in using topical turmeric for reducing erythema, there is insufficient reliable information about the clinical effects of turmeric for this purpose.
• Exercise-induced muscle soreness. It is unclear if oral turmeric is beneficial for reducing muscle soreness from exercise. Details: A small clinical study in healthy males shows that taking turmeric capsules containing curcumin 2.5 grams twice daily for 5 days, starting 2.5 days before exercise, slightly reduces pain from certain movements when compared with placebo (98998). Another small crossover clinical study in professional male soccer players shows that taking curcumin 500 mg (Elite Opti-Turmeric, Health Span) immediately, 12 hours, and 36 hours after a match accelerates muscle recovery and reduces delayed-onset muscle soreness when compared with medium chain triglyceride oil 1000 mg (111356). Turmeric has also been examined in combination with other ingredients. Clinical research in healthy active adults with moderate to severe exercise-induced muscle pain shows that taking a single, 1000-mg dose of turmeric and Boswellia serrata extracts in black sesame oil (Rhuleave-K; Arjuna Natural Private Ltd.) improves pain relief when compared with placebo, with maximal benefits within about 3 hours. The number of people needed to treat to obtain pain relief of at least 50% over a 6-hour period was 1.1 (109277).
• Gingivitis. Small clinical studies suggest that oral turmeric and turmeric mouthwash may reduce the severity of gingivitis. Turmeric mouthwash appears to be similarly effective to chlorhexidine mouthwash. Details: A meta-analysis of generally preliminary clinical research shows that rinsing with a mouthwash containing curcumin for 3-4 weeks is as effective as rinsing with chlorhexidine for reducing the severity of gingivitis or plaque (106059). Mouthwashes in these studies contained 0.05% to 20% curcumin and were usually used twice daily for 3-4 weeks (81127,89723,106059). One mouthwash contained 0.05% turmeric extract and 0.005% eugenol (89723). Another small clinical trial shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily by mouth after breakfast for 4 weeks reduces the severity of gingivitis and gingival bleeding, but not plaque, when compared with placebo in patients with gingivitis and mild periodontitis (104146).
• Gout. Although there is interest in using oral turmeric for gout, there is insufficient reliable information about the clinical effects of turmeric for this condition.
• Gulf war syndrome. It is unclear if oral curcumin is beneficial in patients with Gulf war syndrome. Details: A small preliminary clinical trial in patients with Gulf war syndrome shows that taking curcumin (Meriva, Indena, S.p.A.) 500 mg twice daily for 30 days reduces overall symptoms, including pain, fatigue, gastrointestinal distress, and others, by 19% when compared with baseline. Taking a higher dose of 2000 mg twice daily for an additional 30 days appears to be no more effective than the lower dose (105395).
• Helicobacter pylori. Small clinical studies suggest that oral turmeric is not beneficial for eradicating H. pylori when used alone or in combination with standard triple therapy or famotidine. Details: One small clinical study in patients with H. pylori gastritis shows that taking turmeric 2.1 grams daily for 4 weeks is less effective for eradicating H. pylori than taking an omeprazole-based triple regimen for one week (80957). Another small study in adults with peptic ulcers shows that taking a specific curcumin product (C3 Complex, Sami Labs LTD) 500 mg daily for 7 days, in conjunction with standard triple therapy, does not improve H. pylori eradication rates when compared with standard triple therapy alone. The addition of curcumin increased the resolution of dyspepsia symptoms by an additional 21%, but the clinical significance of this outcome is unclear (97420). In patients with dyspepsia, most of whom tested positive for fecal H. pylori antigen, clinical research shows that taking curcuminoids (C3 Complex, Sami Labs) 500 mg with piperine (Bioperine) 5 mg daily in addition to famotidine 40 mg daily for 30 days is no more effective for reducing fecal H. pylori antigen levels than taking famotidine alone (106063).
• Hypertension. It is unclear if oral curcumin is beneficial in patients with hypertension. Details: A meta-analysis of approximately 30 clinical studies in healthy adults or patients with a variety of conditions shows that taking turmeric, curcumin, curcuminoids, or nano-curcumin for 4 to 24 weeks reduces systolic blood pressure by about 2 mmHg and diastolic blood pressure by about 0.8 mmHg when compared with placebo (113602). However, these blood pressure reductions may not be clinically meaningful. In addition, most of the included studies were small and utilized heterogeneous dosing regimens.
• Impaired glucose tolerance (prediabetes). Oral turmeric may modestly improve glucose control in some patients with prediabetes. Details: In overweight or obese individuals with prediabetes, clinical research shows that taking a turmeric extract (BCM95 or Cucugreen; M/s Arjuna Natural Pvt Ltd.) 500 mg daily, providing 95% curcuminoids and at least 65% curcumin, for 90 days, either alone or in combination with zinc 30 mg as zinc gluconate, results in a small reduction in fasting glucose and glycated hemoglobin (HbA1c) when compared with placebo. There was also a small benefit in insulin sensitivity (105391). Other preliminary clinical research in adults with prediabetes shows that taking 500 mg of a combination of turmeric extract and Indian gooseberry extract in a 1:2 ratio along with phosphatidylcholine (EmbliQur) twice daily for 6 months modestly reduces fasting glucose and improves insulin resistance, when compared with placebo. However, changes in most other endpoints were not significantly different from placebo. Each 500 mg capsule contained turmeric extracts 29.86% and turmeric oil 1.27% (113355). The effect of turmeric on progression to type 2 diabetes in patients with prediabetes has also been investigated. Preliminary clinical research shows that taking a turmeric extract containing curcumin 750 mg twice daily for 9 months reduces the percentage of patients with prediabetes who develop type 2 diabetes when compared with placebo (81163).
• Irritable bowel syndrome (IBS). It is unclear if oral turmeric is beneficial for improving symptoms of IBS. Details: Preliminary clinical research in otherwise healthy adults with IBS shows that taking a turmeric extract (Cynara Turmeric, Lichtwer Pharma) 72-144 mg daily for 8 weeks reduces IBS symptoms by about 40% to 60% when compared to baseline (79565). The validity of this finding is limited by the lack of a comparator group. Taking a combination product (CU-FEO, Alfa Wasserman S.p.A.) containing curcumin 42 mg and fennel essential oil 25 mg per capsule twice daily for 60 days improves overall ratings of abdominal pain, abdominal distention, and quality of life by 24% when compared with placebo (97422). It is unclear if these effects are due to turmeric, fennel, or the combination. Observational research suggests that adding a supplement (Enterofytol PLUS) providing curcumin 42 mg and berberine 200 mg twice daily for 2 months to conventional IBS treatment is associated with improvements in symptoms, such as abdominal discomfort, distension, and stool status, by up to 48% when compared with conventional treatment alone. Use of the supplement was also associated with a 64% reduced need for conventional treatments (113354).
• Joint pain. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking capsules of a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 1500 mg, methylsulfonylmethane 500 mg, white willow bark extract 250 mg, ginger root concentrate 50 mg, Boswellia extract 125 mg, turmeric root extract 50 mg, cayenne 40 m H.U. 50 mg, and hyaluronic acid 4 mg in three divided doses daily for 8 weeks reduces joint pain severity by 37% compared to only 16% with placebo. However, it does not improve joint stiffness or function when compared with placebo (89560). It is unclear if these effects are due to turmeric, other ingredients, or the combination.
• Juvenile idiopathic arthritis (JIA). Although there is interest in using oral turmeric for JIA, there is insufficient reliable information about the clinical effects of turmeric for this condition.
• Knee pain. It is unclear if oral turmeric is beneficial for knee pain. Details: Clinical research in individuals with knee pain not related to existing arthritis shows that taking turmeric extract (TurmXTRA 60N; Inventia Healthcare Ltd. and Laila Nutraceuticals) 250 mg, providing 60% curcuminoids, once daily for 90 days modestly reduces pain associated with walking 80 meters when compared with placebo. The time taken to walk 80 meters and to climb nine steps was reduced by 4-5 seconds (105396).
• Lichen planus. Evidence is conflicting on whether turmeric is beneficial for lichen planus. Details: A meta-analysis of several small, heterogeneous, mostly low-quality clinical and observational studies in adults with oral lichen planus shows that oral or topical curcumin with or without corticosteroids for 2-12 weeks does not improve erythema, lesion size, or pain when compared with control (113605). Similarly, a network meta-analysis of small clinical trials in patients with oral lichen planus shows that applying topical turmeric gel does not improve symptoms, clinical resolution, clinical scores, or reduce pain when compared with other available interventions (111640). However, small individual clinical studies have shown some benefit in using turmeric for lichen planus. A small clinical study shows that taking a specific turmeric extract (Curcumin C3 Complex, Sabinsa Corporation) containing curcuminoids 6000 mg daily in three divided doses for 12 days can reduce erythema and ulceration associated with lichen planus when compared with placebo (81109). Another small clinical study shows that taking a nanocurcumin product (SinaCurcumin, ExirNanoSina) 80 mg orally once daily for 1 month reduces oral lichen planus lesion size, pain, and burning similarly to prednisolone 10 mg taken orally once daily for 1 month (104961).
• Metabolic syndrome. It is unclear if oral turmeric is beneficial for metabolic syndrome. Details: Research is conflicting on how turmeric, curcumin, and other formulations affect various measures of metabolic syndrome. Some clinical research and a meta-analysis of 13 clinical studies in patients with metabolic syndrome show that taking turmeric or curcumin decreases low-density lipoprotein (LDL) cholesterol, waist circumference by 2 cm, fasting blood glucose by 9 mg/dL, and diastolic blood pressure by 3 mmHg and increases high-density lipoprotein (HDL) cholesterol by 5 mg/dL when compared with placebo. However, other research shows that turmeric or curcumin have no effect on body weight, lipids, blood pressure, or blood glucose when compared with placebo (98999,99311,105400,109284,111347,112118). The validity of these effects is limited by high heterogeneity within the included studies and incomplete information about randomization and blinding. Studies have used turmeric, curcumin, and curcumin extract 80-2400 mg, in divided doses, daily for 4-12 weeks, nano-curcumin 80 mg daily for 12 weeks, or calebin A (CurCousin, Sabinsa), which is a constituent of turmeric, 25 mg twice daily for 3 months (98999,99311,105400,109284,111347,112118). Also, taking crude or phosphorylated curcuminoids 1 gram daily for 6 weeks does not improve sleep or reduce weight in these patients (105397).
• Migraine headache. It is unclear if oral curcumin is beneficial for migraine headache. Details: A small clinical trial in females with regular migraines shows that taking curcumin 500 mg twice daily for 8 weeks reduces the severity and duration, but not the frequency, of migraine headaches when compared with placebo. In individuals taking curcumin, the duration of headache per month was reduced by approximately 10.3 hours from baseline (107116).
• Myocardial infarction (MI). It is unclear if oral curcumin is beneficial for reducing myocardial injury following a MI. Details: Clinical research in patients with an acute MI shows that taking curcuminoids 500 mg plus piperine (Bioperine) 5 mg daily (Sami Labs) for 8 weeks does not improve ejection fraction, serum levels of cardiac troponin 1, blood pressure, levels of fasting blood glucose, or kidney function parameters when compared to placebo. However, there were some modest benefits on levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, glycated hemoglobin, and certain liver enzymes such as aspartate aminotransferase (AST) and alkaline phosphatase (ALP) (107115). The validity of this study is limited by its short duration and relatively small sample size.
• Obesity. Oral turmeric might modestly improve weight loss, although any effect is unlikely to be clinically significant. Details: Multiple meta-analyses of small, mostly low-quality clinical studies in adults with a variety of comorbid conditions show that taking various forms and doses of turmeric or curcumin results in an average weight loss of about 0.6-1 kg, a decrease in body mass index (BMI) of about 0.2-0.5 kg/m2, and a decrease in waist circumference of about 1.3 cm when compared with control (102345,111351,111352). A sub-analysis of dose and duration shows that a reduction in waist circumference only occurs with curcumin daily doses above 1000 mg, and duration of treatment longer than 8 weeks (102345).
• Oral submucous fibrosis. Small studies suggest that topical or oral curcumin might be beneficial for oral submucous fibrosis. However, the research is heterogenous with respect to outcomes, comparators, and the turmeric preparations, doses, and routes of administration utilized. Details: A meta-analysis of 3 small clinical trials shows that turmeric modestly improves mouth opening when compared with control. In addition, a systematic review of 11 studies shows that turmeric improves overall symptoms, including mouth opening, tongue protrusion, burning sensation, and cheek flexibility. However, studies were small with short duration and used variable dosing strategies. Most trials have studied oral turmeric 300-400 mg, either alone or with black pepper 100 mg or piperine 5 mg, for 3-6 months. Less commonly, turmeric was provided in lozenge form (105399). Also, a network meta-analysis suggests that the turmeric constituent curcumin with or without piperine is most the effective for reducing tongue protrusion when compared indirectly with various medical and antioxidant therapies; however, this analysis suggests that curcumin does not rank among the most effective interventions for improving mouth opening, burning sensation, or cheek flexibility (113514). Other preliminary clinical research shows that taking a specific oral product containing curcumin 300 mg and piperine 5 mg (Turmix tablets, Sanat Products), three times daily for 12 weeks, improves mouth opening, burning sensation, and tongue protrusion when compared with baseline, but not when compared with an antioxidant product containing alpha-lipoic acid, beta-carotene, copper, lycopene, selenium, and zinc. Mouth opening is further improved by concurrent use of a mouthwash (Turmix mouthwash, Sanat Products), containing 0.1% w/v turmeric extract (standardized to 95% curcumin), with thymol, eucalyptol, clove oil, mentha oil, and tea tree oil, twice daily for 12 weeks (102347). A small clinical study shows that applying topical curcumin gel (Curenext, Abbott Laboratories) 5 mg daily in 3-4 divided doses for 6 weeks, in combination with oral physical therapy, improves mouth opening similarly to using an aloe vera gel in combination with oral physical therapy. However, decreases in burning sensation are greater with aloe gel than curcumin gel (104967). It is not clear whether the gels, oral physical therapy, or the combination of both is responsible for the outcome. Finally, clinical research shows that applying a paste providing turmeric and holy basil 10 grams each, mixed in 10 mL of honey, to the oral mucosa 4 times daily for 3 months modestly improves mouth opening, tongue protrusion, and burning sensation and reduces the presence of fibrous bands when compared with taking a vitamin B supplement. There was no effect on the shape of the uvula (113325).
• Pain (acute). Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with acute musculoskeletal pain shows that taking a specific combination product containing turmeric and Boswellia serrata extracts in black sesame oil (Rhuleave-K; Arjuna Natural Private Ltd.) 1000 mg daily for 7 days is as effective as acetaminophen 1000 mg daily for pain relief, onset of pain relief, and onset of maximal pain relief (109287). This study is limited by its lack of blinding and placebo control. Additionally, the dose of acetaminophen used in this study is below the standard recommended daily dose.
• Periodontitis. There is limited evidence on the oral or topical use of turmeric or its constituent curcumin in patients with periodontitis. Details: A meta-analysis of heterogenous clinical studies in patients with chronic periodontitis suggests that use of local delivery gel products, usually turmeric 2% or a specific product containing curcumin (Curenext), modestly reduces pocket depth when compared with routine products, such as chlorhexidine. However, limited research suggests that curcumin products do not affect plaque or gingivitis measures, and curcumin irrigation does not affect pocket depth based on limited research (107108). A small preliminary clinical study in patients with severe chronic periodontitis shows that placing curcumin gel 2 mg on one side of the mouth along with scaling and root planing (SRP) reduces plaque and probing pocket depth, but not gingival index, when compared with SRP alone (101339). The use of oral curcumin has also been investigated. A small clinical trial in patients with gingivitis and mild periodontitis shows that taking a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily after breakfast for 4 weeks reduces the severity of gingivitis and gingival bleeding, but not plaque, when compared with placebo (104146).
• Physical performance. It is unclear if oral turmeric may be beneficial for improving physical performance in older adults. Details: A very small clinical study in moderately functioning, sedentary adults over age 65 with low-grade chronic inflammation shows that that taking a specific turmeric extract (Curcumin C3 Complex, Sabinsa Corporation) 500 mg twice daily for 12 weeks does not improve measures of physical function, walking speed, or muscle strength when compared with placebo (111357). However, this study may have been inadequately powered to detect any possible differences between groups.
• Polycystic ovary syndrome (PCOS). Small clinical studies suggest that oral curcumin may improve some metabolic parameters in patients with PCOS, but these improvements may not be considered clinically significant. Details: Clinical research in patients with PCOS shows that taking curcumin 500 mg one to three times daily for 6-12 weeks improves some metabolic parameters (104968,105394,106795). Conversely, a small clinical study in patients aged 18 to 45 with PCOS in Iran shows that taking curcumin 1000 mg daily for 12 weeks modestly reduces fasting glucose but does not improve other metabolic parameters when compared with placebo. Taking curcumin also did not improve testosterone levels or hirsutism scores (111355). Meta-analyses show that taking curcumin modestly decreases body mass index (BMI) and improves measures of glycemic control, including fasting glucose and insulin resistance, and levels of total cholesterol when compared with placebo or metformin alone. However, effects on high-density lipoprotein (HDL) cholesterol levels were mixed and there was no effect on low-density lipoprotein (LDL) cholesterol or triglyceride levels (105394,106795,110219). Other preliminary clinical research shows that taking curcumin decreases plasma dehydroepiandrosterone and fasting plasma glucose levels when compared with placebo (104968). Some clinical research also shows that taking nano-curcumin (SinaCurcumin, ExirNanoSina) 80 mg daily for 3 months is beneficial in patients already taking metformin 1500 mg daily. Taking curcumin had modest beneficial effects on fasting insulin and insulin resistance, as well as levels of testosterone, LDL cholesterol, HDL cholesterol, and triglycerides, when compared with metformin alone. There was no effect of curcumin on body weight, fasting blood glucose, or other hormones (106060).
• Postoperative pain. Small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly reduce pain in various postoperative recovery settings. Details: One small clinical study in patients undergoing laparoscopic cholecystectomy shows that taking curcumin 2 grams daily reduces postoperative pain, fatigue, and the need for analgesics by the second postoperative week when compared with placebo (81099). In patients undergoing surgery for inguinal hernia and/or hydrocele, taking curcumin 1.2 grams daily for 5 days reduces inflammation and tenderness by the sixth postoperative day when compared with placebo (81206). Curcumin was taken in 3-4 divided doses daily in these studies. Finally, taking a single dose of curcumin 200 mg after surgical removal of impacted third molars modestly reduces acute postoperative pain when compared with taking mefenamic acid 500 mg (99305).
• Premenstrual syndrome (PMS). It is unclear if oral turmeric may be beneficial for improving symptoms of PMS. Details: Some preliminary clinical research in patients with PMS shows that taking curcumin 100 mg twice daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation, improves physical, behavioral, and mood symptoms, as well as overall severity of symptoms, when compared with placebo (97433). Conversely, in university students aged 18 to 24 in Iran with mild to severe PMS and primary dysmenorrhea, a clinical study shows that taking a specific combination product containing curcumin 500 mg plus extract from black pepper 5 mg (C3 Complex, Sami Labs) daily, starting 7 days prior to menstruation and continuing for 3 days after menstruation for 3 consecutive menstrual cycles, does not improve the severity of symptoms when compared with placebo (106805).
• Prostate cancer. It is unclear if oral turmeric is beneficial for the prevention or treatment of prostate cancer. Details: One small clinical study shows that taking curcumin 1.8 grams orally three times daily for 7 days, starting 4 days prior to docetaxel and prednisone treatment and continuing for up to 6 cycles, reduces PSA levels by at least half in 59% of patients when compared to baseline. Also, all patients with measurable lesions showed at least stable disease after treatment, and 40% of patients showed partial response when compared with baseline (96132). It is unclear if the addition of turmeric is beneficial when compared with docetaxel and prednisone alone. In contrast, an additional small clinical trial shows that taking curcumin 6 grams daily for 7 days every 3 weeks, starting four days before docetaxel, does not improve PSA levels or progression-free or overall survival when compared with docetaxel alone (105392).
• Psoriasis. Evidence is limited to one small study of topical use in patients with scalp psoriasis. Details: Preliminary clinical research in adults with scalp psoriasis shows that applying a tonic of turmeric to the scalp twice daily for 9 weeks modestly improves overall symptoms and quality of life when compared with a placebo tonic (97429).
• Quality of life. Some preliminary clinical research suggests that oral curcumin might improve quality of life in patients with various chronic conditions. Details: Small or low-quality clinical trials in various patient populations show that taking curcumin improves at least some measures of quality of life when compared with placebo. Research has been conducted in patients with cancer, sulfur mustard-induced chronic pruritus, benign prostatic hyperplasia (BPH), or irritable bowel syndrome (IBS). Studies have evaluated curcumin 2250 mg once daily for 6 months, a specific combination product (C3 Complex, Sami Labs LTD) containing curcumin 500-1000 mg plus piperine (Bioperine) daily for 4-9 weeks, or a combination product (CU-FEO, Alfa Wasserman S.p.A.) containing curcumin 42 mg and fennel essential oil 25 mg per capsule twice daily for 60 days (81120,81176,97422,106799,107109,107111). Also, in patients with scalp psoriasis, applying a tonic of turmeric to the scalp twice daily for 9 weeks modestly improves quality of life when compared with a placebo tonic (97429).
• Radiation dermatitis. It is unclear if oral or topical turmeric is beneficial for reducing the severity of radiation dermatitis. Details: A meta-analysis of 4 clinical studies in patients with breast cancer shows that taking curcumin 500-2000 mg three times daily for 3-7 weeks or applying curcumin gel 500 mg three times daily for 7 weeks reduces the radiation dermatitis severity score by about 0.5 points (on a 4-point scale) when compared with placebo or other control (111354). The validity of this analysis is limited by the heterogeneity of the included studies. However, a small clinical study in patients with breast cancer shows that taking nanocurcumin 80 mg twice daily during and for up to 2 weeks after treatment does not reduce skin reaction severity overall, but does modestly reduce pain, when compared with taking placebo. Also, there was a small reduction in skin reaction severity near the end of the study. All patients also used aloe vera leaf as part of the hospital protocol (109281). Another small preliminary clinical study in head and neck cancer patients shows that a specific cream (Vicco turmeric cream, Vicco Laboratories) containing turmeric and sandalwood oil, applied 5 times daily during radiation therapy, seems to reduce frequency and severity of radiation dermatitis when compared with baby oil (99307).
• Radiation proctopathy. It is unclear if oral turmeric is beneficial for preventing proctitis or cystitis in patients receiving radiotherapy for prostate cancer. Details: A small clinical study in patients with prostate cancer shows that taking a specific nanocurcumin product (SinaCurcumin, ExirNanoSina) 120 mg daily, for 3 days before and also during a course of radiotherapy, does not reduce the occurrence of proctitis or cystitis when compared with placebo (100259). This study may have been underpowered to detect small treatment effects.
• Respiratory tract infections. Although there is interest in using oral turmeric for various respiratory tract infections, including bronchitis and the common cold, it has not been clinically evaluated.
• Rheumatoid arthritis (RA). Small clinical studies suggest that oral curcumin, a constituent of turmeric, may modestly improve some symptoms of RA. Details: Meta-analyses of small clinical trials in patients with RA show that taking curcumin alone or with other treatments modestly reduces overall RA symptoms, pain, and markers of inflammation when compared with control groups, including placebo or other treatments. However, some research shows that there is no beneficial effect on tender or swollen joint count from the limited available clinical research (109280,111358), while other research shows that there is a benefit (112117). Clinical studies have evaluated curcumin 120-1200 mg daily for 2 weeks to 3 months (11149,18205,96129). The validity of these findings is limited by the small size of the studies, and in some cases, the lack of a comparator group.
• Sarcopenia. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in elderly patients with sarcopenia shows that taking a specific slow-release product containing turmeric, protein, carbohydrate, and fiber (Cureit, Aurea Biolabs), 500 mg orally daily for 3 months, increases handgrip strength by about 1% and distance walked before feeling tired by about 6% when compared with placebo. It also increases weightlifting capacity by about 6% from baseline, compared with a 5% decrease from baseline in those taking placebo (104973). It is unclear whether these small changes are clinically meaningful.
• Schizophrenia. Although there is interest in using oral turmeric for improving cognitive function in patients with schizophrenia, there is insufficient reliable information about the clinical effects of turmeric for this use.
• Sepsis. It is unclear if oral curcumin, a constituent of turmeric, is beneficial in patients with sepsis. Details: A small clinical trial in patients admitted to the intensive care unit (ICU) with sepsis shows that a specific nanoparticle formulation of curcumin (SinaCurcumin, ExirNanoSina), 80 mg dissolved in water and administered via gastric tube following lavage twice daily for 10 days does not affect length of ICU stay, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, blood pressure, or heart rate when compared with placebo (108873).
• Smoking cessation. Oral turmeric has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing turmeric 50 mg, ashwagandha, Indian gooseberry, tribulus, bacopa, Albizia lebbeck, licorice, clove, ginger, cowhage, and holy basil (Smotect, Smotect India) daily for 3 months reduces the number of cigarettes smoked by approximately 3 per day when compared with placebo. This product also reduces levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity (112115). However, only data from patients who completed treatment were analyzed, which limits the validity of this study. It is unclear if these effects are due to turmeric, other ingredients, or the combination.
• Stress. It is unclear if oral turmeric is beneficial for reducing occupational stress in healthy adults. Details: A small clinical trial in healthy adults with occupational stress-related anxiety and fatigue shows that taking a specific type of turmeric (CurQfen, Akay Flavours and Aromatics Pvt Ltd.) that contains fenugreek dietary fiber for improved bioavailability at a dose of 500 mg twice daily for 30 days reduces stress and fatigue and improves quality of life when compared with placebo, and also when compared with a standard curcumin supplement with lower bioavailability (99308).
• Stroke. It is unclear if oral turmeric is beneficial for stroke. Details: A small clinical study conducted in Iran in adults with a recent ischemic stroke shows that taking curcumin 500 mg and piperine, a pepper constituent, 5 mg (Sami Lans, India) daily for 12 weeks reduces carotid intima-media thickness, triglycerides, total cholesterol, and systolic and diastolic blood pressure, but does not improve low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or quality-of-life indicators when compared with placebo (113601). The validity of this study is limited by the lack of statistical adjustment for multiple comparisons which can lead studies to erroneously show differences between treatment groups.
• Systemic lupus erythematosus (SLE). There is limited evidence on the oral use of turmeric in adults with lupus nephritis. Details: Preliminary clinical research in adults with lupus nephritis shows that taking turmeric 1.5 grams daily in three divided doses for 3 months reduces systolic blood pressure and improves kidney function when compared to baseline (81104). The validity of this finding is limited by the lack of a comparator group.
• Tuberculosis. It is unclear if oral turmeric is beneficial in patients receiving treatment for tuberculosis. Details: A small clinical study in adults receiving antituberculosis treatment shows that taking a formulation containing turmeric 0.5 grams and Tinospora cordifolia 0.5 grams twice daily for 4 months can reduce levels of Mycobacterium tuberculosis in the sputum and improve lesion healing when compared with antituberculosis treatment alone. Also, liver toxicity associated with the antituberculosis treatment seems to be reduced when administered with this formulation (80424). It is unclear if these effects are due to turmeric, Tinospora cordifolia, or the combination.
• Ulcerative colitis. It is unclear if oral or rectal turmeric, or its constituent, curcumin, is beneficial in adults with ulcerative colitis. Details: Although two small clinical studies in adults with ulcerative colitis show that taking oral turmeric extract 2-3 grams daily for 1-6 months improves the rate of remission and reduces relapse rate (79966,97423), a meta-analysis of these studies and one additional clinical study shows that turmeric does not improve remission rates when compared with placebo (99000). A specific product (Cur-Cure, Bara Herbs Inc) was used in some of these studies. Reasons for the conflicting findings are unclear, but may be due to small patient populations, concerns about blinding, and the inclusion of patients who were also taking immunomodulating drugs. It may also be due to differences in how a study measures remission. A meta-analysis of small clinical studies in patients with mild to moderate ulcerative colitis shows that adding oral curcumin 0.5-3 grams daily to standard treatment for 1-6 months may improve clinical remission rates, but not endoscopic remission rates, when compared with placebo (108872). However, the validity of this finding is limited by the small number of studies that evaluated endoscopic remission. A small clinical study shows that administering an enema form of turmeric extract (NCB-02, Himalaya Drug Company) as 20 mL, containing turmeric extract 140 mg, daily for 8 weeks increases response rate from 50% to about 93% and increases remission rate from about 31% to 71% when compared with placebo in patients with active ulcerative colitis. However, patients using the turmeric extract enema for shorter durations did not improve when compared with placebo (89729). Turmeric has also been investigated in combination with the Mediterranean diet. A small clinical trial shows that taking curcumin (VeNatura Curcumin Supplement) 800 mg twice daily while following the Mediterranean diet for 8 weeks is no more effective for improving ulcerative colitis symptom severity than following the Mediterranean diet without supplemental curcumin (113339).
• Uveitis. It is unclear if oral curcumin is beneficial for uveitis. Details: Observational research in patients with acute non-infectious uveitic macular edema shows that taking a specific hydrophilic curcumin product (Cucrcuwin, Diabec, Alfa Intes) 60 mg twice daily for 6 months, in conjunction with standard corticosteroid treatment, and then alone for an additional 6 months, modestly improves best corrected visual acuity, but not macular thickness or intraocular pressure, when compared with standard treatment alone for 6 months (107110).
• Wound healing. Although there is interest in using topical turmeric for wound healing, there is insufficient reliable information about the clinical effects of turmeric for this condition. More evidence is needed to rate turmeric for these uses.

