Estrogen Blocker by Iron Brothers Supplements

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral black pepper for allergic rhinitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Asthma. Although there has been interest in using oral black pepper for asthma, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Athletic performance. Oral black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in untrained males shows that taking a supplement containing black pepper extract 10 mg, caffeine 400 mg, capsicum extract 66.7 mg, and niacin 40 mg as a single dose prior to exercise does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Depression. Although there has been interest in using oral black pepper for depression, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Diarrhea. Although there has been interest in using oral black pepper for diarrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dysmenorrhea. Although there has been interest in using oral black pepper for dysmenorrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dyspepsia. Although there has been interest in using oral black pepper for dyspepsia, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Fall prevention. It is unclear if inhaling black pepper oil as aromatherapy is beneficial for fall prevention in older adults. Details: One small clinical study in older adults shows that applying black pepper oil near the right side of the nose as an olfactory stimulant improves stability while the eyes are closed during a one-minute trial when compared with the application of water. The improvement with black pepper oil is comparable to the improvement seen with the application of lavender oil (29160). It is unclear if any benefit persists after inhalation of black pepper oil.
• Fatigue. It is unclear if oral black pepper is beneficial in patients with fatigue. Details: One small clinical trial in adults with below-average energy levels shows that taking black pepper 2 grams as a single dose does not improve sustained attention, motivation to perform cognitive tasks, or feelings of mental energy and mental fatigue when compared with placebo (91731).
• Flatulence. Although there has been interest in using oral black pepper for flatulence, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Headache. Although there has been interest in using oral black pepper for headache, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Insect bite. Topical black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial shows that applying a specific product (Trikatu) containing black pepper, long pepper, and ginger, as well as camphor, eucalyptus oil, and menthol, directly to mosquito bites does not reduce papule size, erythema, edema, or pruritis when compared with a control compound containing the same base ingredients but without the pepper and ginger components (89893).
• Obesity. Although there has been interest in using oral black pepper for obesity, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Pain (chronic). Although there has been interest in using topical black pepper for chronic pain related to various etiologies, including osteoarthritis, postherpetic neuralgia, and peripheral neuropathy, there is insufficient reliable information about the clinical effects of black pepper for these conditions.
• Rhinosinusitis. Although there has been interest in using oral black pepper for rhinosinusitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Sexual desire. Although there has been interest in using oral black pepper for increasing sexual desire, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Smoking cessation. It is unclear if inhaling black pepper essential oil as aromatherapy is effective for smoking cessation. Details: One small clinical trial in adult male smokers who were deprived from smoking overnight shows that inhaling a vapor from the essential oil of black pepper, as needed over a 3-hour period, reduces cigarette cravings, negative feelings, and anxiety when compared with a placebo vapor (29159). Another small clinical study in patients addicted to dipping, chewing, or smoking tobacco shows that placing a drop of black pepper essential oil on tissue paper and inhaling for 2 minutes at least three times a day for 3 days reduces nicotine cravings when compared to baseline (90502).
• Swallowing dysfunction. It is unclear if inhaling black pepper oil as aromatherapy is beneficial in patients with swallowing dysfunction. Details: One small clinical study in post-stroke residents of nursing homes shows that one minute of olfactory stimulation with black pepper oil before each meal for 30 days decreases swallowing reflex latency by 11 seconds and increases the number of swallowing movements by 3.3 when compared to baseline (29161). A small clinical trial in children with neurological disorders who were on long-term enteral nutrition shows that applying black pepper oil to the nostrils or nasal cavity for one minute improves the amount of oral intake and swallowing movement in 63% of patients. Although oral intake increased, the need for enteral nutrition was not eliminated (29162).
• Vitiligo. It is unclear if topical piperine oil, a constituent of black pepper, is beneficial in patients with vitiligo. Details: A small clinical study in patients with vitiligo shows that applying piperine oil 1% daily in addition to receiving narrowband ultraviolet B (NB-UVB) light therapy every other day for 3 months improves repigmentation more rapidly when compared with using NB-UVB alone (103820). More evidence is needed to rate black pepper for these uses.

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POSSIBLY EFFECTIVE

• Chronic venous insufficiency (CVI). Oral grape leaf extract might improve CVI symptoms. It is unknown if other grape products are beneficial for CVI. Details: Some clinical trials in patients with CVI show that taking a specific grape leaf extract, known as red vine leaf extract (AS 195, Antistax, Boehringer Ingelheim), seems to improve leg edema after 6 weeks of treatment when compared with placebo. Doses of 360 mg and 720 mg daily were both effective, but the higher dose produced a slightly greater effect. Patients also reported decreases in subjective complaints such as tired or heavy legs, tension, and tingling and pain after 2-12 weeks of treatment (2538,52985,53005,53206).

