DIM Advantage [Discontinued] by Thorne

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.

(Read more about DIINDOLYLMETHANE)

POSSIBLY EFFECTIVE

• Hypertension. Oral pomegranate juice seems to modestly reduce blood pressure. Details: Most clinical research evaluating pomegranate juice for reducing systolic blood pressure (SBP) and diastolic blood pressure (DBP) shows modest benefits (8310,13023,13691,69372,69373,69374). A meta-analysis of results from eight clinical studies including 574 patients shows that pomegranate juice reduces SBP by about 5 mmHg, but does not affect DBP, when compared with placebo. Doses of pomegranate juice ranged from 43-330 mL daily for 2 weeks to 18 months. Changes in SBP and DBP were not related to the dose or duration of pomegranate juice consumption (96247).

POSSIBLY INEFFECTIVE

• Diabetes. Most oral pomegranate products do not seem to be beneficial for diabetes. It is unclear if pomegranate seed powder is beneficial. Details: A meta-analysis of clinical research shows that taking pomegranate has no effect on glycated hemoglobin (HbA1c) or plasma levels of insulin, lipids, or fasting glucose when compared with placebo in patients with type 2 diabetes. Various formulations, including juice, fruit extract, peel extract, and seed oil, were used in these studies (105265). However, a more recent clinical trial shows that drinking a beverage twice daily for 8 weeks, made by soaking a 'tea bag' containing pomegranate seed powder 5 grams in hot water for 10 minutes, modestly reduces levels of fasting blood glucose, HbA1c, total cholesterol, and triglycerides when compared with placebo. Fasting blood glucose levels were reduced by approximately 4%, compared with a 6% increase in the placebo group (105270).
• Hyperlipidemia. Oral pomegranate does not seem to be beneficial for hyperlipidemia. Details: Most clinical research shows that taking pomegranate does not increase high-density lipoprotein (HDL) cholesterol levels or reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglyceride levels when compared with placebo (13022,13023,13690,69142,69168,69276). A meta-analysis of results from 12 clinical studies including 545 patients with or without hyperlipidemia shows that taking pomegranate daily for at least 10 days and up to 1 year does not improve blood lipid levels when compared with placebo. Pomegranate formulations evaluated in these studies include juice, seed oil, whole fruit, extract, and vinegar beverage; no specific form or dose of pomegranate was associated with improvements in cholesterol or triglyceride levels (96248). One preliminary clinical study has evaluated pomegranate juice in combination with other fruits. Results from the study show that taking a specific pomegranate-containing combination product (Radical Fruits, Garden of Life) 900 mg orally three times daily before meals reduces total and LDL cholesterol and increases HDL cholesterol in males with hypercholesterolemia (69170). However, it is unclear if these benefits are due to pomegranate, other ingredients, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atherosclerosis. It is unclear if oral pomegranate juice is beneficial for preventing atherosclerosis. Details: Preliminary clinical research shows that drinking pomegranate juice 50 mL daily reduces intima-media thickness of the carotid artery by up to 35% after one year when compared to baseline in patients with atherosclerosis and carotid artery stenosis (13023).
• Athletic performance. It is unclear if oral pomegranate extract is beneficial for athletic performance. Details: Preliminary clinical research in trained male cyclists shows that taking pomegranate extract (POM Wonderful LLC) 15 mg/kg daily for 8 days moderately reduces the amount of oxygen needed to perform submaximal exercise when compared with placebo. However, pomegranate extract does not improve performance in a timed trial (99100). Other preliminary clinical research in regionally competitive male cyclists shows that taking pomegranate extract (Pomanox P30, Euromed S.A.) 750 mg daily for 15 days increases the time to exhaustion by 94 seconds after a prolonged submaximal effort, as well as the time to reach the anaerobic threshold by about 55 seconds, when compared with placebo. There was no effect on the restoration of force or on oxygen consumption (101881).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral pomegranate juice is beneficial for COPD. Details: A small clinical trial shows that drinking pomegranate juice 400 mL daily for 5 weeks does not improve symptoms or respiratory function in patients with COPD when compared with placebo (13692).
• Coronary heart disease (CHD). It is unclear if oral pomegranate juice is beneficial for patients with CHD. Details: Some preliminary clinical research shows that drinking pomegranate juice (POM Wonderful Pomegranate Juice, POM Wonderful LLC) 240 mL daily for 3 months decreases stress-induced myocardial ischemia in patients with CHD. The average improvement in myocardial perfusion was about 17% with pomegranate juice, compared with an 18% worsening of myocardial perfusion in patients taking placebo (13691). However, other preliminary clinical research in patients with moderate CHD risk shows that drinking the same pomegranate juice product 240 mL daily for 18 months does not improve carotid intima-media thickness when compared to control (17329). It is not known if drinking pomegranate juice can prevent or reduce the risk of a myocardial infarction or other cardiovascular outcomes.
• Dental plaque. It is unclear if rinsing the mouth with pomegranate extract is beneficial for reducing dental plaque. Details: Preliminary clinical research shows that rinsing with pomegranate extract mouthwash for one minute once or twice daily reduces dental plaque in patients with or without fixed orthodontic appliances. The antiplaque activity of pomegranate extract is similar to that of chlorhexidine (69171,69316).
• Erectile dysfunction (ED). It is unclear if oral pomegranate juice is beneficial for ED. Details: In patients with mild-to-moderate ED, preliminary clinical research shows that drinking pomegranate juice daily for 4 weeks does not improve symptoms of ED when compared with placebo (69175).