(Read more about TURMERIC)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Biliary disorders. Although there has been interest in using oral wormwood for biliary disorders, there is insufficient reliable information about the clinical effects of wormwood for this purpose.
• Crohn disease. Small clinical studies suggest that oral wormwood may modestly improve symptoms in patients with Crohn disease. Details: Preliminary clinical research in patients with Crohn disease shows that taking a specific product (SedaCrohn, Noor Herbals, LLC) containing powdered wormwood 750 mg 2-3 times daily for 6-10 weeks improves quality of life and mood, increases symptom remission, and reduces corticosteroid requirements when compared with placebo (86545,93468). Clinical remission occurred in 8 out of 10 patients taking wormwood, compared with only 2 out of 10 patients taking placebo (93468).
• Depression. Although there has been interest in using oral wormwood for depression, there is insufficient reliable information about the clinical effects of wormwood for this purpose.
• Dyspepsia. Although there has been interest in using oral wormwood for dyspepsia, there is insufficient reliable information about the clinical effects of wormwood for this purpose.
• Gastritis. Although there has been interest in using oral wormwood for gastritis, there is insufficient reliable information about the clinical effects of wormwood for this purpose.
• IgA nephropathy. It is unclear if oral wormwood is beneficial in patients with IgA nephropathy. Details: Preliminary clinical research in patients with IgA nephropathy shows that taking powdered wormwood (Seda-Leukin, Noor Herbals LLC) 600 mg three times daily for 6 months along with standard treatment reduces proteinuria when compared with baseline. The urinary protein:creatinine ratio decreased from 2340 mg/gram to 315 mg/gram over 6 months. Furthermore, systolic and diastolic blood pressures decreased by 10% and 14%, respectively (93469). The validity of these findings is limited by the lack of a comparator group.
• Insect bite. Although there has been interest in using topical wormwood for insect bites, there is insufficient reliable information about the clinical effects of wormwood for this purpose.
• Osteoarthritis. It is unclear if topical wormwood is beneficial in patients with knee osteoarthritis. Details: Preliminary clinical research in patients with knee osteoarthritis shows that applying an ointment or liniment containing wormwood extract 3% to the knee three times daily for 4 weeks might improve pain, although any pain improvement was not maintained 2 weeks after discontinuation. Topical wormwood appears to be less effective than topical piroxicam gel, which improves pain, stiffness, and physical function when compared with baseline, with benefits maintained 2 weeks after discontinuation (95925). More evidence is needed to rate wormwood for these uses.