POSSIBLY INEFFECTIVE

• Allergic rhinitis (hay fever). Oral grape seed extract does not seem to improve hay fever symptoms. Details: A clinical study in patients with seasonal allergic rhinitis shows that taking grape seed extract 100 mg twice daily for 8 weeks before ragweed pollen season does not seem to decrease seasonal allergic rhinitis symptoms or antihistamine usage when compared with placebo (9182).
• Chemotherapy-induced nausea and vomiting (CINV). Drinking grape juice does not seem to improve CINV. Details: Clinical research shows that taking 4 ounces of chilled Concord grape juice 30 minutes prior to meals for a week following each of four cycles of chemotherapy does not seem to reduce CINV when compared with placebo (53175).
• Lower urinary tract symptoms (LUTS). Drinking grape juice does not seem to improve LUTS. Details: Clinical research in middle-aged and older men with LUTS shows that drinking 100% Concord grade juice 240 mL daily for 3 months does not improve symptoms when compared with placebo (96190).
• Mastalgia. Oral grape seed extract does not seem to improve mastalgia symptoms. Details: Clinical research in patients treated for early breast cancer using high-dose radiotherapy shows that taking the grape seed extract constituent proanthocyanidin 100 mg orally three times daily for 6 months does not reduce breast tissue hardness, pain, or tenderness when compared with placebo (53048).
• Obesity. Oral grape products do not seem to improve weight loss. Details: Clinical research in overweight or obese individuals shows that drinking Concord grape juice 480 mL daily for 12 weeks does not improve weight or body composition when compared to baseline (53181). Furthermore, taking grape pomace alone or in combination with schisandra fruit extract daily for 4-10 weeks does not improve body composition, abdominal fat, or body weight when compared with control (96200,99269,99270). Taking grape pomace 7-8 grams daily for 4-6 weeks seems to improve insulin resistance by about 33%, but does not affect blood lipids or blood pressure, when compared with placebo in overweight or obese adults with at least one metabolic syndrome factor (99269,99270).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral grape skin extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in adults with signs of aging skin shows that taking a specific combination product (Celergen, Laboratories-Dom) containing grape skin extract 10 mg, marine collagen peptides 570 mg, coenzyme Q10 10 mg, luteolin 10 mg, and selenium 0.05 mg, one capsule with breakfast and dinner for 2 months, might improve skin elasticity when compared with baseline. However, there was no effect on moisture or biological skin age (97930). It is not clear if these effects are due to grape skin extract, the other ingredients, or the combination.
• Age-related macular degeneration (AMD). Although there is interest in using oral grape seed for AMD, there is insufficient reliable information about the clinical effects of grape for this condition.
• Atherosclerosis. Oral grape seed extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking a specific combination product (Karinat, INAT-Farma) containing grape seed extract constituent proanthocyanidin 40 mg, garlic 100 mg, hops 160 mg, green tea 115 mg, vitamin C 30 mg, silicon 8 mg, vitamin E 6.6 mg, and beta-carotene 0.5 mg three capsules daily for 12 months might slow the progression of atherosclerosis as measured by mean carotid intima thickness when compared with placebo. However, the combination product does not seem to affect the growth of existing plaques, and it does not seem to improve lipid parameters (97929). It is not clear if these effects are due to grape seed extract, the other ingredients, or the combination.
• Athletic performance. It is unclear if oral grape products are beneficial for athletic performance. Details: A small study in elite athletes shows that taking a specific grape extract (Powergrape, Naturex SA) 400 mg daily for one month can increase total power in a jumping task when compared with placebo, but has no effect on initial power and maintenance of power (53310). Another small study in recreationally active young adults shows that drinking juice prepared from 46 grams of a freeze-dried preparation of whole grapes daily for 6 weeks prior to a running exercise test does not improve maximal oxygen uptake or work capacity during exercise when compared with placebo (91540).
• Atopic dermatitis (eczema). Topical grape products have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with atopic dermatitis shows that twice daily application with a cream containing grape polyphenols, vitamin E, and epigallocatechin gallate for 28 days does not improve symptoms or reduce the affected area based on physician assessment when compared with placebo (96196).
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral grape seed for ADHD, there is insufficient reliable information about the clinical effects of grape for this condition.
• Canker sores. Although there is interest in using oral grape seed for canker sores, there is insufficient reliable information about the clinical effects of grape for this condition.