• Exercise-induced muscle soreness. It is unclear if oral pomegranate juice is beneficial for reducing exercise-induced muscle soreness. Details: Preliminary clinical research shows that drinking pomegranate juice (POM Wonderful Pomegranate Juice, POM Wonderful LLC) 250 mL twice daily for 15 days reduces post-exercise muscle soreness in elbow flexor, but not knee extensor, muscles in resistance-rained males when compared with placebo (69355). However, in non-resistance trained males, drinking the same pomegranate juice 250 mL twice daily for 9 days does not reduce exercise-induced muscle damage or delayed onset soreness of elbow flexor muscles when compared with placebo (101880).
• HIV/AIDS. Although there has been interest in using oral pomegranate for HIV/AIDS, there is insufficient reliable information about the clinical effects of pomegranate for this condition.
• Influenza. Although there has been interest in using oral pomegranate for influenza prevention, there is insufficient reliable information about the clinical effects of pomegranate for this purpose.
• Intrauterine growth restriction (IUGR). It is unclear if oral pomegranate juice is beneficial for preventing brain injury in IUGR neonates. Details: In patients with an IUGR pregnancy, clinical research shows that drinking pomegranate juice 8 ounces daily from 24-34 weeks' gestation until delivery reduces the risk of an MRI-diagnosed gray matter brain injury in the infant by approximately 28%. There was no effect on brain volume or white matter injury (105267).
• Kidney failure. It is unclear if oral pomegranate juice is beneficial for patients on hemodialysis; the available research is conflicting. Details: Some preliminary clinical research shows that taking pomegranate juice (Nutrafood) 100 mL during the first dialysis treatment hour three times weekly for one year reduces antihypertensive medication requirements and the rate of second hospitalization due to infection when compared with placebo. Consuming pomegranate juice also increases high-density lipoprotein (HDL) cholesterol in patients with baseline levels of 40 mg/dL or less and reduces triglycerides in patients with baseline levels of at least 200 mg/dL (91698,91699). Preliminary clinical research also shows that taking pomegranate juice 100 mL immediately after dialysis three times weekly for 8 weeks reduces triglycerides by approximately 20%, as well as systolic and diastolic blood pressure by 5% and 7%, respectively, when compared with baseline. HDL cholesterol was also increased by approximately 23%. These changes were significant when compared with placebo (101882). However, pomegranate juice did not affect total cholesterol, low-density lipoprotein (LDL) cholesterol, liver enzymes, or incidence of cardiovascular events when compared with placebo (91698,91699,101882). Other preliminary clinical research shows that drinking pomegranate juice (POM Wonderful Pomegranate Juice, POM Wonderful LLC) 100 mL or taking pomegranate juice extract tablets (POM Wonderful LLC) 1050 mg daily prior to each dialysis session for 4 weeks does not improve blood pressure, lipids, or markers of inflammation and oxidative stress when compared to baseline in patients receiving maintenance hemodialysis (91697). Although the reason for these conflicting findings is not clear, it may have to do with the timing of consumption. The evidence suggests that offering pomegranate during dialysis or after completion of dialysis might be more effective than prior to dialysis.
• Menopausal symptoms. It is unclear if oral pomegranate seed oil or pomegranate extract is beneficial for menopausal symptoms. Details: Preliminary clinical research shows that taking a specific pomegranate seed oil (Delima, Pekana Naturheilmittel GmbH) 30 mg orally twice daily for 12 weeks does not reduce the frequency of hot flashes when compared with placebo in postmenopausal adults experiencing at least 5 hot flashes per day. However, pomegranate seed oil might improve sleep in some patients with sleep disturbances attributed to menopause (91685). A clinical study in healthy, perimenopausal and menopausal adults with untreated menopausal symptoms shows that taking pomegranate extract 3 mL three times daily for 4 weeks reduces symptoms, including hot flashes and vertigo, and improves physical and mental quality of life when compared with placebo. Additionally, these improvements were sustained 3 weeks after discontinuing treatment (108484). The validity of this study is limited by the short duration of treatment.
• Metabolic syndrome. It is unclear if oral pomegranate juice is beneficial for metabolic syndrome. Details: Preliminary clinical research shows that drinking pomegranate juice 240 mL daily for one month improves endothelial dysfunction in adolescents with metabolic syndrome when compared with drinking grape juice 240 mL daily (53174,69362).
• Muscle strength. It is unclear if oral pomegranate juice is beneficial for increasing muscle strength. Details: Preliminary clinical research shows that taking a specific pomegranate extract (POMx, POM Wonderful LLC) 480 mL twice daily modestly improves recovery of strength 2-3 days after eccentric exercise but does not reduce muscle soreness after exercise when compared with placebo (69261).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral pomegranate seed oil or pomegranate extract improves anthropometric measures in adults with NAFLD. Details: A small clinical study in overweight and obese adults with NAFLD shows that taking a dried pomegranate extract, standardized to contain 90 mg of ellagic acid, twice daily for 12 weeks reduces body mass index and body weight when compared with placebo. A 5 kg weight reduction occurred in the pomegranate group, compared to a small increase in weight in the placebo group. Pomegranate also improved diastolic blood pressure, as well as lipid and glycemic parameters; however, the patients included in this study had normal baseline parameters, limiting the validity of this finding (108481). Pomegranate has also been evaluated in combination with other ingredients. One small clinical crossover study in obese females with NAFLD shows that taking a specific combination product (Xanthigen, Polinat) containing pomegranate seed oil 300 mg and brown marine algae 300 mg (standardized to fucoxanthin 2.4 mg) modestly reduces body weight and liver fat content when compared with placebo (69257).