(Read more about WORMWOOD)

LIKELY SAFE ...when the fruit (nut) is consumed in amounts normally found in food.

POSSIBLY UNSAFE ...when the bark is used orally or topically, due to its juglone content (2). When applied topically, juglone-containing bark can cause skin irritation. When used orally on a daily basis, the juglone-containing bark of a related species (English walnut) is associated with increased risk of tongue cancer and lip leukoplakia (2,12). There is insufficient reliable information available about the safety of the leaf or hull when used orally as a medicine or when applied topically.

PREGNANCY AND LACTATION: LIKELY SAFE
when the fruit (nut) is consumed in amounts normally found in foods.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when the bark is used orally or topically (12); avoid using. There is insufficient reliable information available about the safety of black walnut leaf or hull when used orally in medicinal amounts during pregnancy or lactation; avoid using.

(Read more about BLACK WALNUT)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when clove oil is applied topically (272). A clove oil 1% cream has been applied to the anus with apparent safety for up to 6 weeks (43487). A liposome-based product containing clove oil 45% has been applied to the palms with apparent safety for up to 2 weeks (100596).

LIKELY UNSAFE ...when clove smoke is inhaled. Smoking clove cigarettes can cause respiratory injury (17,43599). ...when clove oil is injected intravenously. This can cause pulmonary edema, hypoxemia, and acute dyspnea (16384). There is insufficient reliable information available about the safety of using clove orally in medicinal amounts.

CHILDREN: LIKELY UNSAFE
when clove oil is taken orally. Ingesting 5-10 mL of undiluted clove oil has been linked to reports of coagulopathy, liver damage, and other serious side effects in infants and children up to 3 years of age (6,17,43385,43395,43419,43457,43652).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (4912). Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of using clove in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about CLOVE)

LIKELY SAFE ...when the fruit (nut), leaf, or hull is consumed in amounts normally found in foods (4912,6431,8476,8477).

POSSIBLY SAFE ...when the leaf extract is used orally at doses of up to 200 mg for up to 3 months (97749,97750).

POSSIBLY UNSAFE ...when the bark is used orally or topically, due to its juglone content (12). When applied topically, juglone-containing bark can cause skin irritation. When used orally on a daily basis, juglone-containing bark is associated with increased risk of tongue cancer and lip leukoplakia (2,12). There is insufficient reliable information available about the safety of the fruit, leaf, or hull when used orally in medicinal amounts or when applied topically.

PREGNANCY AND LACTATION: LIKELY SAFE
when the fruit (nut), leaf, or hull is consumed in amounts normally found in foods (4912).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when the bark is used orally or topically (12); avoid using. There is insufficient reliable information available about the safety of the fruit, leaf, or hull when used orally in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about ENGLISH WALNUT)

LIKELY SAFE ...when the fruit is consumed orally in food amounts (13527). There is insufficient reliable information available about the safety of European barberry when used orally in medicinal amounts or when used topically.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of European barberry can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589). There is insufficient reliable information available about the safety of European barberry when used orally in older children.

PREGNANCY: LIKELY UNSAFE
when used orally. Berberine is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589).

LACTATION: LIKELY UNSAFE
when used orally. Berberine and other harmful constituents can be transferred to the infant through breast milk (2589).

(Read more about EUROPEAN BARBERRY)

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

POSSIBLY SAFE ...when fennel essential oil or extract is used orally and appropriately, short-term. Twenty-five drops (about 1.25 mL) of fennel fruit extract standardized to fennel 2% essential oil has been safely used four times daily for 5 days (49422). Also, two 100 mg capsules each containing fennel 30% essential oil standardized to 71-90 mg of anethole has been safely used daily for 8 weeks (97498). Powdered fennel extract has been used with apparent safety at a dose of 800 mg daily for 2 weeks (104199). ...when creams containing fennel 2% to 5% are applied topically (49429,92509).

CHILDREN: POSSIBLY SAFE
when combination products containing fennel are used to treat colic in infants for up to one week. Studied products include up to 20 mL of a fennel seed oil emulsion; a specific product (ColiMil) containing fennel 164 mg, lemon balm 97 mg, and German chamomile 178 mg; and up to 450 mL of a specific tea (Calma-Bebi, Bonomelli) containing fennel, chamomile, vervain, licorice, and lemon balm (16735,19715,49428).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Observational research has found that regular use of fennel during pregnancy is associated with shortened gestation (100513).

LACTATION: POSSIBLY UNSAFE
when used orally. Case reports have linked consumption of an herbal tea containing extracts of fennel, licorice, anise, and goat's rue to neurotoxicity in two breast-feeding infants. The adverse effect was attributed to anethole, a constituent of fennel and anise (16744). However, levels of anethole were not measured in breastmilk, and the herbal tea was not tested for contaminants. Furthermore, other adverse effects related to use of fennel during lactation have not been reported. However, until more is known, avoid using.

(Read more about FENNEL)

LIKELY SAFE ...when used orally and appropriately. Garlic has been used safely in clinical studies lasting up to 7 years without reports of significant toxicity (1873,4782,4783,4784,4785,4786,4787,4789,4790,4797)(4798,6457,6897,14447,96008,96009,96014,102016,102670,103479)(107238,107239,107352,108607,110722,111763).

POSSIBLY SAFE ...when used topically. Garlic-containing gels, lipid-soluble garlic extracts, garlic pastes, and garlic mouthwashes have been safely used in clinical research for up to 3 months (4766,4767,8019,15030,51330,51386). ...when used intravaginally. A vaginal cream containing garlic and thyme has been safely used nightly for 7 nights (88387).

POSSIBLY UNSAFE ...when raw garlic is used topically (585). Raw garlic might cause severe skin irritation when applied topically.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts. Garlic is reported to have abortifacient activity (11020). One study also suggests that garlic constituents are distributed to the amniotic fluid after a single dose of garlic (4828). However, there are no published reports of garlic adversely affecting pregnancy. In clinical research, garlic 800 mg daily was used during the third trimester of pregnancy with no reported adverse outcomes (9201,51626). There is insufficient reliable information available about the safety of topical garlic during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).

LACTATION: POSSIBLY UNSAFE
when used orally in amounts greater than those found in foods. Several small studies suggest that garlic constituents are secreted in breast milk, and that nursing infants of mothers consuming garlic are prone to extended nursing (3319,4829,4830). There is insufficient reliable information available about the safety of topical garlic during lactation.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately for up to 8 weeks. Garlic extract 300 mg three times daily has been used with apparent safety for up 8 weeks in children ages 8-18 years (4796). There is insufficient reliable information available about the safety of garlic when used over longer durations or in higher doses.

CHILDREN: POSSIBLY UNSAFE
when raw garlic is used topically. Raw garlic might cause severe skin irritation when applied topically (585,51210).

(Read more about GARLIC)

POSSIBLY SAFE ...when used orally and appropriately as a single dose (260,261). There is insufficient reliable information available about the safety of goldenseal when used as more than a single dose.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of goldenseal can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589).

PREGNANCY: LIKELY UNSAFE
when used orally. Berberine is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to goldenseal (2589).

LACTATION:
LIKELY UNSAFE when used orally. Berberine and other harmful constituents can be transferred to the infant through breast milk (2589). Use during lactation can cause kernicterus in the newborn and several resulting fatalities have been reported (2589).

(Read more about GOLDENSEAL)

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

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. A grapefruit seed extract has been safely used in clinical research (5866). In addition, capsules containing grapefruit pectin 15 grams daily have been used in clinical research for up to 16 weeks (2216).

POSSIBLY UNSAFE ...when used orally in excessive amounts. Preliminary population research shows that consuming a quarter or more of a whole grapefruit daily is associated with a 25% to 30% increased risk of postmenopausal breast cancer (14858). Grapefruit juice is thought to reduce estrogen metabolism resulting in increased endogenous estrogen levels. More evidence is needed to validate this finding.

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of using medicinal amounts of grapefruit during pregnancy and lactation; avoid using.

(Read more about GRAPEFRUIT)

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

CHILDREN: POSSIBLY UNSAFE
when recombinant human bile salt-stimulated lipase (rhBSSL) is used orally by premature infants. Adding rhBSSL to infant formula or pasteurized breast milk increases the risk for serious gastrointestinal adverse effects in premature infants (101940).

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

(Read more about LIPASE)

LIKELY SAFE ...when consumed in the amounts commonly found in foods. There is insufficient reliable information available about the safety of phytase when used orally as a supplement.

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

(Read more about PHYTASE)

POSSIBLY SAFE ...when used orally and appropriately. Various proteolytic enzymes have been safely used orally in clinical research (716,964,965,968,969,6252,6253,10622,11457,18281,18284) (91104,91105,91106,91111,96449). Side effects are typically mild to moderate and most often include gastrointestinal effects. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes. ...when used topically and appropriately. Various proteolytic enzymes have been safely used topically in clinical research (67835,67843,67845,91113). Some proteolytic enzymes might cause allergic reactions when used topically. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes.

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

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods.

POSSIBLY SAFE ...when the seed or seed oil is used orally and appropriately in medicinal amounts, short-term. Pumpkin seed has been used with apparent safety in a dose of up to 10 grams daily for up to 12 months (92383). Pumpkin seed oil has been used with apparent safety in a dose of up to 400 mg daily for up to 6 months (92378). There is insufficient reliable information available about the safety of pumpkin seed oil when used topically.

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

(Read more about PUMPKIN)

LIKELY SAFE ...when the stalk is used in amounts commonly found in foods and when the root is used as a food flavoring. Rhubarb has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when the root or rhizome is used orally and appropriately in medicinal amounts for up to 2 years (92294,92295,92297). ...when the stalk is used orally and appropriately in medicinal amounts for up to 4 weeks (71351,71363,97920). ...when used topically and appropriately (10437,97919).

POSSIBLY UNSAFE ...when the leaf is used orally. Rhubarb leaf contains oxalic acid and soluble oxalate, which can cause abdominal pain, burning of the mouth and throat, diarrhea, nausea, vomiting, seizures, and death (17).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used in medicinal amounts, rhubarb root is a stimulant laxative; avoid using (12).

(Read more about RHUBARB)

POSSIBLY SAFE ...when used orally and appropriately (4,12,272,512,1740).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using. Slippery elm bark has historically been inserted into the cervix to induce abortion. As a result, slippery elm has been reported in some sources to have abortifacient activity. However, there is no reliable information available about whether slippery elm has abortifacient activity when taken orally.

(Read more about SLIPPERY ELM)

LIKELY SAFE ...when used orally and appropriately, short-term. Turmeric products providing up to 8 grams of curcumin have been safely used for up to 2 months (10453,11144,11150,17953,79085,89720,89721,89724,89728,101347)(81036,101349,107110,107116,107117,107118,107121,109278,109283). Turmeric in doses up to 3 grams daily has been used with apparent safety for up to 3 months (102350,104146,104148,113357). ...when used topically and appropriately (11148).

POSSIBLY SAFE ...when used as an enema, short-term. Turmeric extract in water has been used as a daily enema for up to 8 weeks (89729). ...when used topically as a mouthwash, short-term. A mouthwash containing 0.05% turmeric extract and 0.05% eugenol has been used safely twice daily for up to 21 days (89723).