• Cardiovascular disease (CVD). It is unclear if oral grape products are beneficial for reducing CVD risk. Details: There is preliminary evidence that taking grape products, such as purple grape juice or red grape juice concentrate, might improve endothelium-dependent vasodilation, prevent low-density lipoprotein (LDL) oxidation, reduce markers of inflammation, and suppress platelet-mediated thrombosis. Theoretically, chronic ingestion of these products might reduce the risk of CVD in various patient populations, including adults with type 2 diabetes or hypercholesterolemia, those undergoing hemodialysis, and children with metabolic syndrome (8745,8746,52954,53030,53062,53106,53155,53174). However, a large meta-analysis shows that although taking grape products, including grape extract, grape juice, raisins, and grape seed extract, reduces levels of blood fats by a small amount in a mixed population of adults, these effects were not present in a subgroup of patients with CVD when compared with placebo. There was a small benefit on total cholesterol and high-density lipoprotein (HDL) cholesterol (102610).
• Cognitive function. It is unclear if oral grape products improve cognitive function. Details: Clinical research in healthy adults aged 55-75 years with no cognitive decline shows that taking a specific grape fruit extract (Cognigrape, Bionap srl) 250 mg daily for 12 weeks improves cognitive functioning by 4.5%, and overall neuropsychological status, including attention, language, and recall, by 6%, compared with no change in the placebo group (96198). Also, a preliminary clinical study in middle-aged women under moderate stress shows that drinking Concord grape juice 355 mL daily for 12 weeks improves immediate spacial memory and may improve executive function and verbal recall when compared with placebo (96195).
• Cognitive impairment. Small clinical studies suggest that oral grape products may not slow cognitive decline in older patients with cognitive impairment. Details: One very small study in in patients with mild cognitive decline shows that taking a freeze-dried grape powder 36 grams twice daily for 6 months does not improve most measures of cognitive function and memory, including immediate memory, delayed memory, speed of information processing, cognitive ability, or language, when compared with placebo (96199). Another very small study in older adults with signs of memory decline shows that drinking 100% Concord grape juice 6-9 mL/kg daily for 12 weeks does not improve delayed verbal recall or spatial memory when compared with placebo, although it does seem to moderately improve verbal learning (53166).
• Colorectal cancer. Oral grape seed extract is has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with colorectal cancer shows that taking a product containing grape seed extract, turmeric extract, fermented soybean extract, green tea extract, spirulina, and Taiwanofungus camphoratus, 1920 mg three times daily for 16 weeks during a chemotherapy regimen might modestly increase the effectiveness of treatment when compared with placebo. No patients in the treatment group experienced disease progression, compared with 15.8% (6 patients) of the placebo group. However, there was no significant effect on overall survival or the best response to treatment (96183).
• Constipation. Although there is interest in using oral grape products for constipation, there is insufficient reliable information about the clinical effects of grape for this condition.
• Dental caries. Although there is interest in using topical grape seed for dental caries, there is insufficient reliable information about the clinical effects of grape for this purpose.
• Diabetes. Oral grape extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study of males with type 2 diabetes mellitus and erectile dysfunction suggests that an oral combination product containing alpha lipoic acid, Gingko biloba, and grape extract (Blunorm Forte, Uriach S.p.A.) taken for 3 months may decrease fasting plasma glucose and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score both alone and when combined with avanafil when compared with baseline and placebo (110707).
• Diabetic retinopathy. It is unclear if oral grape seed extract is beneficial in patients with diabetic retinopathy. Details: A preliminary clinical study in patients with non-proliferative diabetic retinopathy shows that taking a specific grape seed proanthocyanidin extract (Entelon, Hanlim Pharm) 50 mg three times daily for 12 months reduces the severity of hard exudates when compared with calcium dobesilate or placebo. Grape seed extract had a treatment success rate 3-fold and 5.5-fold higher than those of calcium dobesilate and placebo, respectively. Treatment success was defined as a 2-grade decrease in hard exudate severity. No significant improvements in retinopathy grade or visual acuity were reported (100954). However, the study may not have been adequately powered to detect a difference in these outcomes.
