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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Benign prostatic hyperplasia (BPH). Although there is interest in using oral diindolylmethane for BPH, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Breast cancer. It is unclear if oral diindolylmethane is beneficial in patients at high risk for developing breast cancer. Details: Preliminary clinical research in healthy pre- and post-menopausal patients at high risk for breast cancer due to the BRCA mutation shows that taking diindolylmethane (DIM-Evail, Designs for Health Inc) 100 mg daily for 1 year is associated with a 5% decrease in breast density, as measured by the amount of fibroglandular tissue, when compared with baseline (103830). It is unclear whether this reduces the risk of developing breast cancer. Also, the validity of this finding is limited by the lack of a control group.
• Cervical dysplasia. It is unclear if oral diindolylmethane is beneficial in patients with cervical dysplasia. Details: Clinical research in patients with mild cervical abnormalities shows that taking a specific product (BioResponse-DIM, BioResponse) as 150 mg, providing 45 mg diindolylmethane, daily for 6 months does not improve colposcopy or biopsy results when compared with placebo (93836). Additionally, clinical research in patients with grade 2 or 3 cervical neoplasia shows that taking this same product as 2 mg/kg diindolylmethane daily for 12 weeks does not affect Pap smear, colposcopy, or histology results when compared with placebo; however, both groups showed significant improvements when compared with baseline (47709).
• Colorectal cancer. Although there is interest in using oral diindolylmethane for colorectal cancer, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Mastalgia. Although there is interest in using oral diindolylmethane for mastalgia, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Obesity. Although there is interest in using oral diindolylmethane for obesity, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral diindolylmethane for PMS, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Prostate cancer. Although there is interest in using oral diindolylmethane for prostate cancer, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition.
• Uterine cancer. Although there is interest in using oral diindolylmethane for uterine cancer, there is insufficient reliable information about the clinical effects of diindolylmethane for this condition. More evidence is needed to rate diindolylmethane for these uses.

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POSSIBLY EFFECTIVE

• Sexual desire. Oral Eurycoma longifolia seems to improve sexual desire.

POSSIBLY INEFFECTIVE

• Athletic performance. Oral Eurycoma longifolia does not seem to improve athletic performance in healthy persons. Details: One small study in recreational male athletes shows that taking Eurycoma longifolia 150 mg daily for 7 days before, plus one hour prior to, an endurance running trial does not increase endurance when compared with placebo (49133). Furthermore, a larger study in healthy males shows that taking a specific brand of Eurycoma longifolia extract (Physta, Biotropics Malaysia Berhad) 300 mg daily for 12 weeks does not improve physical fitness when compared with placebo (93490).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related testosterone deficiency. It is unclear if oral Eurycoma longifolia is beneficial for increasing testosterone levels in older males. Details: A clinical study in older adult males with testosterone levels below 300 ng/dL shows that taking a specific water extract of Eurycoma longifolia roots (Physta; Biotropics Malaysia) 100-200 mg daily with breakfast for 12 weeks modestly increases total testosterone levels and improves Aging Male Symptoms (AMS) and Fatigue Severity Scale (FSS) scores when compared with placebo. Improvements in testosterone are observed at 4 and 12 weeks in the 200-mg and 100-mg groups, respectively; improvements in AMS and FSS scores are observed as early as week 2 in both groups (108451). Daily food intake, exercise frequency, and other lifestyle details were not reported, limiting the validity of these findings. Another small clinical study in adults with late-onset hypogonadism shows that taking a water-based extract of Eurycoma longifolia 200 mg daily for one month seems to increase testosterone levels by about 2.6 nmol/L and improves Aging Male Symptoms (AMS) scores when compared to baseline (17924). The validity of these findings is limited by the lack of a comparator group. A meta-analysis of 5 mostly small clinical studies in healthy adult males and males with hypogonadism shows that taking Eurycoma longifolia 100-600 mg daily for 2-12 weeks modestly increases serum testosterone levels when compared with placebo (112185). However, the interpretation of this finding is limited by the heterogeneity of the included studies that utilized various dosing regimens.
• Back pain. Although there is interest in using oral Eurycoma longifolia for back pain, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this condition.
• Cancer. Although there is interest in using oral Eurycoma longifolia for cancer, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this condition.
• Diabetes. Although there is interest in using oral Eurycoma longifolia for diabetes, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this condition.
• Dyspepsia. Although there is interest in using oral Eurycoma longifolia for dyspepsia, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this condition.
• Erectile dysfunction (ED). It is unclear if oral Eurycoma longifolia is beneficial for ED. Details: A meta-analysis of two small clinical studies suggests that Eurycoma longifolia has no overall effect on erectile function based on the International Index of Erectile Function (IIEF)-5 scale (93491). However, only one of the studies in the meta-analysis included persons with known ED. This small study found that taking Eurycoma longifolia 200 mg in combination with Persicaria minor 100 mg for 12 weeks may modestly improves erectile function on Sexual Health Inventory for Men (SHIM) and Erection Hardness Scale (EHS) when compared with placebo. However, improvements in erectile function per the IIEF-5 scale were lacking (93496). Additionally, it is unclear if these effects were due to Eurycoma longifolia, Persicaria minor, or the combination.
• Hypertension. Although there is interest in using oral Eurycoma longifolia for hypertension, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this condition.
• Intestinal parasite infection. Although there is interest in using oral Eurycoma longifolia for intestinal parasite infection, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this purpose.
• Malaria. Although there is interest in using oral Eurycoma longifolia for malaria, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this condition.
• Male Infertility. It is unclear if oral Eurycoma longifolia is beneficial for improving male infertility. Details: Preliminary clinical research shows that taking a specific formulation of Eurycoma longifolia (Physta, Biotropics Malaysia Berhad) 200-300 mg daily for 3-9 months results in higher semen volume and sperm concentration, and also improves the percentage of normal sperm morphology and sperm motility, when compared with baseline (18138,93490). In one study, 15% of patients had a spontaneous pregnancy after treatment (18138). The validity of these findings is limited by the lack of a comparator group.
• Menopausal symptoms. Oral Eurycoma longifolia has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in peri-menopausal patients shows that taking a combination product (Nu-femme) containing the standardized ingredients Eurycoma longifolia (Physta, Biotropics Malaysia) 50 mg and Labisia pumila (SLP+, Biotropics Malaysia) daily for 24 weeks seems to reduce hot flashes and other menopausal symptoms when compared to baseline. However, the improvements were no better than placebo (105085).
• Muscle strength. It is unclear if oral Eurycoma longifolia is beneficial for improving muscle strength. Details: One small study in healthy male adults shows that taking Eurycoma longifolia 100 mg daily for 5 weeks in addition to participating in an intense strength training program increases muscle mass and strength when compared with those participating in strength training alone (49134). Another small study in physically active seniors shows that taking Eurycoma longifolia extract (Physta, Biotropics Malaysia Berhad) 400 mg daily for 5 weeks increases muscular force by around 15% when compared to baseline (97312). However, not all research has been positive. One small study in young, healthy males shows that taking Eurycoma longifolia 200 mg daily for 8 weeks in addition to a resistance training program does not increase isokinetic knee muscle strength or peak power when compared with resistance training alone (103619).
• Obesity. Oral Eurycoma longifolia has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with obesity following a reduced-calorie diet and performing 30-60 minutes of daily, light-intensity exercise, shows that a specific oral product (CitruSlim; NHR Science) containing Eurycoma longifolia root extract 17% and bergamot extract 83%, taken as 200 mg or 400 mg daily as three divided doses before meals for 112 days, decreases body mass index by 3.3% and 3.2%, respectively, but does not impact lipid parameters or waist-to-hip ratio, when compared with diet and exercise alone (108452). It is unclear if this effect is due to Eurycoma longifolia, bergamot, or the combination.
• Osteoporosis. Although there is interest in using oral Eurycoma longifolia for osteoporosis, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this condition.
• Syphilis. Although there has been interest in using oral Eurycoma longifolia for syphilis, there is insufficient reliable information about the clinical effects of Eurycoma longifolia for this condition. More information is needed to rate Eurycoma longifolia for these uses.