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in food.

PREGNANCY: LIKELY UNSAFE
when used orally in medicinal amounts; turmeric might stimulate the uterus and increase menstrual flow (12).

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in food. There is insufficient reliable information available about the safety of using turmeric in medicinal amounts during lactation.

(Read more about TURMERIC)

LIKELY SAFE ...when used orally in the amounts commonly found in foods. Wormwood extracts are included in bitters, vermouth, absinthe, and other food or drink products (12814,15007). Wormwood products that are thujone-free have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912); however, products containing thujone might not be safe. Wormwood is described in the pharmacopoeia of various European countries. After being banned for a period of time, it is now allowed in European Union countries; however, beverages must not contain thujone in concentrations greater than 35 mg/kg (12814,15007,86551).

POSSIBLY SAFE ...when wormwood products not containing thujone are used orally in medicinal amounts, short-term (93468,93469). A specific product

POSSIBLY UNSAFE ...when wormwood products containing thujone are used orally. Thujone is a neurotoxin that is present in wormwood oil (12617). Seizures, rhabdomyolysis, and acute kidney failure can occur when as little as 10 mL of wormwood oil is ingested (662,12817).

PREGNANCY:
LIKELY UNSAFE . .when used orally in amounts greater than those found in foods (662,12817). Some wormwood products contain thujone, a neurotoxin. Theoretically, thujone also has potential uterine and menstrual stimulant effects (12617). There is insufficient reliable information available about the safety of wormwood when used topically during pregnancy.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about WORMWOOD)

(Read more about BLACK WALNUT)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, clove oil may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Laboratory research suggests that eugenol, a constituent of clove, has antiplatelet activity (12889,43558,43650,43654). This interaction has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of clove extracts with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical and laboratory research suggest that polyphenol extracts from clove flower buds might lower blood glucose levels (100595). Dosing adjustments for insulin or oral hypoglycemic agents may be necessary when taken with clove. Monitor blood glucose levels closely.

IBUPROFEN (Advil, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, topical application of clove oil with ibuprofen might increase the absorption and side effects of topical ibuprofen.  Details Laboratory research shows that topical application of clove oil increases the absorption of topical ibuprofen (98854). This interaction has not been reported in humans.

(Read more about CLOVE)

(Read more about ENGLISH WALNUT)

ANTICHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking European barberry with anticholinergic drugs might cause additive effects.  Details In vitro evidence suggests that European barberry might have anticholinergic properties (13527).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, European barberry may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro and animal evidence suggest that berberine, a constituent of European barberry, might inhibit platelet aggregation (33591,33660,33661,33694). Theoretically, European barberry might have a similar effect.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking European barberry with antidiabetes drugs might increase the risk of hypoglycemia.  Details Preliminary clinical evidence suggests that European barberry juice reduces fasting glucose levels in patients with type 2 diabetes who are also taking antidiabetes drugs (98575). Additionally, some animal studies show that berberine, a constituent of European barberry, has antiglycemic potential (33622,33667). Monitor blood glucose levels closely.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking European barberry with antihypertensive drugs might increase the risk of hypotension.  Details Animal and human research suggests that European barberry extracts can have hypotensive effects (13528,33604,98575).

CHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking European barberry with cholinergic drugs might decrease the effects of cholinergic drugs.  Details In vitro evidence suggests that European barberry might have anticholinergic properties (13527).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use with drugs that have sedative properties may cause additive effects.  Details Animal research suggests that berberine, a constituent of European barberry, might have sedative effects (33650,33692). Theoretically, European barberry might have a similar effect.

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use with cyclosporine may cause additive effects.  Details Berberine, a constituent of European barberry, can reduce the metabolism and increase serum levels of cyclosporine. This effect is attributed to the ability of berberine to inhibit cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524). Theoretically, European barberry might have a similar effect.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, European barberry might increase the levels and clinical effects of CYP3A4 substrates.  Details There is very preliminary evidence suggesting that berberine, a constituent of European barberry, might inhibit the CYP3A4 enzyme (13524). Theoretically, European barberry might have a similar effect.

(Read more about EUROPEAN BARBERRY)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, fennel might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs.  Details Animal research suggests that fennel oil has antithrombotic and antiplatelet effects (31415,49445).

CIPROFLOXACIN (Cipro) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, fennel might decrease the levels and clinical effects of ciprofloxacin.  Details Animal research shows that fennel reduces ciprofloxacin bioavailability by nearly 50%, possibly due to the metal cations such as calcium, iron, and magnesium contained in fennel. This study also found that fennel increased tissue distribution and slowed elimination of ciprofloxacin (6135).

CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking large amounts of fennel might decrease the effects of contraceptive drugs due to competition for estrogen receptors.  Details Some constituents of fennel have estrogenic activity (11).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, fennel might increase levels of drugs metabolized by CYP3A4.  Details In vitro research suggests that fennel inhibits CYP3A4 enzyme activity (38375,49468). This effect has not been reported in humans.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking large amounts of fennel might interfere with hormone replacement therapy due to competition for estrogen receptors.  Details Some constituents of fennel have estrogenic activity (11).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking large amounts of fennel might decrease the antiestrogenic effect of tamoxifen.  Details Some constituents of fennel have estrogenic activity (11), which may interfere with the antiestrogenic activity of tamoxifen.

(Read more about FENNEL)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Garlic may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397,96013).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking garlic with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research suggests that garlic and garlic extract lower blood glucose levels in healthy and diabetic individuals (51463,96004).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garlic with antihypertensive drugs might increase the risk of hypotension.  Details In human research, both garlic and garlic extracts have blood pressure-lowering effects (277,278,279,1873,4787,6897,16605,51414,51442,51669)(88386,88398,96007).

ATAZANAVIR (Reyataz) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might decrease levels and effects of atazanavir.  Details In a case report, a patient consuming six stir-fried garlic cloves three times weekly developed suboptimal atazanavir levels and increases in HIV viral load. While the exact cause of this interaction is unclear, there is speculation that garlic might decrease the intestinal absorption of atazanavir or increase its metabolism by inducing cytochrome P450 3A4 (CYP3A4) (88388). Until more is known, advise patients not to consume large amounts of garlic while taking atazanavir.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Garlic might increase levels of drugs metabolized by CYP2E1.  Details Clinical research suggests garlic oil can inhibit the activity of CYP2E1 by 39% (10847). Use garlic oil cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic products containing allicin might induce intestinal CYP3A4 and inhibit hepatic CYP3A4. This may increase or decrease levels of drugs metabolized by CYP3A4.  Details Some human research suggests that garlic may induce INTESTINAL CYP3A4, reducing levels of drugs metabolized by this enzyme. This is primarily based on a study showing that taking a specific allicin-containing garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induced CYP3A4 in the gut mucosa (7027,93578). Another study shows that giving docetaxel intravenously, bypassing the CYP3A4 enzymes in the gut mucosa, along with the same specific garlic product for 12 consecutive days, does not affect docetaxel levels (17221). Conversely, there is concern that garlic may inhibit HEPATIC CYP3A4. In a single case report, increased tacrolimus levels and liver injury occurred in a liver transplant patient after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days (96010). Several other studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).

ISONIAZID Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might decrease levels of isoniazid.  Details Animal research suggests that an aqueous extract of garlic reduces isoniazid levels by about 65%. Garlic reduced the maximum concentration (Cmax) and area under the curve (AUC), but not the half-life, of isoniazid. This suggests that garlic extract might inhibit isoniazid absorption across the intestinal mucosa (15031); however, the exact mechanism of this potential interaction is not known.

PROTEASE INHIBITORS (PIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic products containing allicin might decrease levels of PIs.  Details Protease inhibitors are metabolized by cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4, reducing plasma levels of protease inhibitors. This is primarily based on a study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces levels of saquinavir, a PI, by approximately 50%. It is speculated that the allicin constituent induce CYP3A4 in the gut mucosa (7027,93578). Several studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).

SAQUINAVIR (Fortovase, Invirase) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic containing allicin might decrease levels of saquinavir.  Details Saquinavir is a substrate of cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4 and cause subtherapeutic levels of saquinavir. This is primarily based on a pharmacokinetic study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induces CYP3A4 in the gut mucosa (7027,93578). Several pharmacokinetic studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506). Until more is known about this potential interaction, use garlic containing allicin cautiously in patients taking saquinavir.

SOFOSBUVIR (Sovaldi) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garlic with sofosbuvir might decrease its effectiveness.  Details Animal research in rats shows that giving aged garlic extract 120 mg/kg orally daily for 14 days decreases the area under the concentration time curve (AUC) after a single sofosbuvir dose of 40 mg/kg by 36%, increases the clearance by 63%, and decreases the plasma concentrations at 1 and 8 hours by 35% and 58%, respectively. This interaction is hypothesized to be due to induction of intestinal P-glycoprotein expression by garlic (109524).

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic might increase levels of tacrolimus.  Details In one case report, a liver transplant patient taking tacrolimus experienced increased tacrolimus levels and liver injury after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days. It is speculated that garlic inhibited hepatic cytochrome P450 3A4 (CYP3A4), which increased plasma levels of tacrolimus (96010).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might increase the risk of bleeding with warfarin.  Details Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397). In addition, there is a report of two patients who experienced an increase in a previously stabilized international normalized ratio (INR) with concomitant garlic and warfarin use (51228,51631). However, this report has been subsequently debated due to limited clinical information. Other clinical studies have not identified an effect of garlic on INR, warfarin pharmacokinetics, or bleeding risk (15032,16416). More evidence is needed to determine the safety of using garlic with warfarin.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.  Details Goldenseal contains berberine. In vitro and animal research shows that berberine can inhibit platelet aggregation (33660,33694). However, this effect has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the risk of hypoglycemia when used with antidiabetes drugs.  Details Goldenseal contains berberine. Clinical research shows that berberine can lower blood glucose levels (20579,34247,34265,34282). However, this effect has not been reported with goldenseal.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the risk of hypotension when taken with antihypertensive drugs.  Details Goldenseal contains berberine. Animal research shows that berberine can have hypotensive effects (33692,34308). Also, an analysis of clinical research shows that taking berberine in combination with amlodipine can lower systolic and diastolic blood pressure when compared with amlodipine alone (91956). However, this effect has not been reported with goldenseal.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the sedative effects of CNS depressants.  Details Goldenseal contains berberine. Animal research shows that berberine can have sedative effects (13519,33650,33664,33692). However, this effect has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase serum levels of drugs metabolized by CYP2C9.  Details In vitro research shows that goldenseal root extract can modestly inhibit CYP2C9. This effect may be due to its alkaloid constituents, hydrastine and berberine (21117). However, this effect has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Goldenseal might increase serum levels of drugs metabolized by CYP2D6.  Details Clinical and in vitro research shows that goldenseal can significantly inhibit CYP2D6 enzymes, potentially increasing levels of drugs metabolized by CYP2D6 (13536,16848,35907).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase serum levels of drugs metabolized by CYP2E1.  Details In vitro research shows that goldenseal root extract can inhibit the activity of CYP2E1 (94140). However, this effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Goldenseal might increase serum levels of drugs metabolized by CYP3A4.  Details Most clinical and in vitro research shows that goldenseal inhibits CYP3A4 enzyme activity and increases serum levels of CYP3A4 substrates, such as midazolam (6450,13536,21117,91740,111725). However, in one small clinical study, goldenseal did not affect the levels of indinavir, a CYP3A4 substrate, in healthy volunteers (10690,93578). This is likely due to the fact that indinavir has a high oral bioavailability, making it an inadequate probe for CYP3A4 interactions (13536,91740) and/or that it is primarily metabolized by hepatic CYP3A, while goldenseal has more potential to inhibit intestinal CYP3A enzyme activity (111725). Both goldenseal extract and its isolated constituents berberine and hydrastine inhibit CYP3A, with hydrastine possibly having more inhibitory potential than berberine (111725).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase serum levels of dextromethorphan.  Details Goldenseal contains berberine. A small clinical study shows that berberine can inhibit cytochrome P450 2D6 (CYP2D6) activity and reduce the metabolism of dextromethorphan (34279).

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Goldenseal might increase serum levels of digoxin, although this effect is unlikely to be clinically significant.  Details Clinical research shows that goldenseal modestly increases digoxin peak levels by about 14% in healthy volunteers. However, goldenseal does not seem to affect other pharmacokinetic parameters such as area under the curve (AUC) (15132). This suggests that goldenseal does not cause a clinically significant interaction with digoxin. Digoxin is a P-glycoprotein substrate. Some evidence suggests that goldenseal constituents might affect P-glycoprotein; however, it is unclear whether these constituents inhibit or induce P-glycoprotein.

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might decrease the conversion of losartan to its active form.  Details Goldenseal contains berberine. A small clinical study shows that berberine inhibits cytochrome P450 2C9 (CYP2C9) activity and reduces the metabolism of losartan (34279). However, this effect has not been reported with goldenseal.

METFORMIN (Glucophage) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might reduce blood levels of metformin.  Details In vitro research shows that goldenseal extract decreases the bioavailability of metformin, likely by interfering with transport, intestinal permeability, or other processes involved in metformin absorption. It is unclear which, if any, of metformin's transporters are inhibited by goldenseal. Goldenseal does not appear to alter the clearance or half-life of metformin (105764).

OSELTAMIVIR (Tamiflu) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might reduce the therapeutic effects of oseltamivir by decreasing its conversion to its active form.  Details In vitro evidence suggests that goldenseal reduces the formation of the active compound from the prodrug oseltamivir (105765). The mechanism of action and clinical relevance is unclear.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, goldenseal might increase or decrease serum levels of P-glycoprotein (P-gp) substrates.  Details There is conflicting evidence about the effect of goldenseal on P-gp. In vitro research suggests that berberine, a constituent of goldenseal, modestly inhibits P-gp efflux. Other evidence suggests that berberine induces P-gp. In healthy volunteers, goldenseal modestly increases peak levels of the P-gp substrate digoxin by about 14%. However, it does not seem to affect other pharmacokinetic parameters such as area under the curve (AUC) (15132). This suggests that goldenseal is not a potent inhibitor of P-gp-mediated drug efflux. Until more is known, goldenseal should be used cautiously with P-gp substrates.

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase the sedative effects of pentobarbital.  Details Animal research shows that berberine, a constituent of goldenseal, can prolong pentobarbital-induced sleeping time (13519). However, this effect has not been reported with goldenseal.