• Erectile Dysfunction (ED). Oral grape extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large study of males with type 2 diabetes mellitus and erectile dysfunction suggests that a specific combination product containing alpha lipoic acid, grape extract, and gingko biloba (Blunorm Forte, Uriach S.p.A.) administered orally for three months with avanafil prior to sexual acts improves International Index of Erectile Function (IIEF) scores when compared with either product alone, placebo, and baseline, and may reduce markers of ED including high sensitivity-c-reactive protein, nitrates/nitrites, and metalloproteinases-2 and -9. These results suggest that an oral combination nutraceutical consisting of alpha lipoic acid, grape extract, and gingko biloba (Blunorm Forte, Uriach S.p.A.) may react synergistically with avanafil to enhance sexual performance in males with type 2 diabetes and erectile dysfunction. It is unclear if this effect is due to the alpha lipoic acid, grape extract, or gingko biloba, but researchers theorize that it may be due to the inhibition of phosphodiesterase-5 enzymes by grape extract (110707).
• Hemorrhoids. Although there is interest in using oral grape seed for hemorrhoids, there is insufficient reliable information about the clinical effects of grape for this purpose.
• Hypercholesterolemia. Small clinical studies suggest that oral grape products reduce cholesterol levels by a small amount. Details: A large meta-analysis of heterogeneous clinical trials shows that taking grape products, including grape extract, grape juice, raisins, or grape seed extract, for 2-54 weeks reduces levels of total and low-density lipoprotein (LDL) cholesterol, as well as triglycerides, by a small amount when compared with placebo in a mixed population of adults. In a sub-group of patients with any hyperlipidemia, the mean decreases in LDL cholesterol and triglycerides were 11 mg/dL and 14 mg/dL, respectively. There was no effect on levels of high-density lipoprotein (HDL) in the mixed population or in adults with hyperlipidemia (102610). Although some individual studies disagree, the most evidence for benefit is related to use of whole grape extract or grape seed extract. It is not clear if benefit is dependent on dose or duration of use. These results suggest a benefit of grape products in patients with hypercholesterolemia, but any benefit is likely to be small (42585,96816,102610).
• Hypertension. Some research suggests that oral grape products may modestly lower blood pressure; however, results are inconsistent. Details: Some clinical trials have shown modest benefit in patients with prehypertension, mild hypertension, or metabolic syndrome (18228,53149,96197), but conflicting results exists (91541,90079). A 2016 meta-analysis including 16 trials of 810 patients shows that when compared with placebo, grape seed extract or polyphenols reduces systolic blood pressure (SBP) and diastolic blood pressure (DBP) by about 6 mmHg and 3 mmHg, respectively, with greatest improvements observed in those with obesity or metabolic syndrome. This meta-analysis suggests that a minimum treatment duration of 8 weeks may be necessary before benefit is seen (96194). However, other research in adults with hypertension shows that taking grape seed polyphenols 1000 mg daily for 6 weeks does not alter blood pressure. Also, when grape seed polyphenols were combined with vitamin C 500 mg daily, some patients experienced an increase in blood pressure and worsening of nighttime and daytime variation in blood pressure (13162,90079). The reason for these conflicting findings is unclear but may due to patient characteristics and comorbidities. A meta-analysis of clinical research in various patient populations shows that taking grape seed extract 150-2100 mg for 2-25 weeks improves DBP and heart rate when compared with control, but does not improve SBP or flow-mediated dilation, regardless of dose, duration, sex, BMI, or health status. Additionally, subgroup analyses suggest that blood pressure effects may be greater in patients who are otherwise healthy, female, overweight, and/or under 50 years of age. Also, the use of lower doses and longer treatment durations may be associated with greater benefit (108090). The validity of these findings is limited by the high heterogeneity of included studies. A clinical study in adults with mildly elevated blood pressure shows that a specific grape seed extract (Enovita; Indena SpA) standardized to provide at least 95% oligomeric proanthocyanins, taken as 150 mg twice daily for 16 weeks, does not reduce SBP or DBP when compared with placebo. However, a subgroup analysis suggests that taking grape seed extract improves blood pressure in males, but not in females, when compared with placebo (108091). Some research has also evaluated the effects of grape juice on blood pressure. Two clinical studies in patients with hypertension show that drinking grape juice can reduce blood pressure when compared to baseline; however, another study shows that drinking grape juice does not reduce blood pressure when compared with placebo in these patients (53018,53156,53199).
• Melasma. It is unclear if oral grape seed extract is beneficial in patients with melasma. Details: A very small clinical study in Japanese females with melasma shows that taking grape seed extract (Gravinol, Kikkoman Co) containing 54 mg of proanthocyanidins three times daily for 6-11 months reduces skin hyperpigmentation when compared to pretreatment (53016). The validity of this finding is limited by the lack of a control group.