• Obesity. It is unclear if oral pomegranate is beneficial for obesity. Most evidence suggests that it is not beneficial, although some studies have yielded conflicting findings. Details: A meta-analysis of 513 participants shows that taking pomegranate extract, juice, or concentrate for 2-26 weeks does not reduce body weight, body mass index, waist circumference, or body fat percentage when compared with placebo or other control (101883). However, most of these studies were not designed to investigate weight as the primary outcome, and some preliminary clinical research in overweight or obese individuals suggests that some pomegranate products might have some benefit. Drinking pomegranate juice 120 mL daily for one month helps these individuals maintain weight when compared with placebo, although it does not appear to improve glucose, insulin secretion, or insulin sensitivity (91693).
• Oropharyngeal candidiasis. It is unclear if topical pomegranate peel extract is beneficial for oropharyngeal candidiasis. Details: Preliminary clinical research in patients with candidiasis associated with denture stomatitis shows that applying a gel containing the extract of pomegranate fruit peel to the gums three times daily for 15 days seems to be as effective as miconazole gel for improving symptoms of candidiasis (13689).
• Polycystic ovary syndrome (PCOS). It is unclear if oral pomegranate juice is beneficial for PCOS. Details: In patients with PCOS, preliminary clinical research shows that taking pomegranate juice 45 mL daily for 8 weeks reduces systolic and diastolic blood pressures by 10 and 4 mmHg, respectively, when compared with a control group not taking pomegranate juice. Triglyceride and high-density lipoprotein (HDL) cholesterol levels were also modestly improved. However, there was no effect on glycemic measures, and low-density lipoprotein (LDL) cholesterol levels increased by 6 mg/dL (105266). Another clinical trial in patients with PCOS shows that taking synbiotic pomegranate juice containing inulin and lactobacillus as 2 liters weekly for 8 weeks improves insulin sensitivity, body mass index, waist circumference, and testosterone levels when compared with baseline or a control juice. However, patients consuming a drink containing only the synbiotic ingredients experienced the same improvements, whereas patients consuming only regular pomegranate juice experienced no benefits, suggesting that pomegranate was not responsible for these changes (101884).
• Prostate cancer. It is unclear if oral pomegranate extract or juice is beneficial for prostate cancer. Details: Preliminary clinical research shows that pomegranate might slow prostate cancer progression in some patients after surgery or radiation for prostate cancer. The length of time to doubling of prostate specific antigen (PSA) was longer in those who took a specific pomegranate extract (POMx, POM Wonderful LLC) 1-3 grams daily, as well as those who drank 8 ounces of pomegranate juice daily, for up to 24 months (14137,14388,91695). However, the results from a large well-designed study do not support these findings. This study shows that taking 8 ounces of a pomegranate liquid extract does not increase the length of time to doubling of PSA (105271). In patients with favorable-risk localized prostate cancer, a small clinical trial also shows that taking pomegranate fruit extract (POMx, POM Wonderful) 1000 mg daily for 12 months does not affect the length of time to doubling of PSA, although there were some changes in tumor markers of DNA damage (105269). Pomegranate has also been evaluated in combination with other ingredients. Preliminary clinical research in patients with localized prostate cancer shows that taking a combination supplement containing pomegranate powder 100 mg, broccoli powder 100 mg, turmeric powder 100 mg, and green tea extract 20 mg daily for 6 months slows the increase in PSA levels when compared with placebo (89730). It is not clear if this effect is due to pomegranate, the other ingredients, or the combination.
• Rheumatoid arthritis (RA). It is unclear if oral pomegranate extract is beneficial for RA. Details: Preliminary clinical research shows that taking a specific pomegranate extract (POMx, POM Wonderful LLC) 5 mL twice daily for 12 weeks decreases disease activity and reduces tender joint count by 62% when compared to baseline in patients with RA (91686). The validity of these findings is limited by the lack of a control group.
• Rhinosinusitis. It is unclear if intranasal pomegranate extract is beneficial for chronic rhinosinusitis. Details: A clinical study in adults with chronic rhinosinusitis or rhinitis persisting longer than 12 weeks, with or without the presence of nasal polyps, shows that using a nasal spray containing pomegranate extract in an unknown dose twice daily for 30 days does not improve objective or subjective nasal or sinus symptoms when compared with placebo nasal spray. In a subgroup of patients with chronic rhinitis, including allergic and nonallergic rhinitis, improvement in thick nasal discharge is also observed in those receiving the pomegranate nasal spray; however, the study does not report outcomes for each subtype of rhinitis (108480).
• Stroke. Although there has been interest in using oral pomegranate for stroke recovery, there is insufficient reliable information about the clinical effects of pomegranate for this purpose.
• Sunburn. It is unclear if oral pomegranate extract is beneficial for sunburn prevention. Details: A small clinical study shows that taking pomegranate extract standardized to contain ellagic acid 100-200 mg daily for 4 weeks does not reduce skin pigmentation caused by UV light exposure when compared with placebo (69172). However, this study was not adequately powered to detect a difference between treatments.
• Trichomoniasis. It is unclear if oral pomegranate extract is beneficial for trichomoniasis. Details: A very small clinical study in patients with vaginal Trichomoniasis suggests that taking pomegranate extract might help to eradicate Trichomonas vaginalis infection (69286). The validity of this finding is limited by the small study size, unclear reporting, and lack of a control group. More evidence is needed to rate pomegranate for these uses.