(Read more about EURYCOMA LONGIFOLIA)

POSSIBLY EFFECTIVE

• Diabetes. Oral fenugreek seed seems to improve glycemic control in type 2 diabetes. Details: Meta-analyses of 10-14 clinical trials in patients with type 2 diabetes or other metabolic conditions show that taking fenugreek lowers fasting glucose by approximately 14-23 mg/dL, 2-hour postprandial glucose by 21-23 mg/dL, and glycated hemoglobin (HbA1c) by 0.6-1.2% when compared with placebo. The most effective doses and formulations seem to include powdered seed or debitterized seed powder 5-100 grams daily, taken as capsules or added to meals, for up to 3 years or seed hydroalcoholic extract about 1 gram daily for up to 2 months (90112,96065,105016,111503,113499,112120). The validity of these effects is limited by high heterogeneity and low quality in the included studies. Most research also shows that fenugreek seed lowers total cholesterol levels and triglycerides in patients with diabetes, but has inconsistent effects on low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol (96065,102252). Some research shows that taking fenugreek in combination with other ingredients also seems to improve glycemic indices in people with diabetes. These combination products have combined fenugreek with guar gum and gymnema (10284) or millets and legumes (9784). Limited research has also evaluated fenugreek in type 1 diabetes. In one small clinical study, taking 50 grams of defatted fenugreek seed powder twice daily with meals for 10 days reduced 24-hour urine glucose levels by 54% when compared to baseline (622). The validity of this finding is limited by the lack of a comparator group.
• Dysmenorrhea. Oral fenugreek seed might help to reduce menstrual pain. Details: Clinical research in adults with moderate to severe dysmenorrhea shows that taking fenugreek seed powder 1800-2700 mg three times daily for the first 3 days of menstruation followed by 900 mg three times daily for the remainder of two menstrual cycles reduces pain severity when compared with placebo. Patients taking fenugreek seed powder showed a reduction in pain severity of 3.22, compared with a reduction of only 0.18 in the placebo group (90116).
• Sexual arousal. Oral fenugreek seed might help to improve sexual arousal. Details: Clinical research shows that taking a specific fenugreek seed extract (Testofen, Gencor Pacific Ltd) 600 mg daily for 12 weeks increases sexual function by 15% over baseline, compared with no change in the placebo group; the main benefits were in sexual arousal and drive. Morning erection and sexual frequency also improve by 2- to 3-fold (93419). Another clinical study in healthy males shows that taking the same fenugreek seed extract 600 mg daily in combination with magnesium 34 mg, zinc 30 mg, and vitamin B6 10 mg for 6 weeks, improves a composite of symptoms such as sexual cognition, sexual arousal, sexual behavior, and orgasm. The overall improvement in the composite score was 23%, compared with a worsening in the placebo group (93421).
• Sexual dysfunction. Oral fenugreek seed extract might help to improve sexual dysfunction. Details: Clinical research shows that taking a specific fenugreek seed extract (Libifem, Gencor Pacific Ltd.) 300 mg twice daily for two menstrual cycles improves sexual function in healthy pre-menopausal adults with low sex drive. In one clinical trial, overall improvement based on a composite of symptoms was 26% in the fenugreek group, compared with only 2% in the placebo group. Individual scores for sexual cognition, arousal, behavior, drive, and orgasm were all improved. Patients taking fenugreek also had an increased frequency of sexual activity from 1-2 times per month to once per week, compared to no change in the placebo group (93420). Other clinical research in males aged 35-60 years with symptomatic hypogonadism shows that taking a specific fenugreek seed extract (Furosap; Chemical Resources) 500 mg daily after breakfast for 12 weeks improves sexual arousal, mental alertness, and mood when compared with baseline. This fenugreek seed extract was fortified with 20% protodioscin; the other constituents were not specified (108700). The validity of this finding is limited by the lack of comparator group.