• Menopausal symptoms. It is unclear if oral grape seed extract is beneficial in patients with menopausal symptoms. Details: Preliminary clinical research in adults with at least one menopausal symptom shows that taking grape seed extract (Gravinol, Kikkoman Biochemifa Co) containing proanthocyanidin 200 mg daily for 8 weeks reduces anxiety when compared with placebo. It also reduces hot flashes and other physical symptoms when compared to baseline, but not when compared with placebo. A lower dose of proanthocyanidin 100 mg daily does not appear to improve these outcomes. Neither doses improved insomnia or depression (91542).
• Metabolic syndrome. Small studies suggest that various oral grape products might improve lipid levels and blood pressure in patients with metabolic syndrome. Details: A meta-analysis of small clinical studies in adults with type 2 diabetes or metabolic syndrome shows that taking grape products, usually grape seed or grape extract, for 4-48 weeks reduces levels of total and low-density lipoprotein (LDL) cholesterol, as well as triglycerides, by a small amount when compared with placebo. The mean decreases in LDL cholesterol and triglycerides were 2.6 mg/dL and 11 mg/dL, respectively (102610). These findings are limited by significant heterogeneity of the included research. Also, a small clinical study in overweight or obese adults, most with metabolic syndrome, shows that taking grape pomace 8 grams daily for 6 weeks improves insulin resistance by about 33%, but does not affect blood lipids, blood pressure, or fasting glucose, when compared with placebo (99270). Some grape products have also shown benefit for improving blood pressure in patients with metabolic syndrome. One small clinical crossover study in males with metabolic syndrome shows that taking 46 grams daily of a freeze-dried, dehydrated preparation of grape polyphenols (equivalent to about 250 grams of fresh grapes daily) for 30 days seems to modestly lower systolic, but not diastolic, blood pressure, and increase brachial artery flow-mediated dilation (FMD) when compared with placebo (18228). Also, a small clinical study in adolescents with metabolic syndrome suggests that drinking natural grape juice 18 mL/kg daily for one month improves FMD when compared with baseline (53174).The validity of this finding is limited by the lack of a control group. A very small clinical study in patients with metabolic syndrome shows that taking a specific grape seed extract (Meganatural BP, Polyphenolics) 150-300 mg daily for 4 weeks modestly reduces blood pressure when compared with placebo (53149). The validity of this finding is limited due to small study size and because patients in the treatment groups had higher blood pressure at baseline.
• Minor bleeding. Topical grape vine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that topically applying 4 mL of a specific product (Ankaferd blood stopper) containing grape vine, alpinia, licorice, thyme, and stinging nettle reduces bleeding, but does not improve the surgical time for episiotomy repair, when compared with saline (31010). It is unclear if this effect is due to grape vine, other ingredients, or the combination.
• Muscle soreness. It is unclear if oral grape products improve muscle soreness. Details: One small study in active young adults shows that drinking juice, prepared from 46 grams of freeze-dried whole grapes, daily for 6 weeks prior to an eccentric arm exercise test does not reduce muscle inflammation or pain at 24 or 48 hours post-exercise when compared with placebo (91540).
• Night vision. Although there is interest in using oral grape seed extract for improving night vision, there is insufficient reliable information about the clinical effects of grape for purpose.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral grape seed extract reverses fatty liver in patients with NAFLD. Details: One small clinical study in adults with NAFLD shows that taking grape seed extract 1000 mg twice daily for 3 months improves some, but not all, markers of liver damage and improves the grade of fatty liver change when compared with vitamin C supplementation (53190).
• Ocular stress. Although there is interest in using oral grape seed extract for ocular stress, there is insufficient reliable information about the clinical effects of grape for this purpose.
• Premenstrual syndrome (PMS). Although there is interest in using oral grape seed extract for PMS, there is insufficient reliable information about the clinical effects of grape for this condition.
• Wound healing. Limited research suggests that topical grape seed extract might improve wound healing. Details: A small clinical study in adults undergoing surgical removal of minor skin lesions shows that applying red grape seed extract 2% cream twice daily to the affected areas reduces the time to complete wound healing by about 6 days when compared with a placebo cream (91539). Also, preliminary clinical research in patients recovering from cesarean section shows that applying grape seed extract 5% ointment twice daily to cesarean section wounds for 14 days improves wound healing, as measured by a scoring system assessing redness, edema, ecchymosis, discharge, and wound closure, when compared with a placebo ointment. A 2.5% ointment did not improve wound healing measures when compared with placebo (100955). More evidence is needed to rate grape for these uses.