(Read more about POMEGRANATE)

POSSIBLY EFFECTIVE

• Prostate cancer. Oral sulforaphane seems to delay increases in levels of prostate specific antigen (PSA) in patients with prostate cancer. Details: One clinical study in adults who have undergone radical prostatectomy shows that taking a specific sulforaphane product (Prostaphane, Nutrinov) 20 mg three times daily for 6 months attenuates a rise in PSA levels after 3 months, with an 86% increase in the time needed for PSA levels to double when compared with placebo (95251). A small clinical study in adults with recurrent prostate cancer shows that taking a sulforaphane-rich broccoli sprout extract 35.2 mg daily for up to 20 weeks increases the time needed for PSA levels to double by 57% when compared to pre-treatment changes in PSA levels (95260).

POSSIBLY INEFFECTIVE

• Helicobacter pylori. Oral sulforaphane does not seem to improve the H. pylori eradication rate when used in combination with triple therapy treatment. Details: Clinical research shows that taking one capsule of broccoli sprout extract 250 mg, providing sulforaphane 1 mg, three times daily for 4 weeks in combination with clarithromycin-based triple-therapy treatment does not increase H. pylori eradication rate when compared with triple therapy alone or in combination with Saccharomyces boulardii (108138).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral sulforaphane is beneficial for improving cognitive function in older adults. Details: Clinical research in older adults shows that taking the sulforaphane precursor glucoraphanin (Kagome Co., Ltd.) 30 mg daily for 12 weeks modestly improves some measures of cognitive function, specifically working memory and processing speed, when compared with placebo. Half of all patients also underwent brain-training by playing a specific game (Brain Age) 15 minutes daily and the other half played an active control game (Tetris). However, the combination of brain-training and glucoraphanin does not seem to be more beneficial than either intervention alone (108133).
• Allergic rhinitis (hay fever). It is unclear if oral sulforaphane is beneficial for allergic rhinitis. Details: Clinical research in patients with grass-induced allergic rhinitis shows that using a daily steroid nasal spray in conjunction with an oral broccoli seed and sprout extract (Avmacol, Nutramax) 1500 mg daily, providing sulforaphane 60-70 micromoles, for 3 weeks improves nasal flow and symptom severity for up to about 30 minutes when compared with using a saline spray and oral placebo. However, use of either intervention alone did not improve nasal flow or symptoms when compared with placebo (108132). This study was small and may not have been adequately powered to detect beneficial effects of sulforaphane alone.
• Asthma. It is unclear if oral sulforaphane is beneficial for asthma. Details: Preliminary clinical research in adults with asthma shows that taking broccoli sprout extract containing sulforaphane 17.6 mg daily for 14 days attenuates the bronchoconstriction effects of methacholine by approximately 21% when compared to baseline. However, after taking sulforaphane, 20% of patients experienced a worsening of bronchoconstriction and 20% experienced no change. Taking sulforaphane did not improve most measures of pulmonary function, including forced expiratory volume, forced vital capacity, lung capacity, and residual capacity (95262).
• Autism spectrum disorder. It is unclear if oral sulforaphane is beneficial in children or adults with autism spectrum disorder; any benefits seen in clinical studies may not be considered clinically significant. Details: Research is conflicting on whether sulforaphane improves symptoms of autism. One small clinical study in children 4-12 years old with moderate to severe autism symptoms shows that taking sulforaphane 10-20 mg daily in combination with risperidone for 10 weeks improves irritability scores by 14% and hyperactivity scores by 12% when compared with placebo and risperidone. However, it is unclear if these improvements are clinically meaningful. Taking sulforaphane did not improve stereotypic, social/lethargy, or speech scores when compared with placebo. Children weighing up to 45 kg took approximately 10 mg daily and children weighing at least 45 kg took approximately 20 mg daily (104537). In contrast, a small clinical study in children 3-12 years old with moderate to severe autism symptoms shows that taking sulforaphane as a specific broccoli seed and sprout extract blend (Avmacol, Nutramax) daily for 15 weeks does not improve clinical impressions or most symptoms of autism when compared with placebo. The extract blend was dosed to provide approximately 1 mcmol sulforaphane per pound or 2.2 mcmol per kg body weight (108131). This study was small and may not have been adequately powered to detect differences between groups. Another very small clinical study in children aged 3-7 years old with autism spectrum disorder shows that taking a specific product containing broccoli sprout powder standardized for sulforaphane (BroccoPhane, Bioriginal) with red radish sprout daily for 36 weeks does not improve measures of aberrant behavior, communication, play and imagination, restricted interests, or