POSSIBLY INEFFECTIVE

• Benign prostatic hyperplasia (BPH). Oral fenugreek extract does not seem to improve BPH symptoms. Details: A clinical study in healthy adults with BPH shows that taking a specific fenugreek extract (Testofen, Bluegum Pharmaceuticals) 300 mg twice daily for 12 weeks does not improve BPH symptoms when compared with placebo (102253).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alopecia areata. Although there is interest in using oral fenugreek for alopecia areata, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Alzheimer disease. It is unclear if oral fenugreek seed extract is beneficial for Alzheimer disease. Details: A moderate-sized study in adults with mild to moderate Alzheimer disease shows that taking fenugreek seed extract 5 mL daily for 4 months modestly improves memory but does not improve depression or quality of life measures when compared with placebo (113498).
• Athletic performance. It is unclear if oral fenugreek seed is beneficial for improving athletic performance. Details: Two small clinical studies in resistance-trained young males shows that taking a fenugreek supplement (AI or Torabolic, Indus Biotech) 500 mg daily for 8 weeks in addition to training 4 days every week, decreases body fat by about 2% and sometimes increases leg and bench press performance, but does not improve power, when compared with placebo (18352,18353). Another small study in healthy males undergoing strength training also shows that taking a specific fenugreek extract enriched in furostanol glycosides (Fenu-FG, Indus Biotech Private Limited) 300 mg twice daily for 8 weeks might help to modestly increase the number of bench press repetitions, but not overall strength, when compared with placebo (93423).
• Atopic dermatitis (eczema). Although there is interest in using topical fenugreek for eczema, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Cough. Although there is interest in using oral fenugreek for cough, there is insufficient reliable information about the clinical effects of fenugreek for this purpose.
• Gastroesophageal reflux disease (GERD). It is unclear if oral fenugreek fiber is beneficial for improving heartburn symptoms. Details: A small clinical study in patients with frequent heartburn shows that taking a specific fenugreek fiber product (FenuLife, Frutarom Belgium), 2 grams twice daily 30 minutes before the two biggest meals of the day, improves heartburn after one week of treatment and continuing through the 2-week study period. Fenugreek seemed to be similarly effective to ranitidine 75 mg twice daily (17372).
• Gout. Although there is interest in using topical fenugreek for gout, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Hyperlipidemia. Small clinical studies suggest that oral fenugreek supplements might be beneficial for improving lipid levels. Details: Overall, fenugreek powdered seed seems to modestly reduce lipid levels in people with or without hyperlipidemia; however, most studies have been low-quality, small, and exploratory. Meta-analyses of these studies show that fenugreek reduces total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and increases high-density lipoprotein (HDL) cholesterol (103283,103284). Powdered fenugreek seed has been studied in doses of 0.5-100 grams daily for 10 days to 3 years. While some studies show modest improvement, others show no benefit (622,7389,9783,18359,18361,18362,102252,103283,103284,113497).
• Hypertension. Analysis of small clinical studies suggests that oral fenugreek might slightly improve systolic blood pressure (SBP). Details: A meta-analysis of 6 small clinical studies in healthy adults or those with diabetes, prediabetes, or metabolic syndrome shows that taking fenugreek seed 0.5-50 grams daily for 6-144 weeks reduces SBP by 3.5 mmHg but does not improve diastolic blood pressure (DBP) when compared with placebo. However, subgroup analysis suggests that taking fenugreek at a dose of 15 grams or more daily or for a duration of 12 weeks or less modestly reduces DBP (112110).
• Impaired glucose tolerance (prediabetes). It is unclear if oral fenugreek is beneficial in patients with prediabetes. Details: A small clinical study in adults with prediabetes shows that taking a specific fenugreek seed extract (Trigogen, Gencor Pacific Ltd.) 250 mg twice daily for 12 weeks reduces fasting blood glucose and postprandial blood glucose but not glycated hemoglobin (HbA1c), fasting insulin, or postprandial insulin when compared with placebo (113497). Another small clinical trial in patients with prediabetes shows that taking fenugreek seed extract 200 mg, bergamot extract 500 mg, and olive leaf extract 100 mg daily for 6 months does not improve glycated hemoglobin or fasting blood glucose when compared with placebo (102251).
• Joint pain. Although there is interest in using oral fenugreek for joint pain, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Lactation. Small clinical studies suggest that oral fenugreek, either as a supplement or tea, might increase lactation. Details: A network meta-analysis of 4 small clinical trials shows that taking fenugreek shortly after delivery may modestly increase breast milk production when compared with placebo. Patients in the included studies took fenugreek 1-2 grams as capsules or tea up to 3 times daily for 21-244 days. In most cases, fenugreek treatment was initiated one or two days after delivery. However, fenugreek might be less beneficial for breast milk production when compared with the natural ingredients Indian borage or palm date (96067). Fenugreek has also been used in combination with other ingredients. A small clinical study suggests that drinking a specific herbal tea containing fenugreek. hibiscus, fennel, rooibos, vervain, raspberry, goat's rue, and fennel oil (Humana Still-Tee, Humana, Germany) 200 mL three times daily modestly increases milk production when compared with placebo (22569). Another study in exclusively breastfeeding parents of 2-month-old infants shows that eating lactation cookies containing fenugreek, oatmeal, brewer's yeast, and flaxseed meal daily for 30 days do not improve milk production, perceived insufficiency, or breastfeeding self-efficacy when compared with control (112116).