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POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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

POSSIBLY SAFE ...when black pepper oil is applied topically. Black pepper oil is nonirritating to the skin and is generally well tolerated (11). ...when black pepper oil is inhaled through the nose or as a vapor through the mouth, short-term. Black pepper oil as a vapor or as an olfactory stimulant has been used with apparent safety in clinical studies for up to 3 days and 30 days, respectively (29159,29160,29161,90502). There is insufficient reliable information available about the safety of black pepper when used orally in medicinal amounts.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

CHILDREN: POSSIBLY UNSAFE
when used orally in large amounts. Fatal cases of pepper aspiration have been reported in some patients (5619,5620). There is insufficient reliable information available about the safety of topical pepper oil when used in children.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

PREGNANCY: LIKELY UNSAFE
when used orally in large amounts. Black pepper might have abortifacient effects (11,19); contraindicated. There is insufficient reliable information available about the safety of topical pepper when used during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (11). There is insufficient reliable information available about the safety of black pepper when used in medicinal amounts during breast-feeding.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Grapes and grape skin extracts have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when the whole fruit of the grape, or extracts of the fruit, seed, or leaf, are used orally and appropriately in medicinal amounts. Grape seed extracts have been used with apparent safety in doses up to 200 mg daily for up to 11 months (9182,53016) and in doses up to 2000 mg daily for up to 3 months (53149,53190). Specific grape fruit extracts (Stilvid, Actafarma; Cognigrape, Bionap srl) have been used with apparent safety in doses up to 250-350 mg daily for 3-12 months or 700 mg daily for 6 months (53254,53256,96198). A specific grape leaf extract (AS 195, Antistax, Boehringer Ingelheim) has been used with apparent safety in doses up to 720 mg daily for up to 3 months (2538,52985,53005,53206). A preparation of dehydrated whole grapes, equivalent to 250 grams of fresh grapes daily, has also been used with apparent safety for up to 30 days (18228). A specific grape seed extract (Enovita; Indena SpA) 150 mg twice daily, standardized to provide at least 95% oligomeric proanthocyanins, has been used with apparent safety for up to 16 weeks (108091) ...when used topically and appropriately. Creams and ointments containing grape seed extract 2% or 5% have been used topically with apparent safety for up to 3 weeks (91539,100955). There is insufficient reliable information available about the safety of other grape plant parts when used topically.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods. Grapes and grape skin extracts have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). However, whole grapes should be eaten with caution in children aged 5 years and under. Whole grapes can be a choking hazard for young children (96193). To reduce the risk of choking, whole grapes should be cut in half or quartered before being given to children. There is insufficient reliable information available about the safety of grape when used in medicinal amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of medicinal amounts during pregnancy and breast-feeding; avoid using in amounts greater than what is commonly found in foods.

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

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

LACTATION:
Insufficient reliable information available; avoid using.

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AMOXICILLIN (Amoxil, Trimox) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of amoxicillin.  Details Animal research shows that taking piperine, a constituent of black pepper, with amoxicillin increases plasma levels of amoxicillin (29269). This has not been reported in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the risk of bleeding when taken with antiplatelet or anticoagulant drugs.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit platelet aggregation (29206). This 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, black pepper might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research shows that piperine, a constituent of black pepper, can reduce blood glucose levels (29225). Monitor blood glucose levels closely. Dose adjustments might be necessary.

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase blood levels of atorvastatin.  Details Animal research shows that taking piperine, a constituent of black pepper, 35 mg/kg can increase the maximum serum concentration of atorvastatin three-fold (104188). This has not been reported in humans.

CARBAMAZEPINE (Tegretol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, black pepper might increase blood levels of carbamazepine, potentially increasing the effects and side effects of carbamazepine.  Details One clinical study in patients taking carbamazepine 300 mg or 500 mg twice daily shows that taking a single 20 mg dose of purified piperine, a constituent of black pepper, increases carbamazepine levels. Piperine may increase carbamazepine absorption by increasing blood flow to the GI tract, increasing the surface area of the small intestine, or inhibiting cytochrome P450 3A4 (CYP3A4) in the gut wall. Absorption was significantly increased by 7-10 mcg/mL/hour. The time to eliminate carbamazepine was also increased by 4-8 hours. Although carbamazepine levels were increased, this did not appear to increase side effects (16833). In vitro research also shows that piperine can increase carbamazepine levels by 11% in a time-dependent manner (103819).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of cyclosporine.  Details In vitro research shows that piperine, a constituent of black pepper, increases the bioavailability of cyclosporine (29282). This has not been reported in humans.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP1A1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP1A1 (29213). This has not been reported in humans.

CYTOCHROME P450 2B1 (CYP2B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2B1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP2B1 (29332). This has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2D6.  Details In vitro research suggests that some constituents of black pepper inhibit CYP2D6 (29207,29212,38375). This 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 = D Theoretically, black pepper might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that piperine, a constituent of black pepper, as well as the pepper fruit seem to inhibit CYP3A4 (14375,29212). This has not been reported in humans.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, black pepper might increase blood levels of lithium due to its diuretic effects. The dose of lithium might need to be reduced.  Details Black pepper is thought to have diuretic properties (11).