social responsiveness and interaction when compared with placebo (112450). Sulforaphane has also been evaluated in older children or young adults. A small study in males 13-27 years of age with autism shows that taking sulforaphane daily for 18 weeks improves behavior scores by 33% and social scores by 17% when compared with placebo. After treatment discontinuation, behavior and social scores returned to baseline levels. Dosing was weight-based as follows: sulforaphane 26.6 mg daily in those weighing at least 91 kg, 17.6 mg daily in those weighing 45-91 kg, and 8.8 mg daily in those weighing up to 45 kg (95267). A small study in males and females 7-21 years of age with autism shows that taking sulforaphane as a specific broccoli seed and sprout blend (Avmacol, Nutramax Laboratories Consumer Care, Inc.) daily for 12 weeks improves social scores by 6%, but does not affect behavior scores, when compared with baseline. It is unclear if this improvement is clinically meaningful. The product used in this study contains glucoraphanin and myrosinase and was dosed to provide approximately 2.5 mcmol of glucoraphanin per pound of body weight (98501). The validity of these findings is limited by the lack of a comparator group.
• Cancer. Although there is interest in using oral sulforaphane for cancer, there is insufficient reliable information about the clinical effects of sulforaphane for this condition.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral sulforaphane is beneficial for COPD. Details: Preliminary clinical research shows that taking sulforaphane 4.4 mg or 26.6 mg daily for 4 weeks does not improve symptoms of COPD when compared with placebo (95268).
• Depression. It is unclear if oral sulforaphane is beneficial for depression. Details: A small clinical trial in patients with mild to moderate depression related to cardiac interventions shows that taking sulforaphane (Acer) 30 mg daily for 6 weeks reduces depression score by at least 50% in 30% of patients, compared with only 7% of those taking placebo. However, there was no significant difference in remission rate between groups (108136).
• Exercise-induced muscle damage. It is unclear if oral sulforaphane is beneficial for exercise-induced muscle damage. Details: A small clinical trial in adult males shows that taking sulforaphane 30 mg daily for 4 weeks attenuates an increase in creatine kinase levels at 24 hours following heavy resistance exercise when compared with placebo. This suggests that sulforaphane may reduce muscle damage associated with exercise (108135). However, another small preliminary clinical trial in young adult males shows that taking the sulforaphane precursor glucoraphanin (Kagome Co., Ltd.) 30 mg daily, starting 2 weeks before exercise and continuing until 4 days after, does not reduce markers of muscle damage, including aldolase, aspartate aminotransferase, lactate dehydrogenase, or creatine kinase, when compared with not taking sulforaphane (108134).
• Exercise-induced muscle soreness. It is unclear if oral sulforaphane is beneficial for exercise-induced muscle soreness. Details: A small preliminary clinical trial in young adult males shows that taking the sulforaphane precursor glucoraphanin (Kagome Co., Ltd.) 30 mg daily, starting 2 weeks before exercise and continuing until 4 days after, reduces palpation-related muscle soreness and improves range of motion two days after exercise when compared with not taking sulforaphane. However, there was no difference between groups on days 1, 3, or 4 and there was no difference in pain related to extension (108134).
• Liver disease. Although there is interest in using oral sulforaphane to improve liver health, there is insufficient reliable information about the clinical effects of sulforaphane for this use.
• Pregnancy-induced hypertension. It is unclear if oral sulforaphane is beneficial for hypertension during pregnancy. Details: A small nonrandomized clinical trial in patients with pregnancy-induced hypertension or pre-eclampsia shows that taking broccoli extract modestly decreases diastolic, but not systolic, blood pressure, when compared with baseline. Patients took a single dose of either four or eight tablets of a myrosinase-activated broccoli seed extract (BroccoMax, Jarrow Formulas) providing an unknown dose sulforaphane (108130). This study was small and may not have been adequately powered to detect differences in blood pressure.
• Schizophrenia. It is unclear if oral sulforaphane is beneficial for schizophrenia. Details: Preliminary clinical research in patients with schizophrenia shows that taking sulforaphane as a specific broccoli seed and sprout blend (Avmacol, Nutramax) daily for 16 weeks does not improve positive or negative symptoms when compared with taking placebo (108137).
• Sickle cell disease. Although there is interest in using oral sulforaphane for sickle cell disease, there is insufficient reliable information about the clinical effects of sulforaphane for this condition.
• Sunburn. Although there is interest in using topical sulforaphane for sunburn prevention, there is insufficient reliable information about the clinical effects of sulforaphane for this use. More evidence is needed to rate sulforaphane for these uses.