• Male infertility. It is unclear if oral fenugreek seed is beneficial for improving sperm quality in males with infertility. Details: A small clinical study in healthy male patients ages 20-30 years with oligospermia shows that taking fenugreek seed oil 12 macro drops orally three times daily for 4 months improves sperm count from 6.2 million to 20.1 million, increases sperm motility from 43% to 61%, and reduces sperm abnormality from 68% to 53% when compared with baseline. However, taking the remaining fenugreek seed components 10 grams three times daily for 4 months does not seem to have this effect (90119). The validity of this finding is limited by the lack of a comparator group.
• Menopausal symptoms. It is unclear if oral fenugreek seed is beneficial for improving menopausal symptoms. Details: A small clinical study in perimenopausal patients shows that taking a specific fenugreek seed extract (FenuSMART) 250 mg, standardized to protodioscin 10.3%, trigonelline 3.1%, and total saponin 42.6%, twice daily with meals for 42 days does not improve menopausal symptoms when compared with placebo. However, there was a non-significant trend to reduced hot flashes, night sweats, depression, and insomnia in the treatment group (105000). This study was funded by the supplement manufacturer.
• Metabolic syndrome. It is unclear if oral fenugreek seed is beneficial for metabolic syndrome. Details: A meta-analysis of 29 small clinical studies in healthy adults or those with type 2 diabetes or other metabolic conditions shows that taking fenugreek at doses ranging from 25 mg to 60 grams daily for up to 144 weeks reduces fasting blood glucose by 17 mg/dL, triglycerides by 20 mg/dL, waist circumference by 2.5 cm, and systolic blood pressure by 3.5 mmHg and increases high-density lipoprotein cholesterol by 3.5 mg/dL when compared with control. However, no effect was found on diastolic blood pressure or body mass index (113500).
• Muscle strength. It is unclear if oral fenugreek seed is beneficial for increasing muscle strength. Details: A small study in healthy, active males shows that taking fenugreek seed extract 400 mg or 500 mg daily for 60 days increases grip strength when compared with placebo (103285).
• Myalgia. Although there is interest in using topical fenugreek for myalgia, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Obesity. Small clinical studies suggest that oral fenugreek seed or fiber may increase satiety and decrease caloric intake. Details: Two small clinical studies in overweight and normal weight males shows that taking fenugreek seed extract modestly reduces daily fat intake. At a dose of 392 mg three times daily for 2-6 weeks, fat intake is reduced by 13% to 17%. However, a lower dose of 196 mg three times daily appears to be ineffective. Neither of the doses affect weight, appetite, or satiety (18348,18349). Another small clinical study in obese adults shows that adding 8 grams of fenugreek fiber powder (FenuLife, Frutarom Inc) to a low-calorie beverage increases feelings of satiety and decreases hunger and lunchtime food intake. A lower dose of 4 grams appears to be less effective for reducing hunger but was considered to be more palatable (18350).
• Parkinson disease. It is unclear if oral fenugreek seed is beneficial for Parkinson disease symptoms. Details: One small clinical study in patients with Parkinson disease who are also using levodopa shows that taking fenugreek seed extract (Indus Biotech Private Limited, Pune) 300 mg twice daily for 6 months does not seem to improve behavioral or motor symptoms when compared with placebo (90113).
• Peptic ulcers. Although there is interest in using oral fenugreek for peptic ulcers, there is insufficient reliable information about the clinical effects of fenugreek for this condition.
• Polycystic ovary syndrome (PCOS). It is unclear if oral fenugreek seed is beneficial for PCOS. Details: A small clinical study in adults with symptomatic PCOS shows that adding a specific fenugreek seed extract (Goldarou Pharmaceutical Co.) 500 mg twice daily to metformin for 8 weeks does not improve insulin resistance, insulin sensitivity, or other symptoms when compared with placebo and metformin (90117). However, other small clinical studies in adults with PCOS show that taking another specific fenugreek seed extract (Furocyst, Cepham Inc.) 1000 mg, enriched with 40% furostanolic saponins, daily for 90 days is associated with a reduction in ovarian cyst size in 46% of patients, complete dissolution in 36% of patients, normalization of menstrual cycles in 71% to 80% of patients, and subsequent pregnancy in 12% of patients. Further, this extract appears to reduce mean cyst size by 42% to 45%, the number of cysts by 38%, ovary volume by 24% to 40%, and hirsutism by 27% while reducing luteinizing hormone, follicle-stimulating hormone, free testosterone, and prolactin and improving liver function and the severity of PCOS-associated ailments including insulin resistance and dyslipidemia (93422,112112,113502). The validity of some of these findings is limited by the lack of a comparator group. Furthermore, this study was funded by the supplement manufacturer.
• Vaginitis. There is limited evidence on the topical use of fenugreek cream in patients with atrophic vaginitis. Details: One small clinical study in postmenopausal patients with atrophic vaginitis shows that administration of 0.5 grams of fenugreek 5% cream intravaginally twice weekly for 12 weeks reduces symptoms of atrophic vaginitis and reduces vaginal pH when compared to baseline. However, fenugreek was not as effective as vaginal cream containing conjugated estrogens (103286). Another small clinical study in postmenopausal patients with vaginal atrophy shows that applying a fenugreek cream 5% intravaginally daily for 8 weeks seems to reduce dyspareunia and vaginal dryness and increase vaginal maturation when compared with a placebo cream (105023).
• Wound healing. Although there is interest in using topical fenugreek for wound healing, there is insufficient reliable information about the clinical effects of fenugreek for this purpose. More evidence is needed to rate fenugreek for these uses.