NEVIRAPINE (Viramune) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Black pepper might increase blood levels of nevirapine.  Details Clinical research shows that piperine, a constituent of black pepper, increases the plasma concentration of nevirapine. However, no adverse effects were observed in this study (29209).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of P-glycoprotein substrates.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit P-glycoprotein (14375,29281,29283).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the sedative effects of pentobarbital.  Details Animal research shows that piperine, a constituent of black pepper, increases pentobarbital-induced sleeping time (29214).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of phenytoin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption, slow elimination, and increase levels of phenytoin (537,14442). Taking a single dose of black pepper 1 gram along with phenytoin seems to double the serum concentration of phenytoin (14375). Consuming a soup with black pepper providing piperine 44 mg/200 mL of soup along with phenytoin also seems to increase phenytoin levels when compared with consuming the same soup without black pepper (14442).

PROPRANOLOL (Inderal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of propranolol.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of propranolol (538).

RIFAMPIN (Rifadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of rifampin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and serum levels of rifampin (14375,29284).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Black pepper might increase blood levels of theophylline.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of theophylline (538).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, grape extracts may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro evidence suggests that grape extracts might decrease platelet aggregation (53017,53087).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Ingesting grape juice with cyclosporine can reduce cyclosporine absorption.  Details A small pharmacokinetic study in healthy young adults shows that intake of purple grape juice 200 mL along with cyclosporine can decrease the absorption of cyclosporine by up to 30% when compared with water (53177). Separate doses of grape juice and cyclosporine by at least 2 hours to avoid this interaction.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, grape juice might reduce the levels of CYP1A2 substrates.  Details A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of CYP1A2 (2539).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D It is unclear if grape juice or grape seed extract inhibits CYP2C9; research is conflicting.  Details In vitro evidence shows that grape seed extract or grape juice might inhibit CYP2C9 enzymes (11094,53011,53089). However, a small pharmacokinetic study in healthy adults shows that drinking 8 ounces of grape juice once does not affect the clearance of flurbiprofen, a probe-drug for CYP2C9 metabolism (11094). The effects of continued grape juice consumption are unclear.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grape seed extract may increase the levels of CYP2D6 substrates.  Details In vitro evidence suggests that grape seed extract might inhibit CYP2D6 enzymes (53011). However, this interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, grape seed extract might increase the levels of CYP2E1 substrates.  Details In vitro and animal research suggests that grape seed proanthocyanidin extract inhibits CYP2E1 enzymes (52949). However, this interaction 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 = D It is unclear if grape seed extract inhibits or induces CYP3A4; research is conflicting.  Details In vitro evidence suggests that grape seed extract might inhibit CYP3A4 enzymes (53089). However, evidence from animal research shows that grape seed extract may induce CYP3A4 in the liver (53011). So far, these interactions have not been reported in humans.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, long-term intake of grape seed extract might decrease the effects of midazolam.  Details Animal research shows that subchronic ingestions of grape seed extract can increase the elimination of intravenous midazolam by increasing hepatic CYP3A4 activity. Single doses of grape seed extract do not appear to affect midazolam elimination (53011).

PHENACETIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Grape juice might decrease phenacetin absorption.  Details A small pharmacokinetic study in healthy adults shows that ingestion of 200 mL of grape juice decreases phenacetin plasma levels. This is thought to be due to induction of cytochrome P450 1A2 (CYP1A2) (2539).

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

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

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

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General ...Orally, black pepper seems to be well tolerated when used in the amounts found in food or when taken as a medicine as a single dose. Topically and as aromatherapy, black pepper oil seems to be well tolerated.
Most Common Adverse Effects:
Orally: Burning aftertaste, dyspepsia, and reduced taste perception.
Inhalation: Cough.
Serious Adverse Effects (Rare):
Orally: Allergic reaction in sensitive individuals.

Gastrointestinal ...Orally, black pepper can cause a burning aftertaste (5619) and dyspepsia (38061). Single and repeated application of piperine, the active constituent in black pepper, to the tongue and oral cavity can decrease taste perception (29267). By intragastric route, black pepper 1.5 grams has been reported to cause gastrointestinal microbleeds (29164). It is not clear if such an effect would occur with oral administration.

Immunologic ...In one case report, a 17-month-old male developed hives, red eyes, facial swelling, and a severe cough following consumption of a sauce containing multiple ingredients. Allergen skin tests were positive to both black pepper and cayenne, which were found in the sauce (93947).

Ocular/Otic ...Topically, ground black pepper can cause redness of the eyes and swelling of the eyelids (5619).

Pulmonary/Respiratory ...When inhaled through the nose as an olfactory stimulant, black pepper oil has been reported to cause cough in one clinical trial (29162).

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General ...Orally, the whole fruit, as well as the seed, fruit, and leaf extracts, seem to be well tolerated. Topically, grape seed extracts seem to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, dry mouth, dyspepsia, headache, joint pain, and nausea.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis to grape skin has been reported.