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, goldenseal might increase serum levels of tacrolimus.  Details Goldenseal contains berberine. In a 16-year-old patient with idiopathic nephrotic syndrome who was being treated with tacrolimus 6.5 mg twice daily, intake of berberine 200 mg three times daily increased the blood concentration of tacrolimus from 8 to 22 ng/mL. Following a reduction of tacrolimus dosing to 3 mg daily, blood levels of tacrolimus decreased to 12 ng/mL (91954).

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ACEBUTOLOL (Sectral) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of acebutolol, potentially decreasing the clinical effects of acebutolol.  Details Clinical research shows that grapefruit juice can modestly decrease acebutolol levels by 7% and reduce peak plasma concentration by 19% by inhibiting organic anion transporting polypeptide (OATP) (17603,18101). The acebutolol half-life is also extended by 1.1 hours when grapefruit juice is consumed concomitantly (18101). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

ALISKIREN (Tekturna, Rasilez) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of aliskiren, potentially decreasing the clinical effects of aliskiren.  Details Clinical research shows that grapefruit juice can decrease aliskiren levels by approximately 60% by inhibiting organic anion transporting polypeptide (OATP) (91428). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

AMIODARONE (Cordarone) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of amiodarone, potentially increasing the effects and adverse effects of amiodarone.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of amiodarone. Grapefruit juice increases amiodarone plasma levels by 50% and peak concentration by 84% (17601,17672,22120).

AMPRENAVIR (Agenerase) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of amprenavir, although this is not likely to be clinically significant.  Details Some clinical research shows that grapefruit juice can slightly decrease amprenavir levels (17673); however, this is probably not clinically significant.

ARTEMETHER (Artenam, Paluther) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral artemether, potentially increasing the effects and adverse effects of artemether.  Details Clinical research shows that grapefruit juice increases the levels of oral artemether by 90% to 250% in healthy males (5065,5066).

BENZODIAZEPINES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice might increase blood levels of some oral benzodiazepines, potentially increasing the effects and adverse effects of these drugs.  Details Clinical research shows that grapefruit juice can increase plasma triazolam concentrations. Repeated consumption of grapefruit juice greatly increases triazolam concentrations and prolongs the half-life, probably due to inhibition of cytochrome P450 3A4 (CYP3A4) (7776,22118,22131,22133). Some studies show that grapefruit juice, particularly when taken in large quantities, reduces the clearance and increases the maximum blood levels, area under the plasma concentration curve (AUC), and duration of effect of midazolam. However, there is no effect on intravenous midazolam (4300,10159,11275,17601,22117,22119,16711,91427,95978). Grapefruit juice has also been shown to increase the maximum blood levels and duration of effect of diazepam, but the clinical significance of this is not known (3228). This interaction does not appear to occur with alprazolam (17674).

BLONANSERIN (Lonasen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of blonanserin, potentially increasing the effects and adverse effects of blonanserin.  Details Blonanserin is metabolized primarily by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral blonanserin increases exposure to blonanserin almost 6-fold due to inhibition of intestinal CYP3A4 by grapefruit juice and prolongs the elimination half-life of blonanserin by 2.2-fold due to inhibition of hepatic CYP3A4 by grapefruit juice (96943).

BUDESONIDE (Entocort, UCERIS) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of budesonide, potentially increasing the effects and adverse effects of budesonide.  Details Budesonide is metabolized by cytochrome P450 3A4 (CYP3A4). A small clinical study shows that taking grapefruit juice along with oral budesonide increases the plasma concentration of budesonide. This effect is attributed to grapefruit-induced inhibition of CYP3A4 in both the colon and small intestine (91425).

BUSPIRONE (BuSpar) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of buspirone, potentially increasing the effects and adverse effects of buspirone.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of buspirone (3771).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Grapefruit juice can decrease the clearance of caffeine, potentially increasing the effects and adverse effects of caffeine.  Details Clinical research shows that grapefruit juice decreases caffeine clearance (4300).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral calcium channel blockers, potentially increasing the effects and adverse effects of these drugs.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of amlodipine (523), nifedipine (528,22114), nisoldipine (529), verapamil (7779,8285), felodipine, nimodipine, nicardipine, diltiazem, pranidipine, nitrendipine, and manidipine (524,528,1388,4300,7780,11276,22136,53338,22138,22139) (22140,22141,22142,22143,22147,22148,22149,53367,22158), This interaction is likely the result of the inhibition of intestinal metabolism of these drugs by CYP3A4 (7779,7780), although some research suggests grapefruit may alter plasma drug levels by reducing the rate of gastric emptying (22167). Consuming grapefruit juice 1 liter daily increases steady state concentrations of verapamil by as much as 50% (8285). However, some references dispute the clinical relevance of the interactions with amlodipine, diltiazem, and verapamil (3230,4300,22159). Other research in healthy individuals suggests plasma levels of felodipine and nifedipine are not affected when given intravenously (22144,22146). There is considerable interindividual variability in the effect of grapefruit juice on drug metabolism, which might account for inconsistent study results (7777,7779,8285). In healthy older adults, the hemodynamic response to felodipine plus grapefruit juice might be influenced by altered autonomic regulation. In older healthy adults, a single dose of grapefruit juice and felodipine enhanced the blood pressure-lowering effects of felodipine. However, after a week of grapefruit juice and felodipine (steady state), the hypotensive activity was reduced, possibly due to compensatory tachycardia (1392). Research indicates it is necessary to withhold grapefruit juice for as long as 3 days to avoid interactions with felodipine and nisoldipine (5068,5069,6453,22145).

CARBAMAZEPINE (Tegretol) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of carbamazepine, potentially increasing the effects and adverse effects of carbamazepine.  Details Clinical research shows that grapefruit juice increases absorption and plasma concentrations of carbamazepine (524).

CARVEDILOL (Coreg) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of carvedilol, potentially increasing the effects and adverse effects of carvedilol.  Details Clinical research shows that grapefruit juice increases the bioavailability of a single dose of carvedilol by 16% (5071).

CELIPROLOL (Celicard) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of celiprolol, potentially decreasing the clinical effects of celiprolol.  Details In human research, taking grapefruit juice within two hours of celiprolol appears to decrease absorption and blood levels of celiprolol by approximately 85% (91421). This interaction is due to grapefruit-induced inhibition of organic anion transporting polypeptide (OATP) (17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

CISAPRIDE (Propulsid) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of cisapride, potentially increasing the effects and adverse effects of cisapride.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of cisapride. According to the cisapride prescribing information, grapefruit juice is contraindicated in patients taking cisapride (1383,3226,17601,22164,22165).

CLOMIPRAMINE (Anafranil) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, grapefruit juice might increase blood levels of clomipramine, potentially increasing the effects and adverse effects of clomipramine.  Details Case reports have shown that clomipramine trough levels increase significantly after the addition of grapefruit juice to the therapeutic regimen (5064).

CLOPIDOGREL (Plavix) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of clopidogrel, thereby decreasing the antiplatelet effect of clopidogrel.  Details Clopidogrel is an antiplatelet prodrug that is metabolized primarily by cytochrome P450 2C19 (CYP2C19) to form the active metabolite. A small clinical study shows that taking grapefruit juice with clopidogrel decreases plasma levels of the active metabolite by more than 80% and impairs the antiplatelet effect of clopidogrel. This effect is possibly due to grapefruit-induced inhibition of CYP2C19 (91419).

COLCHICINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, grapefruit juice might increase blood levels of colchicine, potentially increasing the effects and adverse effects of colchicine.  Details Colchicine is an alkaloid that undergoes P-glycoprotein (P-gp) mediated drug efflux in the intestines, followed by metabolism by cytochrome P450 3A4 (CYP3A4). There is concern that grapefruit juice will increase the effects and adverse effects of colchicine due to grapefruit-induced inhibition of P-gp and/or CYP3A4. In vitro evidence shows that grapefruit juice increases absorption of colchicine by inhibiting P-gp (94158). A case of acute colchicine toxicity has been reported for an 8-year-old female who drank grapefruit juice while taking high-dose colchicine, long-term (94157). However, one small clinical study in healthy adults shows that drinking grapefruit juice 240 mL twice daily for 4 days does not affect the bioavailability or adverse effects of a single dose of colchicine 0.6 mg taken on the fourth day (35762).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of oral cyclosporine, potentially increasing the effects and adverse effects of cyclosporine.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of cyclosporine (522,11270,22113,22150,22152,22153,22154,22155). The mechanism of action is unclear. However, there is no effect on intravenous cyclosporine (22151).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP1A2.  Details In vitro research suggests that grapefruit juice might inhibit CYP1A2 enzymes (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C19.  Details In vitro research suggests that grapefruit juice might inhibit CYP2C19 enzymes (12479). Also, a small clinical study shows that taking grapefruit juice with clopidogrel, an antiplatelet prodrug that is metabolized primarily by CYP2C19, decreases plasma levels of the active metabolite and impairs the antiplatelet effect of clopidogrel. This effect is likely due to grapefruit-induced inhibition of CYP2C19 (91419).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase levels of drugs metabolized by CYP2C9.  Details In vitro research suggests that grapefruit juice might inhibit CYP2C9 enzymes (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase levels of drugs metabolized by CYP3A4.  Details Clinical research shows that grapefruit juice can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects (3227,3774,8283,8285,8286,22129,91427,104190). When taken orally, effects of grapefruit juice on CYP3A4 levels appear to last at least 48 hours (91427). Grapefruit's ability to inhibit CYP3A4 has even been harnessed to intentionally increase levels of venetoclax, which is metabolized by CYP3A4, in an elderly patient with acute myeloid leukemia who could not afford full dose venetoclax. The lower dose of venetoclax in combination with grapefruit juice resulted in serum levels of venetoclax in the therapeutic reference range of full dose venetoclax and positive treatment outcomes for the patient (112287). Professional consensus recommends the consideration of patient age, existing medical conditions, additional medications, and the potential for additive adverse effects when evaluating the risks of concomitant use of grapefruit juice with any medication metabolized by CYP3A4. While all patients are at risk for interactions with grapefruit juice consumption, patients older than 70 years of age and those taking multiple medications are at the greatest risk for a serious or fatal interaction with grapefruit juice (95970,95972).

DAPOXETINE (Priligy) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of dapoxetine, potentially increasing the effects and adverse effects of dapoxetine.  Details Pharmacokinetic research shows that drinking grapefruit juice 250 mL prior to taking dapoxetine 60 mg can increase the maximum plasma concentration of dapoxetine by 80% and prolong the elimination half-life by 43%. This effect is attributed to the inhibition of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) by grapefruit (95975).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of dextromethorphan, potentially increasing the effects and adverse effects of dextromethorphan.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism, causing increased dextromethorphan levels (11362).

ERYTHROMYCIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of erythromycin, potentially increasing the effects and adverse effects of erythromycin.  Details Clinical research shows that concomitant use of erythromycin with grapefruit can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of erythromycin, increasing plasma concentrations of erythromycin by 35% (8286).

ESTROGENS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of estrogens, potentially increasing the effects and adverse effects of estrogens.  Details Clinical research shows that grapefruit increases the levels of endogenous and exogenous estrogens by inhibiting cytochrome P450 3A4 (CYP3A4) enzymes (525,526,14858). Grapefruit juice increases exogenously administered 17-beta-estradiol by about 20% in females without ovaries and ethinyl-estradiol in healthy females (525,526,22160).

ETOPOSIDE (VePesid) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of etoposide, potentially decreasing the clinical effects of etoposide.  Details Clinical research shows that grapefruit juice decreases the absorption and plasma concentrations of etoposide. There is some evidence that grapefruit juice co-administered with oral etoposide can reduce levels of etoposide by about 26% (8744). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can decrease blood levels of fexofenadine, thereby decreasing the clinical effects of fexofenadine.  Details Clinical research shows that grapefruit juice can significantly decrease oral absorption and blood levels of fexofenadine. In one study, consuming a drink containing grapefruit juice 25% decreased bioavailability of fexofenadine by about 24%. Consuming a full-strength grapefruit juice drink reduced bioavailability by 67% (7046). In another study, consuming grapefruit juice 300 mL decreased fexofenadine levels by 42%. Consuming 1200 mL of grapefruit juice reduced levels by 64% (17602). Similarly, drinking grapefruit juice 240 mL decreased the oral bioavailability of fexofenadine by 25% in another pharmacokinetic study (112288). Fexofenadine manufacturer data indicates that concomitant administration of grapefruit juice and fexofenadine results in larger wheal and flare sizes in research models. This suggests that grapefruit also reduces the clinical response to fexofenadine (17603). Grapefruit juice seems to inhibit organic anion transporting polypeptide (OATP), which is a drug transporter in the gut, liver, and kidney (7046,17603,17604,22161). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can increase blood levels of fluvoxamine, potentially increasing the effects and adverse effects of fluvoxamine.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases fluvoxamine levels and peak concentration (17675).

HALOFANTRINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of halofantrine, potentially increasing the effects and adverse effects of halofantrine.  Details Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism, which increases halofantrine levels and peak concentration, as well as a marker of ventricular tachyarrhythmia potential (22129).

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of statins that are metabolized by cytochrome P450 3A4 (CYP3A4), potentially increasing the effects and adverse effects of these statins. Additionally, grapefruit juice might interfere with the bioavailability of statins that are substrates of organic anion transporting polypeptides (OATP).  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption and plasma concentrations of statins that are metabolized by CYP3A4. These include lovastatin (527,11274), simvastatin (3774,7782,22127), and atorvastatin (3227,12179,22126). Keep in mind that there is considerable variability in the effect of grapefruit juice on drug metabolism, so individual patient response is difficult to predict (7777,7781). Some statins, including pravastatin, fluvastatin, pitavastatin, and rosuvastatin, are not metabolized by CYP3A4. However, grapefruit juice might still affect the bioavailability of these statins. These statins are substrates of OATP. Grapefruit juice can inhibit OATP. Therefore, grapefruit juice may reduce the bioavailability or increase drug levels of these statins depending on the type of OATP. However, grapefruit juice affects OATP for only a short time. Therefore, separating drug administration by at least 4 hours is likely to avoid this interaction (3227,12179,17601,22126,91420).