(Read more about FENUGREEK)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Breast cancer. Although there has been interest in using oral indole-3-carbinol for breast cancer, there is insufficient reliable information about the clinical effects of indole-3-carbinol for this purpose.
• Cervical dysplasia. It is unclear if oral indole-3-carbinol is beneficial in patients with cervical dysplasia. Details: Preliminary clinical research shows that taking indole-3-carbinol 200-400 mg orally daily for 12 weeks is associated with complete regression of precancerous lesions in 45% to 50% of women with grade II or III, biopsy-proven cervical intraepithelial neoplasia (CIN, cervical dysplasia), the majority of whom are positive for human papilloma virus (HPV) infection (7173).
• Colorectal cancer. Although there has been interest in using oral indole-3-carbinol for colorectal cancer, there is insufficient reliable information about the clinical effects of indole-3-carbinol for this purpose.
• Fibromyalgia. Although there has been interest in using oral indole-3-carbinol for fibromyalgia, there is insufficient reliable information about the clinical effects of indole-3-carbinol for this purpose.
• Liver disease. Although there has been interest in using oral indole-3-carbinol for liver disease, there is insufficient reliable information about the clinical effects of indole-3-carbinol for this purpose.
• Nonmelanoma skin cancer. It is unclear if oral indole-3-carbinol is beneficial in patients with nonmelanoma skin cancer. Details: Preliminary clinical research in patients with vulvar intraepithelial neoplasia (VIN), a precancerous condition that can progress to squamous cell carcinoma, shows that taking indole-3-carbinol 200 mg or 400 mg daily for 6 months improves symptoms and reduces lesion size and severity when compared with baseline. However, tissue biopsies taken from the women with the most severely affected areas did not show any improvement in grade of VIN (93241). The validity of this finding is limited by the small study size and lack of a comparator group. Additionally, it is unclear if treatment with indole-3-carbinol reduces the risk of progression to cancer.
• Ovarian cancer. It is unclear if oral indole-3-carbinol is beneficial in patients with ovarian cancer. Details: Preliminary clinical research in patients with previously untreated stage III-IV ovarian cancer shows that taking indole-3-carbinol 200 mg orally twice daily with or without epigallocatechechin-3-gallate (EGCG) 200 mg twice daily, in conjunction with neoadjuvant chemotherapy and surgery, increases median overall survival and progression-free survival by 16 and 18 months, respectively, when compared with chemotherapy and surgery alone. The addition of indole-3-carbonol with or without EGCG also reduced the tumor recurrence rate by about 16% when compared with chemotherapy and surgery alone (98610).
• Recurrent respiratory papillomatosis. It is unclear if oral indole-3-carbinol is beneficial in patients with recurrent respiratory papillomatosis. Details: Preliminary clinical evidence shows that taking indole-3-carbinol 200 mg twice daily for a mean of 57.6 months (range 31 months to 76 months) after complete surgical removal of respiratory papillomas stops regrowth in about a third of patients and slows regrowth, reducing the need for repeated surgery, in another third (7172,47645,93239).
• Systemic lupus erythematosus (SLE). It is unclear if oral indole-3-carbinol is beneficial in patients with SLE. Details: Preliminary clinical research shows that taking indole-3-carbinol 125 mg orally three times daily for 3 months does not significantly decrease disease activity when compared with baseline in women aged 20-49 years with SLE (93240). More evidence is needed to rate indole-3-carbinol for these uses.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. The typical diet supplies 2-24 mg of diindolylmethane daily (7170,7176,7664).