(Read more about SULFORAPHANE)

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.

(Read more about DIINDOLYLMETHANE)

LIKELY SAFE ...when pomegranate fruit or fruit juice is used orally and appropriately. Pomegranate juice has been safely used in studies lasting up to 3 years (4912,8310,13022,13023,13690,14137,14388,17329,91693).

POSSIBLY SAFE ...when pomegranate extract is taken orally and appropriately. A specific pomegranate ellagitannin-enriched polyphenol extract (POMx, POM Wonderful) 1-3 grams daily has been safely used for up to 18 months (17729,69261,91686,91695,91697,99100,105269). ...when pomegranate seed oil is used orally and appropriately. Pomegranate seed oil 60 mg daily has been used with apparent safety for up to 12 weeks (91685). ...when a hot water extract of pomegranate seed powder is used orally and appropriately. Pomegranate seed powder 5 grams daily has been used with apparent safety for up to 8 weeks (105270). ...when pomegranate extract is used topically on oral mucosa (13689).

POSSIBLY UNSAFE ...when the pomegranate root, stem, and peel are used orally in large amounts. Bark of the pomegranate root and stem contains the piperidine alkaloids pelletierine, pseudopelletierine, isopelletierine, and methyl isopelletierine. These alkaloids have muscle relaxant properties that have been associated with paralysis and death in animals (13687,13694,13695). Dried pomegranate peel may contain aflatoxin, which is a potent hepatocarcinogen and toxin (92018).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when the fruit or fruit juice is consumed orally and appropriately (13686,105267). There is insufficient reliable information available regarding the safety of using other forms of pomegranate or other parts of the plant during pregnancy or lactation; avoid using.

(Read more about POMEGRANATE)

LIKELY SAFE ...when used orally in amounts found in foods (10264).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Sulforaphane-rich broccoli sprout extract has been used with apparent safety in clinical studies at a sulforaphane dose of up to 35.2 mg daily for up to 20 weeks (95260,95262,95265,95267,95268,104537,108136,108137,108138). A specific brand of sulforaphane (Prostaphane, Nutrinov) has been used with apparent safety in clinical research at a dose of up to 60 mg daily for up to 6 months (95251). A specific broccoli seed extract (BroccoMax, Jarrow Formulas) containing glucoraphanin 180 mg daily has been used with apparent safety in clinical research for up to 8 weeks (95269).

CHILDREN: LIKELY SAFE
when used orally in amounts found in foods (10264). There is insufficient reliable information available about the safety of sulforaphane in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (10264). There is insufficient reliable information available about the safety of sulforaphane in medicinal amounts.