ITRACONAZOLE (Sporanox) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can interfere with itraconazole absorption, although the clinical significance of this interaction is unclear.  Details Clinical research shows that grapefruit juice can affect itraconazole absorption and might increase or decrease itraconazole levels (310,17601,22123).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can decrease blood levels of levothyroxine, potentially decreasing the effectiveness of levothyroxine.  Details Clinical research shows that grapefruit juice modestly decreases levothyroxine levels by 11% by inhibiting organic anion transporting polypeptide (OATP) (17604,22163). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of losartan, potentially decreasing the clinical effects of losartan.  Details Losartan is an inactive prodrug which must be metabolized to its active form, E-3174, to be effective. In one human study, grapefruit juice reduced losartan metabolism, increased losartan AUC, and reduced the AUC of the major active losartan metabolite, E-3174 (1391).

METHADONE (Dolophine) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of methadone, potentially increasing the effects and adverse effects of methadone.  Details Clinical research shows that grapefruit juice inhibits the metabolism of methadone, increasing methadone levels and peak concentrations (17676). In one case, a 51-year-old male taking methadone 90 mg daily and no other medications was found unresponsive. The patient reported drinking grapefruit juice 500 mL daily for 3 days prior to the event. Methadone is a substrate of cytochrome P450 3A4 (CYP3A4), and grapefruit juice-induced inhibition of CYP3A4 is the likely cause of this interaction (102056).

METHYLPREDNISOLONE Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of methylprednisolone, potentially increasing the effects and adverse effects of methylprednisolone.  Details Clinical research shows that grapefruit juice can increase the plasma concentration of orally administered methylprednisolone. Grapefruit juice 200 mL three times daily given with methylprednisolone 16 mg increased methylprednisolone half-life by 35%, peak plasma concentration by 27%, and total area under the curve by 75% (3123).

NADOLOL (Corgard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of nadolol, potentially decreasing the clinical effects of nadolol.  Details Nadolol is a substrate of organic anion transporting polypeptide 1A2 (OATP1A2) (17603,17604,22161). Some research shows that grapefruit juice and its constituent naringin can inhibit organic anion transporting polypeptides (OATP), which can reduce the bioavailability of OATP substrates (17603,17604,22161,91427). However, preliminary clinical research shows that grapefruit juice containing a low amount of naringin does not significantly affect levels of nadolol (91422). It is not known if grapefruit juice containing higher amounts of naringin reduces the bioavailability of nadolol.

NILOTINIB (Tasigna) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of nilotinib, potentially increasing the effects and adverse effects of nilotinib.  Details Clinical research shows that grapefruit juice inhibits metabolism and increases absorption of nilotinib. Grapefruit juice increases nilotinib levels by 29% and peak concentration by 60% (17677).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can decrease levels of drugs that are substrates of OATP.  Details In vitro and clinical research show that consuming grapefruit juice inhibits OATP, which reduces the bioavailability of oral drugs that are substrates of OATP. Various clinical studies have shown reduced absorption of OATP substrates when taken with grapefruit, including fexofenadine, acebutolol, aliskiren, celiprolol, levothyroxine, nadolol, and pitavastatin (17603,17604,18101,22126,22134,22161,22163,91420,91427,91428,112288). Grapefruit juice is thought to affect OATP for only a short time. Therefore, separating drug administration and consumption of grapefruit by at least 4 hours is likely to prevent this interaction (17603,17604).

OXYCODONE (Oxycontin) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of oxycodone, potentially increasing the effects and adverse effects of oxycodone.  Details Oxycodone is metabolized by both cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6). A small clinical study shows that grapefruit juice can increase plasma levels of oral oxycodone about 1.7-fold by inhibiting CYP3A4. While the analgesic effects of oxycodone do not seem to be affected, taking grapefruit juice along with oxycodone may theoretically increase the adverse effects of oxycodone (91423).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice does not seem to affect renal P-glycoprotein (P-gp). Theoretically, it might inhibit intestinal P-gp, but evidence is conflicting.  Details While most in vitro research shows that grapefruit products inhibit P-gp, (1390,11270,11278,11362,95976), research in humans is less clear. Two small clinical studies in healthy adults using digoxin as a probe substrate show that grapefruit juice does not inhibit P-gp in the kidneys (11277,11282). It is unclear whether this applies to intestinal P-gp, for which digoxin is not considered to be a sensitive probe (105568). Grapefruit juice has been shown to reduce levels of fexofenadine (7046,17602,112288), and increase levels of quinidine (5067,22121). However, as both of these drugs are also substrates of other enzymes and transporters, it is unclear what role, if any, intestinal P-gp has in these findings.

PITAVASTATIN (Livalo) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of pitavastatin, potentially increasing the effects and adverse effects of pitavastatin.  Details Pharmacokinetic research shows that taking grapefruit juice with pitavastatin 2-4 mg can increase blood levels of pitavastatin by 13% to 14%. Unlike simvastatin and atorvastatin, pitavastatin is not significantly metabolized by cytochrome P450 3A4 (CYP3A4) enzymes. Grapefruit juice appears to increase levels of pitavastatin by inhibiting its uptake by organic anion transporting polypeptide 1B1 (OATP1B1) into hepatocytes for metabolism and clearance from the body (22126,91420). Grapefruit juice seems to increase levels of pitavastatin to a greater degree in patients homozygous for a specific polymorphism (388A>G) in the OATP1B1 gene compared to those heterozygous for this polymorphism (91420).

PRASUGREL (Effient) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of the active metabolite of prasugrel, thereby decreasing the antiplatelet effect of prasugrel.  Details Prasugrel is a prodrug that is metabolized by cytochrome P450 3A4 (CYP3A4) into its active metabolite. A small pharmacokinetic study in healthy volunteers shows that drinking grapefruit juice 200 mL three times daily for 4 days and taking a single dose of prasugrel 10 mg with an additional 200 mL of grapefruit juice on day 3, results in a 49% lower peak plasma level and a 26% lower overall plasma exposure to the active metabolite when compared with drinking water. However, despite the reduced exposure, platelet aggregation seems to be reduced by an average of only 5% (105567). The clinical significance of this interaction is unclear.

PRAZIQUANTEL (Biltricide) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of praziquantel, potentially increasing the effects and adverse effects of praziquantel.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of praziquantel. Plasma concentrations of praziquantel can increase by as much as 160% when administered with 250 mL of commercially available grapefruit juice (8282).

PRIMAQUINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice may increase blood levels of primaquine, potentially increasing the effects and adverse effects of primaquine.  Details Clinical research shows that grapefruit juice increases the bioavailability of primaquine by approximately 20% (22130). The clinical significance of this interaction is not clear.

QT INTERVAL-PROLONGING DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit or grapefruit juice, especially if consumed in large amounts, can cause additive QT interval prolongation when taken with QT interval-prolonging drugs, potentially increasing the risk of ventricular arrhythmias.  Details Clinical research in healthy volunteers shows that drinking 6 liters of grapefruit juice over 6 hours prolonged the QTc by a peak amount of 14 milliseconds (ms). This prolongation was similar to the QT prolongation caused by the drug moxifloxacin. In individuals with long QT syndrome, a smaller dose of grapefruit juice, 1.5 liters, resulted in a greater peak QTc prolongation of about 30 ms (100249). The effect of smaller quantities of grapefruit juice on the QT interval is unclear.

QUETIAPINE (Seroquel) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice may increase blood levels of quetiapine, increasing the effects and adverse effects of quetiapine.  Details Quetiapine is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4 (3227,3774,8283,8285,8286,22129,91427,104190). In one case report, a healthy 28-year-old female with bipolar disorder stabilized on quetiapine 800 mg daily presented with quetiapine toxicity considered to be related to consuming a gallon of grapefruit juice over the past 24 hours (108848).

QUINIDINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can alter blood levels of quinidine, potentially increasing or decreasing the clinical effects of quinidine.  Details Clinical research shows that grapefruit juice decreases quinidine absorption, clearance, and metabolism, and prolongs the half-life by about 20% (5067,22121).

SAQUINAVIR (Fortovase, Invirase) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of saquinavir, potentially increasing the effects and adverse effects of saquinavir.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of saquinavir (3773,22132).

SCOPOLAMINE (Transderm Scop) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of scopolamine, potentially increasing the effects and adverse effects of scopolamine.  Details Clinical research shows that grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of scopolamine, increasing its absorption and plasma concentrations. Oral bioavailability of scopolamine can increase by 30% when administered with 150 mL of grapefruit juice (8284).

SERTRALINE (Zoloft) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice can increase blood levels of sertraline, potentially increasing the effects and adverse effects of sertraline.  Details Clinical research shows that grapefruit juice inhibits the cytochrome P450 3A4 (CYP3A4) metabolism of sertraline, increasing blood levels of sertraline (22122).

SILDENAFIL (Viagra) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of sildenafil, potentially increasing the effects and adverse effects of sildenafil.  Details Clinical research shows that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism of sildenafil, increasing its absorption and plasma concentrations. Oral bioavailability of sildenafil can increase by 23% when administered with 500 mL of commercially available grapefruit juice (8283).

SUNITINIB (Sutent) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Grapefruit juice may slightly increase blood levels of sunitinib, potentially increasing the effects and adverse effects of sunitinib.  Details Sunitinib is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit and grapefruit juice can inhibit CYP3A4 and increase levels of some drugs metabolized by this enzyme. One small clinical study shows that drinking 200 mL of grapefruit juice three times daily can increase the bioavailability of sunitinib by 11% (91429). While this effect is unlikely to be clinically significant, patients should use caution when using grapefruit along with sunitinib. Dose adjustments may be necessary.

TACROLIMUS (Prograf) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = B Grapefruit juice can increase blood levels of tacrolimus, potentially increasing the effects and adverse effects of tacrolimus.  Details Clinical research shows that drinking grapefruit juice 200 mL daily while taking tacrolimus 3 mg daily increases the trough blood concentration of tacrolimus by approximately 3-fold in patients with connective tissue diseases (95974). A single case has also reported a 10-fold increase in tacrolimus trough levels after the ingestion of grapefruit juice over 3 days (22122). This effect is attributed to the inhibition of cytochrome P450 3A4 (CYP3A4) by grapefruit (95974).

TADALAFIL (Cialis) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, grapefruit juice might increase blood levels of tadalafil, potentially increasing the effects and adverse effects of tadalafil.  Details Animal research shows that grapefruit juice increases tadalafil serum concentrations and overall exposure, likely through inhibition of cytochrome P450 3A4 enzymes (104189).

TALINOLOL Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grapefruit juice might decrease blood levels of talinolol, potentially decreasing the clinical effects of talinolol.  Details Clinical research suggests that grapefruit juice reduces talinolol bioavailability, likely by inhibiting intestinal uptake (22135). The clinical significance of this effect is unclear.

TERFENADINE (Seldane) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of terfenadine, potentially increasing the effects and adverse effects of terfenadine.  Details Clinical research shows that grapefruit juice increases the absorption and plasma concentrations of terfenadine (530,22124,22125). The mechanism of action is unclear.

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can decrease blood levels of theophylline, potentially decreasing the effectiveness of theophylline.  Details Clinical research shows that grapefruit juice seems to modestly decrease theophylline levels when given concurrently with sustained-release theophylline (11013). The mechanism of this interaction is unknown.

TICAGRELOR (Brilinta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of ticagrelor, thereby increasing the effects and adverse effects of ticagrelor.  Details Ticagrelor is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that taking grapefruit juice with ticagrelor increases blood levels of ticagrelor more than two-fold and increases the antiplatelet activity of ticagrelor (91418).

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Grapefruit juice can increase blood levels of tolvaptan, potentially increasing the effects and adverse effects of tolvaptan.  Details Tolvaptan is metabolized by cytochrome P450 3A4 (CYP3A4). Grapefruit can inhibit CYP3A4. A small clinical study shows that grapefruit juice can increase the bioavailability and blood levels of tolvaptan by approximately 1.6-fold for up to 16 hours (91426).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, drinking large amounts of grapefruit juice might increase the effects and adverse effects of warfarin.  Details In one case report, a patient experienced significantly increased international normalized ratio (INR) associated with consumption of 50 ounces of grapefruit juice daily (12061). However, smaller amounts of grapefruit juice might not be a problem. In a small clinical trial, consumption of 24 ounces of grapefruit juice daily for one week had no effect on INR in males treated with warfarin (12063).

(Read more about GRAPEFRUIT)

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(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Pumpkin might reduce excretion and increase levels of lithium.  Details Pumpkin is thought to have diuretic properties (92383). Theoretically, this might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

(Read more about PUMPKIN)

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, frequent and high doses of rhubarb might increase the risk of hypokalemia when taken with corticosteroids.  Details Rhubarb has stimulant laxative effects. Overuse of rhubarb might compound corticosteroid-induced potassium loss (2,12).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rhubarb with cyclosporine might reduce cyclosporine levels.  Details Animal research shows that co-administration of rhubarb decoction 0.25 or 1 gram/kg with cyclosporine 2.5 mg/kg, decreases cyclosporine maximum plasma concentration and overall exposure levels when compared with taking cyclosporine alone. The authors theorize that rhubarb might reduce cyclosporine bioavailability by inducing of P-glycoprotein and/or cytochrome P450 3A4 (92304). However, since rhubarb was administered as a single oral dose and enzyme induction usually occurs after multiple doses, it is possible that cyclosporine absorption was actually reduced via rhubarb's stimulant laxative effects (12). Also, the composition of the rhubarb decoction was not described.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, overuse of rhubarb might increase the risk of adverse effects when taken with digoxin.  Details Rhubarb has stimulant laxative effects. Overuse of rhubarb might cause potassium depletion, increasing the risk of digoxin toxicity (12,19).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, frequent and high doses of rhubarb might increase the risk of hypokalemia.  Details Rhubarb has stimulant laxative effects. Overuse of rhubarb might cause potassium depletion and compound diuretic-induced potassium loss (12,19).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of rhubarb with potentially hepatotoxic drugs might increase the risk of developing liver damage.  Details Some animal research suggests that anthraquinones in rhubarb might have hepatotoxic effects (105960). Also, rhubarb use has been linked to at least 24 cases of liver injury, although details on the dose of rhubarb and duration of use in these cases is unclear (100963).

NEPHROTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, long-term use of anthraquinones from rhubarb might increase the risk of nephrotoxicity when used with nephrotoxic drugs.  Details The anthraquinone constituents of rhubarb have been shown to induce nephrotoxicity in animal research (71322). Additionally, in a case report, a 23-year old female presented with kidney failure after taking 6 tablets of a proprietary slimming agent (found to contain the anthraquinones emodin and aloe-emodin from rhubarb) daily for 6 weeks and then adding diclofenac 25 mg 4 times daily for 2 days. The authors postulate that the anthraquinone constituents of rhubarb contributed to the renal dysfunction, and the addition of diclofenac, a nephrotoxic drug, led to renal failure (15257). Until more is known, advise patients to avoid taking rhubarb if they are taking other potentially nephrotoxic drugs.