POSSIBLY SAFE ...when used orally and appropriately in medicinal doses. Diindolylmethane has been used with apparent safety at a dose of 45 mg daily for up to 6 months or at a higher dose of 100-140 mg daily for up to 3 months (47709,47729,93836,103830).

POSSIBLY UNSAFE ...when used orally in doses of 600 mg daily. In one clinical study, two cases of grade 3 asymptomatic hyponatremia were associated with taking diindolylmethane 600 mg daily (47729).

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods. The typical diet supplies 2-24 mg of diindolylmethane daily (7170,7176,7664).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. The typical diet supplies 2-24 mg of diindolylmethane daily (7170,7176,7664). There is insufficient reliable information available about the safety of diindolylmethane when used in amounts greater than those found in foods during pregnancy and lactation; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Eurycoma longifolia has been safely used in doses of 400 mg daily for up to 3 months and in doses of 200 mg daily for up to 9 months (17924,18138,93490,97312).

POSSIBLY UNSAFE ...when used orally in excessive amounts, long-term. There are some concerns about the safety of Eurycoma longifolia due to contamination with mercury and lead or adulteration with sildenafil (17925,17926,17927,18137,49087,93494). Some research shows that 36% and 17% of Eurycoma longifolia preparations from Malaysia contain high levels of mercury and lead, respectively (17925,17926,17927,49087). While safety issues related to these contaminants have not been reported in humans, taking high doses of Eurycoma longifolia long-term might cause symptoms of heavy metal poisoning or sildenafil-related adverse effects.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using. Animal research suggests that there are no negative effects of Eurycoma longifolia on the offspring (93493). However, research in humans is lacking.

(Read more about EURYCOMA LONGIFOLIA)

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

POSSIBLY SAFE ...when the seed is used orally in medicinal amounts. Fenugreek seed powder 5-10 grams daily has been used with apparent safety for up to 3 years. Fenugreek seed extract 1 gram daily has been used with apparent safety for up to 3 months (7389,9783,18359,18362,49868,90112,90113,90117,93419,93420)(93421,93422,93423,96065,103285,108704).

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods (4912). There is insufficient reliable information available about the safety of fenugreek when used in larger amounts. Unusual body and urine odor has been reported after consumption of fenugreek tea. Although the odor appears to be harmless, it may be misdiagnosed as maple syrup urine disease (9782,96068).

PREGNANCY: LIKELY UNSAFE
when used orally in amounts greater than those found in food. Fenugreek has potential oxytoxic and uterine stimulant activity (12531). There are case reports of congenital malformations, including hydrocephalus, anencephaly, cleft palate, and spina bifida, after consumption of fenugreek seeds during pregnancy (96068). Consumption of fenugreek immediately prior to delivery may cause the neonate to have unusual body odor. Although this does not appear to cause long-term sequelae, it may be misdiagnosed as maple syrup urine disease (9781,96068).

LACTATION: POSSIBLY SAFE
when used orally to stimulate lactation, short-term. Although most available clinical studies lack safety testing in the lactating parent or infant (12535,22569,22570), some evidence suggests that taking fenugreek 1725 mg three times daily orally for 21 days does not cause negative side effects in the infant (90115).

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POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Doses up to 400 mg daily have been used safely for 3-76 months (7173,93239,93240,93241). There is also some evidence that 400 mg twice daily can be used safely for 4 weeks (93242).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in medicinal amounts. There is limited evidence from 9 children with recurrent respiratory papillomatosis that indole-3-carbinol can be safely used in children ages 1.2-16 years for 12-76 months at doses of 6-17 mg/kg of body weight daily (7172,93239).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of indole-3-carbinol when used during pregnancy and lactation; avoid using.

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CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, diindolylmethane might lower serum levels of CYP1A2 substrates.  Details In vitro evidence suggests that diindolylmethane can induce CYP1A2 (7667,47745). Theoretically, it might increase metabolism of CYP1A2 substrates and lower serum concentrations. This interaction has not been reported in humans.

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, diindolylmethane might increase the risk of hyponatremia if used with sodium-depleting diuretics.  Details Large doses of diindolylmethane (600 mg daily) have been associated with two cases of asymptomatic hyponatremia in clinical research (47729).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, diindolylmethane might increase or decrease the effects of estrogens.  Details Diindolylmethane might have mild estrogenic or antiestrogenic effects (7664). Theoretically, large amounts of diindolylmethane might interfere with hormone replacement therapy.

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CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, Eurycoma longifolia might increase levels CYP1A2 substrates.  Details In vitro research suggests that methanolic Eurycoma longifolia root extract weakly inhibits CYP1A2 enzymes (93489). This effect has not been reported in humans.

CYTOCHROME P450 2A6 (CYP2A6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, Eurycoma longifolia might increase levels of CYP2A6 substrates.  Details In vitro research suggests that methanolic Eurycoma longifolia root extract weakly inhibits CYP2A6 enzymes (93489). This effect has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = D Theoretically, Eurycoma longifolia might increase levels of CYP2C19 substrates.  Details In vitro research suggests that methanolic Eurycoma longifolia root extract weakly inhibits CYP2C19 enzymes (93489). This effect has not been reported in humans.