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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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ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking pomegranate with ACEIs might increase the risk of adverse effects.  Details Pomegranate juice is thought to have ACE inhibitor-like effects (8310).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking pomegranate with antihypertensive drugs might increase the risk of hypotension.  Details Consuming pomegranate juice can modestly lower blood pressure (8310,13023,69373,69374).

CARBAMAZEPINE (Tegretol) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking pomegranate with carbamazepine might increase the risk of adverse effects, although research suggests this interaction is unlikely to be clinically significant.  Details Animal research shows that pomegranate juice may inhibit cytochrome P450 3A4 (CYP3A4) metabolism of carbamazepine and increase levels of carbamazepine by 1.5 times without prolonging the elimination half-life. This suggests that pomegranate juice inhibits intestinal CYP3A4, but might not inhibit hepatic CYP3A4 (13188). However, some human research suggests that pomegranate does not significantly inhibit CYP3A4 drug metabolism in humans (16711,16712,17326).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, pomegranate might increase levels of drugs metabolized by CYP2C9.  Details Some animal and in vitro research shows that pomegranate juice inhibits intestinal, but not hepatic, CYP2C9 isoenzyme activity (17327). However, clinical research shows that neither pomegranate juice nor pomegranate extract have a significant effect on CYP2C9 activity in humans (91694).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, pomegranate might increase levels of drugs metabolized by CYP2D6.  Details In vitro, pomegranate juice inhibits CYP2D6 (13703). However, the clinical significance of this potential interaction in humans is not known.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, pomegranate might increase levels of drugs metabolized by CYP3A4, but most research suggests this interaction is unlikely to be clinically significant.  Details Pomegranate contains several polyphenols that have individually been shown to inhibit CYP3A4. However, there is contradictory evidence about the effect of whole pomegranate juice on CYP3A4 activity. In vitro, pomegranate juice significantly inhibits the CYP3A4 enzyme, with comparable inhibition to grapefruit juice (13188,16711,17326). In an animal model, pomegranate juice inhibits CYP3A4 metabolism of carbamazepine and increases levels of carbamazepine by 1.5 times (13188); however, in human volunteers, drinking a single glass of pomegranate juice 240 mL or taking 200 mL daily for 2 weeks does not significantly affect levels of the CYP3A4 substrate midazolam after oral or intravenous administration (16711,17730). Another study in healthy volunteers shows that consuming pomegranate juice 300 mL three times daily for three days also does not significantly affect levels of simvastatin, a CYP3A4 substrate (16712,91696) This suggests that pomegranate is unlikely to significantly affect levels of CYP3A4 substrates in humans (17326).

ROSUVASTATIN (Crestor) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking pomegranate with rosuvastatin might increase the risk of adverse effects.  Details In one case, a patient taking rosuvastatin 5 mg every other day in combination with ezetimibe 10 mg daily developed rhabdomyolysis after drinking pomegranate juice 200 mL twice weekly for 3 weeks. This patient had a history of elevated creatine kinase levels while not receiving any statin treatment. This suggests a possible underlying myopathy and predisposition to rhabdomyolysis (14465).

TOLBUTAMIDE (Orinase) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, pomegranate might increase levels of tolbutamide, although research suggests this interaction is unlikely to be clinically significant.  Details Animal research shows that pomegranate juice inhibits the cytochrome P450 2C9 (CYP2C9) metabolism of tolbutamide. Pomegranate juice increased tolbutamide levels by 1.2 times without prolonging the elimination half-life. This suggests that pomegranate juice inhibits intestinal CYP2C9, but might not inhibit hepatic CYP2C9 (17327). Despite this evidence, clinical research shows that neither pomegranate juice nor pomegranate extract have a significant effect on CYP2C9 activity in humans (91694). This interaction does not appear to be clinically significant in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, pomegranate might increase warfarin levels and increase the risk of bleeding. Also, discontinuing regular consumption of pomegranate juice might decrease warfarin levels.  Details In one case report, a patient had a stable, therapeutic bleeding time, as measured by international normalized ratio (INR), while taking warfarin in combination with pomegranate juice 2-3 times per week. The patient became subtherapeutic within about 10 days after discontinuing pomegranate juice, which required a warfarin dose increase (17328). In another case report, a patient with a stable INR for over one year presented with an INR of 14. The patient noted no changes to medications or diet but did report consuming around 3 liters of pomegranate juice over the previous week. The patient's INR stabilized upon moderation of pomegranate juice consumption (24273). The mechanism of this potential interaction is unclear.