STIMULANT LAXATIVES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, rhubarb might increase the risk for fluid and electrolyte loss when taken with other stimulant laxatives.  Details Rhubarb has stimulant laxative effects (12). Concomitant use with stimulant laxatives might compound fluid and electrolyte loss (24427).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, excessive use of rhubarb might increase the risk of bleeding when taken with warfarin.  Details Rhubarb has stimulant laxative effects and can cause diarrhea (12,19). Diarrhea can increase the effects of warfarin, increase international normalized ratio (INR), and increase the risk of bleeding. Advise patients who take warfarin not to take excessive amounts of rhubarb.

(Read more about RHUBARB)

ORAL DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, slippery elm may slow the absorption and reduce serum levels of oral drugs.  Details Slippery elm inner bark contains mucilage, which may interfere with the absorption of orally administered drugs (19).

(Read more about SLIPPERY ELM)

ALKYLATING AGENTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric has antioxidant effects. Theoretically, this may reduce the activity of chemotherapy drugs that generate free radicals. However, research is conflicting.  Details In vitro research suggests that curcumin, a constituent of turmeric, inhibits mechlorethamine-induced apoptosis of breast cancer cells by up to 70%. Also, animal research shows that curcumin inhibits cyclophosphamide-induced tumor regression (96126). However, some in vitro research shows that curcumin does not affect the apoptosis capacity of etoposide. Also, other laboratory research suggests that curcumin might augment the cytotoxic effects of alkylating agents. Reasons for the discrepancies may relate to the dose of curcumin and the specific chemotherapeutic agent. Lower doses of curcumin might have antioxidant effects while higher doses might have pro-oxidant effects (96125). More evidence is needed to determine what effect, if any, turmeric might have on alkylating agents.

AMLODIPINE (Norvasc) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Taking turmeric with amlodipine may increase levels of amlodipine.  Details Animal research shows that giving amlodipine 1 mg/kg as a single dose following the use of turmeric extract 200 mg/kg daily for 2 weeks increases the maximum concentration and area under the curve by 53% and 56%, respectively, when compared with amlodipine alone (107113). Additional animal research shows that taking amlodipine 1 mg/kg with a curcumin 2 mg/kg pretreatment for 10 days increases the maximum concentration and area under the curve by about 2-fold when compared with amlodipine alone (103099).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Turmeric may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs. However, research is conflicting.  Details Curcumin, a constituent of turmeric, has demonstrated antiplatelet effects in vitro (11143,81204,81271). Furthermore, two case reports have found that taking turmeric along with warfarin or fluindione was associated with an increased international normalized ratio (INR) (89718,100906). However, one clinical study in healthy volunteers shows that taking curcumin 500 mg daily for 3 weeks, alone or with aspirin 100 mg, does not increase antiplatelet effects or bleeding risk (96137). It is possible that the dose of turmeric used in this study was too low to produce a notable effect.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking turmeric with antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research and case reports suggest that curcumin, a turmeric constituent, can reduce blood glucose levels in patients with diabetes (79692,79984,80155,80313,80315,80476,80553,81048,81219). Furthermore, clinical research in adults with type 2 diabetes shows that taking curcumin 475 mg daily for 10 days prior to taking glyburide 5 mg decreased postprandial glucose levels for up to 24 hours when compared with glyburide alone, despite the lack of a significant pharmacokinetic interaction (96133). Another clinical study in patients with diabetes on hemodialysis shows that taking curcumin 80 mg daily for 12 weeks can reduce blood glucose levels when compared with placebo (104149).

ANTITUMOR ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric has antioxidant effects. Theoretically, this may reduce the activity of chemotherapy drugs that generate free radicals. However, research is conflicting.  Details In vitro and animal research shows that curcumin, a constituent of turmeric, inhibits doxorubicin-induced apoptosis of breast cancer cells by up to 65% (96126). However, curcumin does not seem to affect the apoptosis capacity of daunorubicin. In fact, some research shows that curcumin might augment the cytotoxic effects of antitumor antibiotics, increasing their effectiveness. Reasons for the discrepancies may relate to the dose of curcumin and the chemotherapeutic agent. Lower doses of curcumin might have antioxidant effects while higher doses might have pro-oxidant effects (96125). More evidence is needed to determine what effects, if any, antioxidants such as turmeric have on antitumor antibiotics.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase or decrease levels of drugs metabolized by CYP1A1. However, research is conflicting.  Details Most in vitro and animal research suggests that the turmeric constituent, curcumin, INHIBITS CYP1A1, primarily in the liver (15823,21495,80876,81411). However, some evidence from in vitro research suggests that curcumin may INDUCE CYP1A1 in the intestines (21500).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase levels of drugs metabolized by CYP1A2. However, research is conflicting.  Details In vitro and animal research show that the turmeric constituent, curcumin, inhibits CYP1A2 (15823,21497,81304). However, other in vitro research suggests that curcumin does not significantly affect CYP1A2 (22000).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric might increase levels of drugs metabolized by CYP3A4.  Details In vitro and animal research show that turmeric and its constituents curcumin and curcuminoids inhibit CYP3A4 (21497,21498,21499). Also, 8 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking turmeric and cancer medications that are CYP3A4 substrates, including everolimus, ruxolitinib, ibrutinib, and palbociclib, and bortezomib (111644). In another case report, a transplant patient presented with acute nephrotoxicity and elevated tacrolimus levels after consuming turmeric powder at a dose of 15 or more spoonfuls daily for ten days prior. It was thought that turmeric increased levels of tacrolimus due to CYP3A4 inhibition (93544). Conversely, other in vitro research suggests that turmeric induces CYP3A4 activity, leading to reduced levels of CYP3A4 substrates (111404). However, this interaction has not been reported in humans.

DOCETAXEL (Taxotere) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase blood levels of oral docetaxel.  Details Animal research suggests that the turmeric constituent, curcumin, enhances the oral bioavailability of docetaxel (80999). However, the significance of this interaction is unclear, as this drug is typically administered intravenously in clinical settings.

ESTROGENS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, large amounts of turmeric might interfere with hormone replacement therapy through competition for estrogen receptors.  Details In vitro research shows that curcumin, a constituent of turmeric, displaces the binding of estrogen to its receptors (21486).

GLYBURIDE (Diabeta, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking turmeric and glyburide in combination might increase the risk of hypoglycemia.  Details Clinical research shows that taking curcumin 475 mg daily for 10 days prior to taking glyburide 5 mg increases blood levels of glyburide by 12% at 2 hours after the dose in patients with type 2 diabetes. While maximal blood concentrations of glyburide were not affected, turmeric modestly decreased postprandial glucose levels for up to 24 hours when compared to glyburide alone, possibly due to the hypoglycemic effect of turmeric demonstrated in animal research (96133).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase the risk of liver damage when taken with hepatotoxic drugs.  Details There is concern that turmeric might cause hepatotoxicity, especially when highly bioavailable formulations are used in high doses (103633,107122,109288,110221).

LOSARTAN (Cozaar) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase the effects of losartan.  Details Research in hypertensive rats shows that taking turmeric can increase the hypotensive effects of losartan (110897).

METHOTREXATE (Trexall, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might have additive effects when used with hepatotoxic drugs such as methotrexate.  Details In one case report, a 39-year-old female taking methotrexate, turmeric, and linseed oil developed hepatotoxicity (111644).

NORFLOXACIN (Noroxin) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase the effects and adverse effects of norfloxacin.  Details Animal research shows that taking curcumin, a turmeric constituent, can increase blood levels of orally administered norfloxacin (80863).

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase blood levels of OATP4C1 substrates.  Details In vitro research shows that the turmeric constituent curcumin competitively inhibits OATP4C1 transport. This transporter is expressed in the kidney and facilitates the renal excretion of certain drugs (113337). Theoretically, taking turmeric might decrease renal excretion of OATP substrates.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might increase the absorption of P-glycoprotein substrates.  Details In vitro and animal research shows that curcuminoids and other constituents found in turmeric can inhibit P-glycoprotein expression and activity (21472,21473,21474,21475,21476,21477,21478,21479,21480)(21482,21484,111644).

PACLITAXEL (Abraxane, Onxol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, turmeric might alter blood levels of paclitaxel, although any effect may not be clinically relevant.  Details Clinical research in adults with breast cancer receiving intravenous paclitaxel suggests that taking turmeric may modestly alter paclitaxel pharmacokinetics. Patients received paclitaxel on day 1, followed by either no treatment or turmeric 2 grams daily from days 2-22. Pharmacokinetic modeling suggests that turmeric reduces the maximum concentration and area under the curve of paclitaxel by 12.1% and 7.7%, respectively. However, these changes are not likely to be considered clinically relevant (108876). Conversely, animal research suggests that curcumin, a constituent of turmeric, enhances the oral bioavailability of paclitaxel (22005). However, the significance of this interaction is unclear, as this drug is typically administered intravenously in clinical settings.

SULFASALAZINE (Azulfidine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Turmeric might increase the effects and adverse effects of sulfasalazine.  Details Clinical research shows that taking the turmeric constituent, curcumin, can increase blood levels of sulfasalazine by 3.2-fold (81131).

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric might increase the effects and adverse effects of tacrolimus.  Details In one case report, a transplant patient presented with acute nephrotoxicity and elevated tacrolimus levels of 29 ng/mL. The patient previously had tacrolimus levels within the therapeutic range at 9.7 ng/mL. Ten days prior to presenting at the emergency room the patient started consumption of turmeric powder at a dose of 15 or more spoonfuls daily. It was thought that turmeric increased levels of tacrolimus due to cytochrome P450 3A4 (CYP3A4) inhibition (93544). In vitro and animal research show that turmeric and its constituent curcumin inhibit CYP3A4 (21497,21498,21499).

TALINOLOL Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Turmeric may reduce the absorption of talinolol in some situations.  Details Clinical research shows that taking curcumin for 6 days decreases the bioavailability of talinolol when taken together on the seventh day (80079). The clinical significance of this effect is unclear.

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, turmeric might reduce the levels and clinical effects of tamoxifen.  Details In a small clinical trial in patients with breast cancer taking tamoxifen 20-30 mg daily, adding curcumin 1200 mg plus piperine 10 mg three times daily reduces the 24-hour area under the curve of tamoxifen and the active metabolite endoxifen by 12.8% and 12.4%, respectively, as well as the maximum concentrations of tamoxifen, when compared with tamoxifen alone. However, in the absence of piperine, the area under the curve for endoxifen and the maximum concentration of tamoxifen were not significantly reduced. Effects were most pronounced in patients who were extensive cytochrome P450 (CYP) 2D6 metabolizers (107123).

TOPOISOMERASE I INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric has antioxidant effects. There is some concern that this may reduce the activity of chemotherapy drugs that generate free radicals. However, research is conflicting.  Details In vitro research shows that curcumin, a constituent of turmeric, inhibits camptothecin-induced apoptosis of breast cancer cells by up to 71% (96126). However, other in vitro research shows that curcumin augments the cytotoxic effects of camptothecin. Reasons for the discrepancies may relate to the dose of curcumin and the chemotherapeutic agents. Lower doses of curcumin might have antioxidant effects while higher doses might have pro-oxidant effects (96125). More evidence is needed to determine what effect, if any, turmeric might have.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Turmeric might increase the risk of bleeding with warfarin.  Details One case of increased international normalized ratio (INR) has been reported for a patient taking warfarin who began taking turmeric. Prior to taking turmeric, the patient had stable INR measurements. Within a few weeks of starting turmeric supplementation, the patient's INR increased to 10 (100906). Additionally, curcumin, the active constituent in turmeric, has demonstrated antiplatelet effects in vitro (11143,81204,81271), which may produce additive effects when taken with warfarin.

(Read more about TURMERIC)

ANTICONVULSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking wormwood might interfere with the effects of anticonvulsant drugs.  Details Thujone, a constituent of wormwood, has convulsant effects (12816).

(Read more about WORMWOOD)

General ...Orally, black walnut fruit (nut) is well tolerated. However, the leaf, bark, and hull of black walnut contain high quantities of tannins, which may cause adverse effects when used orally or topically.
Most Common Adverse Effects:
Orally: The leaf, bark, and hull can cause gastrointestinal upset.
Topically: Hull preparations may cause a temporary yellow or brown discoloration at the site of application. The leaf, bark, and hull can cause skin irritation.
Serious Adverse Effects (Rare):
Orally: The bark may increase the risk for tongue cancer or lip leukoplakia when used long-term.
All routes of administration: Allergic reactions, including anaphylaxis.

Dermatologic ...Topically, black walnut leaf, bark, or hull may have an irritating effect on the skin due to tannin content. Black walnut hull preparations might cause a temporary yellow or brown discoloration of the skin at the site of application (12).

Gastrointestinal ...Orally, black walnut leaf, bark, or hull may cause gastrointestinal upset due to tannin content (12). Also, daily use of the juglone-containing bark of a related species (English walnut) is associated with increased risk of tongue cancer and lip leukoplakia (2,12).

Hepatic ...Orally, black walnut leaf, bark, or hull may cause liver damage if taken for extended periods of time due to tannin content (12).

Immunologic ...Tree nuts, which include black walnuts, can cause allergic reactions in sensitive individuals. Due to the prevalence of this allergy in the general population, tree nuts are classified as a major food allergen in the United States (105410).

Renal ...Orally, black walnut leaf, bark, or hull may cause kidney damage if taken for extended periods of time due to tannin content (12).

(Read more about BLACK WALNUT)

General ...Orally, clove is well tolerated when consumed as a spice; however, clove oil in doses of only 5-10 mL can be toxic in children. Topically, clove is generally well tolerated. When inhaled or used intravenously, clove may be unsafe.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, dental decay, itching, mucous membrane irritation, tingling, ulcers.
Inhaled: Dental decay, hypertension, itching, tachycardia.
Serious Adverse Effects (Rare):
Orally: Liver failure, respiratory distress.
Inhaled: Pneumonitis, pulmonary edema, respiratory distress.

Cardiovascular ...Smoking clove cigarettes increases heart rate and systolic blood pressure (12892).

Dental ...Population research has found that the risk of dental decay is increased in clove cigarette smokers (43332). Repeated topical application of clove in the mouth can cause gingival damage and skin and mucous membrane irritation (4,272,512). Eugenol, a constituent of clove and a material commonly found in dentistry, has been associated with side effects including gum inflammation and irritation (43365,43373,43522).