PROPRANOLOL (Inderal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Eurycoma longifolia can reduce the levels and clinical effects of propranolol.  Details A small clinical study in healthy persons shows that taking a single dose of a water-based Eurycoma longifolia extract 200 mg, in combination with a single dose of propranolol 80 mg, reduces the propranolol area under the curve (AUC) by 29%, reduces the peak concentration by 42%, and increases time to peak concentration by 86% when compared with control. Since the elimination half-life of propranolol did not change, it seems that Eurycoma longifolia alters the kinetics of propranolol by decreasing its absorption in the gut, and not by altering its metabolism (17923). It is not known if separating administration will prevent this interaction.

TESTOSTERONE Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Eurycoma longifolia may further increase levels of testosterone.  Details A clinical study in aging males with testosterone levels below 300 ng/dL shows that taking a specific water extract of Eurycoma longifolia roots (Physta; Biotropics Malaysia) 100-200 mg daily with breakfast for 12 weeks increases total testosterone levels by 8% to 11% when compared with placebo (108451). It is unclear whether this increase would occur in individuals with normal testosterone levels.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, fenugreek might have additive effects when used with anticoagulant or antiplatelet drugs.  Details Some of the constituents in fenugreek have antiplatelet effects in animal and in vitro research. However, common fenugreek products might not contain sufficient concentrations of these constituents for clinical effects. A clinical study in patients with coronary artery disease or diabetes shows that taking fenugreek seed powder 2.5 grams twice daily for 3 months does not affect platelet aggregation, fibrinolytic activity, or fibrinogen levels (5191,7389,49643).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, fenugreek seed might have additive hypoglycemic effects when used with antidiabetes drugs.  Details Clinical research shows that fenugreek seed can reduce fasting blood glucose and 2-hour postprandial glucose levels in adults with type 2 diabetes (10284,90112,96065,105016).

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, fenugreek seed might alter the clinical effects of clopidogrel by inhibiting its conversion to the active form.  Details Animal research shows that fenugreek seed 200 mg/kg daily for 14 days increases the maximum serum concentration of clopidogrel by 21%. It is unclear how this affects the pharmacokinetics of the active metabolite of clopidogrel; however, this study found that concomitant use of fenugreek seed and clopidogrel prolonged bleeding time by an additional 11% (108701).

METOPROLOL (Toprol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, fenugreek seed might have additive hypotensive effects when used with metoprolol.  Details Animal research shows that fenugreek seed 300 mg/kg daily for 2 weeks decreases systolic and diastolic blood pressure by 9% and 11%, respectively, when administered alone, and by 15% and 22%, respectively, when given with metoprolol 10 mg/kg (108703).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, fenugreek might decrease plasma levels of phenytoin.  Details Animal research shows that taking fenugreek seeds for 1 week decreases maximum concentrations and the area under the curve of a single dose of phenytoin by 44% and 72%, respectively. This seems to be related to increased clearance (110905). So far, this interaction has not been reported in humans.

SILDENAFIL (Viagra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of sildenafil and fenugreek might reduce levels and therapeutic effects of sildenafil.  Details Animal research shows that taking fenugreek seeds for 1 week reduces maximum concentrations and the area under the curve of a single dose of sildenafil by 27% and 48%, respectively (110898). So far, this interaction has not been reported in humans.

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, fenugreek may reduce the levels and clinical effects of theophylline.  Details Animal research shows that fenugreek 50 grams daily for 7 days reduces the maximum serum concentration (Cmax) of theophylline by 28% and the area under the plasma drug concentration-time curve (AUC) by 22% (90118).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, fenugreek might have additive effects with warfarin and increase the international normalized ratio (INR).  Details Some fenugreek constituents have antiplatelet effects, although these might not be present in concentrations that are clinically significant (7389). In one case report, a patient taking warfarin experienced an increased INR when starting to take fenugreek in combination with boldo (5191).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, indole-3-carbinol might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs.  Details In vitro research shows that indole-3-carbinol inhibits platelet aggregation (98611).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, indole-3-carbinol might increase the metabolism of CYP1A2 substrates and lower serum concentrations.  Details Animal research shows that indole-3-carbinol induces CYP1A2 enzymes (7187).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Indole-3-carbinol might interfere with the effects of estrogen therapy.  Details Preliminary clinical and in vitro evidence shows that indole-3-carbinol has antiestrogenic activity (7173,47621,93238,93240).

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General ...Orally, diindolylmethane is generally well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, gas, headache, nausea, rash, and vomiting.
Serious Adverse Effects (Rare):
Orally: Drug rash with eosinophilia and systemic symptoms (DRESS).

Dermatologic ...Orally, diindolylmethane can cause rash (47615,93836). In one case report, a patient developed drug rash with eosinophilia and systemic symptoms (DRESS) after consuming a product containing diindolylmethane, vitamin E, and broccoli powder. An allergen patch test was positive for diindolylmethane (93840).

Endocrine ...Orally, diindolylmethane was associated with grade 3 asymptomatic hyponatremia in 2 of 4 patients taking 600 mg daily for 28 days in one clinical study. Hyponatremia was not seen in the 8 patients taking diindolylmethane 150-450 mg daily (47729).

Gastrointestinal ...Orally, diindolylmethane can cause nausea, vomiting, diarrhea, and gas (47652,47676,47709,47729,93836).