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CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sulforaphane might alter the levels and clinical effects of CYP1A2 substrates.  Details Animal and in vitro research shows that sulforaphane inhibits CYP1A2 enzyme activity. However, its precursor glucoraphanin also appears to increase the expression of the CYP1A2 enzyme, which could lead to increased metabolism of CYP1A2 substrates (12701,105083,105085). These effects have 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, sulforaphane might increase the levels and effects of CYP2E1 substrates.  Details In vitro evidence shows that sulforaphane inhibits CYP2E1 enzymes (105083). 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 Theoretically, sulforaphane might increase the levels and effects of CYP3A4 substrates.  Details Animal and in vitro research shows that sulforaphane inhibits CYP3A4 enzyme activity and downregulates its expression (105083,105434,105435). This interaction has not been reported in humans.

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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, pomegranate fruit juice is generally well tolerated. Pomegranate fruit extract and seed oil seem to be well tolerated. Pomegranate root, stem, and peel should not be used orally in large amounts. Topically, pomegranate fruit extract seems to be well tolerated.
Most Common Adverse Effects:
Oral: Diarrhea, flatulence.

Cardiovascular ...In one clinical trial, 2% of patients experienced hyperlipidemia and hypertension after consumption of pomegranate juice (69175). However, most clinical research shows that pomegranate does not increase cholesterol or blood pressure and may actually improve these parameters in some patients (8310,13022,13023,69168,69373,69374).

Dermatologic ...Topically, pomegranate may cause urticaria (hives) in some patients (8445).

Gastrointestinal ...Orally, pomegranate may cause mild gastrointestinal adverse effects. In one clinical study, drinking pomegranate juice 8 ounces daily caused diarrhea and flatulence in 2% of patients (69175). In another clinical study, taking pomegranate extract (POMx, POM Wonderful LLC) 3000 mg daily caused diarrhea in 10% of patients. This dose of pomegranate extract also caused nausea, abdominal pain, constipation, gastrointestinal upset, and vomiting in a small number of patients (91695).

Immunologic ...Orally, pomegranate fruit or seeds may cause allergic reactions. These allergic reactions occur more commonly in people who are allergic to other plants (7674). In rare cases, pomegranate fruit can cause angioedema. Angioedema seems to occur without warning and in people who have eaten pomegranate for many years. Patients should be told to stop eating pomegranate if swelling of the tongue or face develops (7673). In one report, a patient experienced pomegranate-dependent, exercise-induced anaphylaxis. The patient developed widespread urticaria (hives) and lip edema after eating pomegranate seeds and then exercising (17331). In another report, an atopic patient experienced an allergic reaction to pomegranate fruit. Symptoms included urticaria (hives), facial angioedema, and hypotension (91692).
Topically, pomegranate may cause contact hypersensitivity characterized by urticaria (hives), angioedema, rhinorrhea, red itchy eyes, and dyspnea arising within a few minutes of exposure (8445).

Pulmonary/Respiratory ...Orally, pomegranate juice may cause nasal congestion, but this event is rare. In one clinical study, pomegranate juice was associated with nasal congestion in 2% of patients (69175). There is also one case report of a 7-year-old asthmatic child who developed bronchospasm moments after ingesting several pomegranate seeds (69149).

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General ...Orally, sulforaphane seems to be well tolerated.
Most Common Adverse Effects:
Orally: Bowel discomfort, heartburn, stomach upset, and vomiting.

Gastrointestinal ...Orally, sulforaphane and sulforaphane-rich extracts can cause bowel discomfort, stomach upset, heartburn, and vomiting (95251,95252,95260,95265,95267,95268,98501,104537,108132). A specific stabilized form of sulforaphane (Cavamax W6) caused mild stomach upset in 60% of subjects in a small study (95252). However, in some clinical studies, the gastrointestinal side effects reported with sulforaphane did not occur more frequently than with placebo (95268).

Hepatic ...Orally, sulforaphane has been associated with one case of elevated liver enzyme levels. However, the patient ran a marathon the day before testing, and levels returned to normal within one week (95262).

Neurologic/CNS ...Orally, sulforaphane has been reported to cause headache in one clinical study (104537). In another clinical trial, insomnia and irritability were reported (108131). Sulforaphane has also been associated with two cases of seizure in males with autism. In one case, a patient with a recent history of seizure experienced a seizure after taking sulforaphane for 3 weeks. In another case, a patient with seizures which had been well-controlled with antiepileptic drugs for more than 1 year experienced a seizure 3 weeks after discontinuing sulforaphane. It is unclear if sulforaphane precipitated seizures in these patients (95267).

Other ...Orally, sulforaphane has been reported to cause increased weight gain. In one clinical study in males 13-27 years of age with autism, patients taking sulforaphane gained an additional 4 pounds on average over 18 weeks when compared with those taking placebo (95267).

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