Dermatologic ...The American Dental Association has accepted clove for professional use, but not nonprescription use, due to potential damage to soft tissue that may be induced by clove application. In clinical research, small aphthous-like ulcers appeared in the area of the mouth where clove gel was applied in four participants (43448). Skin irritation and stinging have been reported with clove oil application (43338,43626). In a 24-year-old, exposure to a clove oil spill resulted in permanent local anesthesia and anhidrosis, or lack of sweating, at the affected area (43626).

Endocrine ...A case of hypoglycemia and metabolic acidosis have been reported after administration of one teaspoon of clove oil to a seven-month-old infant (43457). A case of electrolyte imbalance following accidental ingestion by a seven-month-old has also been reported (6).

Hematologic ...A case of disseminated intravascular coagulation has been reported in a 2-year-old patient after consuming between 5-10 mL of clove oil. The patient was treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III. On the fifth day, the patient started to improve and made a full recovery (43652).

Hepatic ...There are three cases of hepatic failure occurring in children after ingestion of 5-10 mL of clove oil (43395,43419,43652). Liver injury also occurred in a 3-year-old male (96949). These patients were successfully treated with N-acetylcysteine. The course of liver injury seems to be milder and shorter with early N-acetylcysteine treatment (43395,43419,96949). Another patient, who also presented with disseminated intravascular coagulation, was successfully treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III (43652).

Immunologic ...Contact dermatitis and urticaria has been reported following topical exposure to clove oil or eugenol, a constituent of clove oil (12635,43339,43606,43346).

Neurologic/CNS ...CNS depression has been reported in a 7-month-old who was given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457). A case of confusion and inability to speak has been reported secondary to oral exposure to clove oil and alcohol. The patient required intubation and was successfully treated with thiamine and normal saline (43580). Seizure and coma have been reported in a two-year-old male after ingesting 5-10 mL of clove oil (43652).

Pulmonary/Respiratory ...Clove cigarettes have been associated with throat and chest tightness (43337), pulmonary edema (43618), and fatal aspiration pneumonitis (43599). The causative factor may be clove alone or clove along with other substances found in cigarettes. Clove cigarettes contain significant amounts of nicotine, tar, and carbon monoxide and increase plasma levels of nicotine and exhaled carbon monoxide, which might cause long-term health effects similar to tobacco smoking (12892). According to the American Medical Association, inhaling clove cigarette smoke has been associated with severe lung injury in a few susceptible individuals with prodromal respiratory infection. Also, some individuals with normal respiratory tracts have apparently suffered aspiration pneumonitis as the result of a diminished gag reflex induced by a local anesthetic action of eugenol, which is volatilized into the smoke (43602).
Intravenous injection of clove oil in a 32-year-old female resulted in hypoxia, acute dyspnea, interstitial and alveolar infiltrates, and non-cardiogenic pulmonary edema. The patient was managed with supplemental oxygen and recovered over the next seven days (16384).
Occupational exposure to eugenol, a constituent of clove, has also been reported to cause asthma and rhinitis (43492).

Renal ...Proteinuria and other urinary abnormalities were observed in a seven-month-old infant given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457).

(Read more about CLOVE)

General ...Orally, the fruit (nut) of English walnut is well tolerated (8476,8477); however, it can cause softening of stools and mild bloating (6431). Oral allergy syndrome may occur in people who are allergic to English walnuts. This is characterized by itching of the oral cavity immediately after consumption. Rarely this syndrome may cause swelling of the lips and tongue (angioedema) (8479). English walnut leaf extract has been reported to cause gastrointestinal adverse events, especially mild diarrhea (97750). Daily use of English walnut bark is associated with increased risk of tongue cancer and lip leukoplakia due to its juglone content (2,12).
Topically, English walnut hull preparations can lead to yellow or brown discoloration of skin and mucous membranes due to its juglone content. It can also cause contact dermatitis (12,12980).

Dermatologic ...Topically, English walnut hull preparations, which contain juglone, can cause a temporary yellow or brown discoloration of skin and mucous membranes. It can also cause contact dermatitis (12,12980).

Gastrointestinal ...Orally, the fruit (nut) of English walnut might cause softening of stools and mild bloating (6431). Oral allergy syndrome may occur in people who are allergic to English walnuts. This is characterized by itching of the oral cavity immediately after consumption. Rarely this syndrome may cause swelling of the lips and tongue (angioedema) (8479). Walnut leaf extract has been reported to cause gastrointestinal adverse events, especially mild diarrhea, in 39% of adults in one study (97750). Daily use of walnut bark is associated with increased risk of tongue cancer and lip leukoplakia due to its juglone content (2,12).

Immunologic ...Tree nuts, which include English walnuts, can cause allergic reactions in sensitive individuals. Due to the prevalence of this allergy in the general population, tree nuts are classified as a major food allergen in the United States (105410).
Oral allergy syndrome may occur in people who are allergic to English walnuts. This is characterized by itching of the oral cavity immediately after consumption. Rarely this syndrome may cause swelling of the lips and tongue (angioedema) (8479).

(Read more about ENGLISH WALNUT)

General ...European barberry is generally well tolerated when consumed in amounts commonly found in food. A thorough evaluation of safety outcomes has not been conducted for the use of larger, medicinal amounts. Topically, European barberry seems to be well tolerated.

Hepatic ...Orally, a case of hepatitis-associated aplastic anemia is reported in an adult male after consuming European barberry 15 drops and nannari root 15 drops twice a day for 2 weeks. The patient presented with lethargy, loss of appetite, and jaundice that progressed to high-grade fevers, chills, rigors, severe pancytopenia, and abnormal liver function tests. Liver biopsy was suggestive of drug-induced liver injury. The patient was hospitalized for multiple infections and symptomatic thrombocytopenia. Despite receiving supportive care, blood transfusions, and corticosteroids, the patient died 7 weeks after diagnosis (110021). The exact reason for this adverse effect is not clear.

(Read more about EUROPEAN BARBERRY)

General ...Orally and topically, fennel seems to be well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal discomfort, photosensitivity, and allergic reactions in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Seizures.

Dermatologic ...Advise patients to avoid excessive sunlight or ultraviolet light exposure while using fennel (19). Allergic reactions affecting the skin such as atopic dermatitis and photosensitivity may occur in patients who consume fennel (6178,49507).

Gastrointestinal ...Orally, fennel may cause gastrointestinal complaints, including nausea and vomiting (19146,104196).

Hematologic ...Methemoglobinemia has been reported in four infants following intoxication related to ingestion of a homemade fennel puree that may have been made from improperly stored fennel (49444).

Immunologic ...A case report describes an 11-year-old male who developed an allergy to fennel-containing toothpaste. Immediately after using the toothpaste, the patient experienced sneezing, coughing, itchy mouth, rhinorrhea, nasal congestion, wheezing, difficulty breathing, and palpitations, which resolved within 10 minutes of spitting out the toothpaste and rinsing the mouth. In challenge tests, the patient reacted to chewing fresh fennel root, but not ground fennel seeds (103822).

Neurologic/CNS ...Orally, fennel oil has been associated with tonic clonic and generalized seizures (12868). New-onset cluster headaches are reported in a 24-year-old female while using a toothpaste containing fennel and camphor for 3 months. The headaches resolved upon stopping the toothpaste (112368). It is unclear if this adverse effect can be attributed to fennel, camphor, or the combination.

Pulmonary/Respiratory ...Orally, fennel and fennel seed have been reported to cause bronchial asthma (49478).

(Read more about FENNEL)

General ...Orally, garlic is generally well tolerated. Topically, garlic seems to be well tolerated. Intravenously, there is insufficient reliable information available about adverse effects.
Most Common Adverse Effects:
Orally: Abdominal pain, body odor, flatulence, malodorous breath, and nausea. Allergic reactions in sensitive individuals.
Topically: Burns and dermatitis with fresh garlic.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with garlic.

Dermatologic ...Orally, garlic may cause pruritus (51316,51474,107239), flushing, and acne (107239). Oral intake of a specific garlic product containing allicin (Allimax) has been associated with a case of pruritic rash (51474). Enteric-coated garlic tablets standardized to 1.5% allicin have also been associated with a case of pruritus (51316). Garlic has also been associated with a case of superficial pemphigus in a 49-year-old male with type 2 diabetes (51564). Garlic-induced oral ulcers have also been reported (51467).
Topically, garlic may cause contact dermatitis and urticaria (4833,5004,12635,51258,51265,51375,51403,51412,51459,51483)(51511,51512,51530,51616,51617,51618,111769), as well as contact cheilitis (51384). Fresh garlic may be more likely to elicit a reaction than garlic extract. Most reactions have resolved following withdrawal of garlic therapy. In one case report, applying crushed garlic on the neck to help ease a sore throat resulted in an itchy, burning, erythematous lesion in a young female patient. The lesion healed after one week of treatment with topical antibiotics, steroids, and antihistamine ointments (88390). Cases of occupational eczema or dermatitis have been reported in cooks (51303,51210), food handlers (51292), and caterers (51304). According to one case report, dermatitis appeared in chefs exposed to garlic (15033). Treatment with acitretin 25 mg daily or topical psoralen-ultraviolet A (PUVA) for 12 weeks proved effective in mitigating the symptoms. A 34-year-old female with a history of hand dermatitis and paronychia had a worsening of these conditions after peeling raw garlic. She had a positive skin patch test to fresh, raw garlic but not to any other tested allergens, and the conditions resolved when she avoided contact with garlic (105528). Topically, garlic may also cause chemical burns, usually within 12 hours of application. Second- and third-degree chemical burns have been reported in adults, children, and infants exposed to topical garlic, often as an unintended consequence of using garlic medicinally on the skin (585,4832,51226,51230,51252,51281,51377,51418,51468,51495,51536)(51558,51576,51577,88409,96006). A case of painful blisters on the soles of the feet of a 23-year-old Chinese female has been attributed to chemical burns caused by applying crushed raw garlic for 3 hours (51440). Topically, garlic may also cause hyperpigmentation, ulcers, necrotic lesions, facial flushing, and local irritation (4832,15030,51268,51269,108606). In one case report, applying crushed raw garlic to the palatal mucosa for several minutes to relieve mouth pain resulted in a chemical burn that produced a 3 cm necrotic ulcer in an adult female with trigeminal neuralgia (108606).

Gastrointestinal ...Orally, dehydrated garlic preparations or raw garlic may cause malodorous breath (51438,51444), body odor (732,1873,4784,4793,4795,4798,9201,10787,42692,49769)(51269,51316,51467,51602), abdominal pain or fullness, anorexia, diarrhea, constipation, flatulence, belching, heartburn, nausea, unpleasant taste, reflux, and bowel obstruction (1884,6457,6897,9201,49769,51269,51343,51380,51438,51442)(51450,51457,51466,51471,51474,51520,51593,51602,51623,88398)(88405,111766).
Large quantities of garlic may damage the gastrointestinal tract. In one case report, a patient taking garlic for hypertension reported odynophagia and retrosternal pain after taking garlic without any water the previous day. An esophageal lesion 3 cm in length was detected upon endoscopy. The symptoms resolved 3 days after starting a liquid diet and taking lansoprazole 30 mg twice daily and sucralfate four times daily (88389). One case of bowel obstruction was reported in a 66-year-old male who ingested an entire garlic bulb (51525). Esophageal perforation has been reported in at least 17 individuals who consumed entire garlic cloves. In one case the perforation led to mediastinitis and death (102672).
Garlic has also been associated with eosinophilic infiltration of the gastrointestinal tract. In one case report a 42-year-old female presented with symptoms of eosinophilic gastroenteritis, which included pollinosis, asthma, diarrhea, heart burn, peripheral eosinophilia, and urticaria. After stopping use of garlic and sesame, the patient improved (51441). In a case report of eosinophilic esophagitis, garlic was determined to be the causative agent in a patient with long-standing gastrointestinal symptoms. The patient had attempted to treat upper gastrointestinal symptoms as gastrointestinal reflux disease without success for many years. Skin prick testing showed a positive reaction to garlic, of which the patient noted frequent consumption. Marked symptom improvement was noted within 3 weeks of garlic avoidance (88393).
Intravenously, garlic 1 mg/kg of body weight daily diluted into 500 mL saline and administered over 4 hours has been reported to cause abdominal discomfort, vomiting, diarrhea, nausea, anorexia, flatulence, weight loss, and garlicky body odor (51462).
Clinical research suggests that patients with metabolic syndrome taking 1600 mg of powdered garlic by mouth daily for 3 months may experience improved intestinal transit time when compared with placebo, suggesting that garlic powder may reduce symptoms of constipation (110722).

Genitourinary ...Orally, garlic might cause dysuria, hematuria, or polyuria (51438,51450,51467,113618). In one case, an older male with high dietary and supplemental garlic intake at doses of 300-5400 mg daily for 3-4 years developed severe hematuria with clots after undergoing a minimally invasive prostate procedure (113618).

Hematologic ...Oral use of dietary garlic or supplements containing garlic has caused platelet dysfunction, increased fibrinolytic activity, prolonged bleeding time, retrobulbar hemorrhage (bleeding behind the eye) postoperative bleeding, and spinal epidural hematoma (586,587,4801,4802,11325,51397,51473,51491,51532,51534)(51570,51584,51593,51594,113618). Also, a case of kidney hematoma following extracorporeal shock-wave lithotripsy (SWL) has been reported in a patient with nephrolithiasis who took aged garlic (51630). A case of increased bleeding time that complicated epistaxis management has been reported in a patient taking garlic, aspirin, and milk thistle (51426).
Intravenously, garlic has been associated with the development of thrombophlebitis at the injection site (51462).

Immunologic ...There is a case report of an immediate sensitivity reaction to oral raw garlic, resulting in wheals, in a 31-year-old female. The patient did not react to cooked garlic, and skin prick tests showed allergy only to raw garlic (96015). Researchers note that at least some allergens in raw garlic are heat labile (88392,96012,96015). This suggests that consuming cooked rather than raw garlic may help avoid this reaction in patients allergic to raw garlic. However, different people react to different allergens in garlic. At least some of these allergens are heat stable (96012). While rare, garlic-induced anaphylaxis has been reported (88392,96012).
Topically, allergic contact dermatitis has been reported in case reports (51406,51498,51510,51519,51560).

Musculoskeletal ...Orally, garlic has been associated with individual cases of gout and low back pain (51474,51467), but it is not clear if these adverse events can be attributed to garlic.