Genitourinary ...Orally, diindolylmethane can cause the urine to darken (93836).

Hematologic ...In one case report, a 65-year-old male developed a deep vein thromboembolism (DVT) and bilateral pulmonary emboli (PE) within a few weeks of initiating treatment with diindolylmethane. It is unclear if diindolylmethane contributed to this event; the patient was at increased risk for emboli due to his age, weight, tobacco use, and possible history of pulmonary embolism (93835).

Hepatic ...In one case report, a patient developed drug rash with eosinophilia and systemic symptoms (DRESS), involving elevated liver transaminases, after consuming a product containing diindolylmethane, vitamin E, and broccoli powder. An allergen patch test was positive for diindolylmethane (93840).

Immunologic ...In one case report, a patient developed drug rash with eosinophilia and systemic symptoms (DRESS) after consuming a product containing diindolylmethane, vitamin E, and broccoli powder. The patient developed fever, activated lymphocytes, and swollen lymph nodes. An allergen patch test was positive for diindolylmethane (93840).

Musculoskeletal ...Orally, diindolylmethane has been reported to cause arthralgias (47615).

Neurologic/CNS ...Orally, diindolylmethane can cause headache (47652,47676,93836). One case has reported ischemic stroke in a 38-year-old female with a history of a patent foramen ovale (PFO), traumatic subdural hematoma, right partial hemicraniectomy, and use of several supplements, including 200 mg of diindolylmethane daily, vitamin D3, vitamin K2, elderberry, caffeine, and possibly cannabis (112895). It is unclear if diindolylmethane contributed to this event; the patient was at increased risk for stroke due to PFO and other factors.

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General ...Orally, Eurycoma longifolia seems to be well tolerated.
Most Common Adverse Effects:
Orally: None reported.

Endocrine ...Some research in both humans and animals suggests that Eurycoma longifolia might increase testosterone levels (17924). If testosterone levels are increased beyond the normal range, there is risk of testosterone-related side effects which could include acne, insulin resistance, hepatotoxicity, and others.

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General ...Orally, fenugreek seed is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, diarrhea, dyspepsia, flatulence, hypoglycemia, and nausea.
Serious Adverse Effects (Rare):
All ROA: Severe allergic reactions including angioedema, bronchospasm, and shock.

Endocrine ...Orally, large doses of fenugreek seed, 100 grams daily of defatted powder, have caused hypoglycemia (164,96068).

Gastrointestinal ...Orally, fenugreek seed can cause mild gastrointestinal symptoms, such as diarrhea, dyspepsia, abdominal distention and pain, nausea, and flatulence, especially when taken on an empty stomach (622,12534,18349,93421,96065,96068,105016).

Immunologic ...Fenugreek can cause allergic reactions when used orally and topically, and when the powder is inhaled (719,96068). Orally, fenugreek has caused bronchospasm, diarrhea, and itching, and skin reactions severe enough to require intravenous human immunoglobulin (96068). Topically, fenugreek paste has resulted in facial swelling, wheezing, and numbness around the head (719,96068). When used both orally and topically by a single individual, asthma and rhinitis occurred (96068). Inhalation of fenugreek powder has resulted in fainting, sneezing, runny nose, and eye tearing (719,96068).

Neurologic/CNS ...Orally, loss of consciousness has occurred in a 5 week-old infant drinking tea made from fenugreek (9782). Dizziness and headaches have been reported in clinical research of fenugreek extract (49551,93419). However, these events are rare.

Renal ...Orally, fenugreek aqueous see extract may increase the frequency of micturition, although this even appears to be rare (49551).

Other ...Consumption of fenugreek during pregnancy, immediately prior to delivery, may cause the neonate to have an unusual body odor, which may be confused with maple syrup urine disease. It does not appear to cause long-term sequelae (9781). This unusual body odor may also occur in children drinking fenugreek tea. A case of a specific urine and sweat smell following oral fenugreek extract use has been reported for a patient in one clinical trial (18349).
In 2011, outbreaks of enteroaggregative hemorrhagic Escherichia coli (EATEC) O104:H4 infection occurred in Germany and Spain. Epidemiological studies linked the outbreaks to fenugreek seeds that had been imported from Africa. However, laboratory analyses were unable to isolate the causative strain of bacteria from fenugreek seed samples (49776,49777,49781,90114).

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General ...Orally, indole-3-carbinol seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, imbalance, nausea, rash, tremor, unsteadiness.

Dermatologic ...Orally, indole-3-carbinol has been associated with reports of rash (93242). A woman taking indole-3-carbinol 375 mg daily for treatment of systemic lupus erythematosus (SLE) developed a generalized maculopapular rash which resolved when indole-3-carbinol was discontinued and recurred when it was restarted (93240).

Gastrointestinal ...Orally, indole-3-carbinol increases gastrointestinal motility and has been associated with diarrhea (93242,93243).

Neurologic/CNS ...Indole-3-carbinol has been associated with reports of unsteadiness and imbalance, especially at higher doses (7172). An adult male taking 400 mg twice daily for treatment of recurrent respiratory papillomatosis developed imbalance and tremor after 10 days of treatment. This resolved when the dose was halved (93238). Two children who took 3 times the intended weight-based dose of indole-3-carbinol in one day developed unsteadiness and nausea (93238).

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