Dermatologic ...Orally, mild hair thinning has been reported in a patient taking a specific grape leaf extract AS195 KG) (2538). Urticaria (hives) has also been reported with this same extract (53206). Cases of contact dermatitis have been reported in grape workers, including those working in California vineyards (53270,53272,53275).

Gastrointestinal ...Orally, abdominal pain and nausea have been reported with use of grape seed extract, but these effects typically occur at rates similar to placebo (9182,13162). In a case report of a 57-year-old man, intermittent nausea, vomiting, and diarrhea occurred over a 10-day period and improved once grape seed extract was stopped (96764). Gastrointestinal adverse effects have also been reported with use of a different grape seed extract (Entelon, Hanlim Pharm). However, the specific types of gastrointestinal effects were not described (100954). A specific grape leaf extract AS195 (Antistax, Boehringer Ingelheim Pharma GmbH & Co. KG) has reportedly caused flatulence, mild constipation, gastrointestinal discomfort, diarrhea, dyspepsia, dry mouth, and retching (2538,52985,53206). Diarrhea, gastrointestinal distress, indigestion, and aversion to taste have been reported with use of Concord grape juice (52972,53166,53175,53181,53199). Loose stools have been reported in a clinical trial of grape pomace (99270). Bowel obstruction caused by intact grapes and grape seeds has been described in case reports (53241,53284,53278). Excessive consumption of grapes, dried grapes, raisins, or sultanas might cause diarrhea due to laxative effects (4201).

Hematologic ...Orally, one case of leg hematoma following a minor trauma was reported in a person using grape leaf extract (2538). Also, one case of bruising was reported in a person drinking Concord grape juice daily for 2 weeks (52972).

Immunologic ...Orally, there is one report of an anaphylactic reaction to oral grape skin extract, which included urticaria and angioedema (4073).

Musculoskeletal ...Orally, musculoskeletal disorders, including back pain, have been reported with use of a specific grape leaf extract AS195 KG) (2538,53206). Joint pain and lumbago have been reported with use of grape seed extract, but these effects occur at rates similar to placebo (91541).

Neurologic/CNS ...Orally, headache has been reported with use of grape seed extract, but this effect occurs at rates similar to placebo (9182,91541). A specific grape leaf extract AS195 (Antistax, Boehringer Ingelheim Pharma GmbH & Co. KG) has reportedly caused dizziness, tiredness, headache, and sleep problems (2538,53206). As a class, nervous system adverse effects have been reported with use of a specific grape seed extract (Entelon, Hanlim Pharm). However, the specific types of adverse neurologic effects were not described (100954).

Ocular/Otic ...Orally, ocular adverse effects have been reported with use of a specific grape seed extract (Entelon, Hanlim Pharm). However, the specific types of ocular adverse effects were not described (100954).

Pulmonary/Respiratory ...Orally, nasopharyngitis and oropharyngeal pain have been reported with use of a specific grape leaf extract AS195 KG) (53206). Sore throat, cough, allergic rhinitis, and nasopharyngitis have been reported with use of grape seed extract, but these effects occur at rates similar to placebo (9182,91541). One case report describes a 16-year-old female who developed increased levels of immunoglobulin E (IgE) following skin-prick exposure to grape vine pollen, as well as positive test responses following bronchial and conjunctival provocation (53301). Reduced forced vital capacity has been described in California grape workers (53080,53081). Occupational eosinophilic lung was diagnosed in a grape grower with a history of asthma. Respiratory exposure to sulfites in grape was implicated as the cause of the adverse reaction (53285).

Other ...Orally, grape products can cause adverse effects due to contamination with pesticides or mycotoxins. Some evidence has shown that pesticides used in vineyards may remain on grape surfaces post-harvesting. For example, the fungicide folpet sprayed on grapevines has been shown to remain on the grape surface. Although there was minimal penetration of the epicuticular wax, it showed high resistance to washing (52935). Carbaryl has been identified in over 58% of juice samples collected in Canada. This pesticide reportedly occurred more frequently in grape than in other juices. However, estimates of short-term intake were below proposed acute reference doses (53003).
Ochratoxin A is a mycotoxin that is suspected to be nephrotoxic, teratogenic, hepatotoxic and carcinogenic and has been identified in grape juice, frozen grape pulps, and red and white wine sold in Rio de Janeiro, Brazil. However, the highest levels identified in grape products were lower than the established virtually safe dose of 5 ng/kg of body weight daily (53010,53004). Ochratoxin A has also been identified in red, but not white, grape juice marketed in Switzerland, Canada, and the U.S. (53292,53020).

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

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

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

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

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

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

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

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

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