Estrogen Balance by Nature's Health Supply, Inc.

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

• Constipation. Oral flaxseed is a bulk forming laxative that helps to relieve constipation. Details: Flaxseed is a source of dietary fiber and has a bulk forming laxative effect (6803,12910). One clinical study in healthy young adults shows that consuming muffins containing 25 grams of milled flaxseed twice daily for 4 weeks increases weekly bowel movements by 30% when compared to a control group (6803). Other clinical research in diabetic patients with constipation shows that taking flaxseed 10 grams twice daily for 12 weeks improves stool form and reduces constipation by a moderate amount when compared with placebo (101950). Furthermore, a small clinical study in patients in China with functional constipation shows that consuming brown flaxseed flour 50 grams in divided doses with meals daily for 4 weeks seems to modestly improve frequency of bowel movements and pain and reduce failure to evacuate when compared with taking lactulose 15 mL every morning (105474). Flaxseed has also been evaluated in combination with other natural ingredients. A preliminary clinical trial in elderly patients with mild constipation shows that eating yogurt containing galacto-oligosaccharide syrup (Elixor, Borculo Whey Products) 6 grams, prunes 6 grams, and flaxseed 3 grams twice daily for 3 weeks increases stool frequency when compared with a control yogurt (21191). It is unclear if the effects were due to flaxseed, other constituents, or the combination.
• Diabetes. Oral ground flaxseed modestly reduces blood glucose in patients with diabetes and pre-diabetes. It is unclear if oral whole flaxseed reduces blood glucose. Details: Most evidence from meta-analyses and clinical research in adults with prediabetes and diabetes shows that taking ground flaxseed reduces fasting blood glucose and insulin levels (21194,21196,26479,101950,111061). A meta-analysis of 7 small to moderate clinical trials shows that taking flaxseed, usually ground, 13 to 40 grams daily for 8-12 weeks has a small beneficial effect on fasting blood glucose, insulin, insulin resistance, and glycated hemoglobin (HbA1c), compared with no intervention or another fiber source. A sub-analysis shows that the benefit of flaxseed on fasting glucose levels remains in patients with type 2 diabetes (111061). Other research disagrees. A meta-analysis of three small clinical trials in patients with type 2 diabetes shows that taking flaxseed does not improve fasting blood glucose, insulin resistance, or HbA1c (111062). Another meta-analysis of 24 clinical studies involving 1,879 patients with and without diabetes shows that whole and ground flaxseed seem to reduce blood glucose levels by an average of 6 mg/dL and insulin levels by an average of 1 mIU/mL and modestly reduce insulin resistance when compared with control treatments such as wheat germ or raw rice. Whole and ground flaxseed were not shown to significantly reduce HbA1c when compared with control, although there was a non-significant trend towards a reduction (96428). Significant heterogeneity in study size and study population limit the validity of these findings. The effects of flaxseed lignan extract in patients with type 2 diabetes is unclear. A small clinical study in Chinese adults with type 2 diabetes show that using a specific standardized flaxseed lignan extract (Flax Essence, Jarrow Formulas) 600 mg three times daily, providing 360 mg secoisolariciresinol diglucoside, slightly reduces HbA1c when compared with placebo (16768). However, a small meta-analysis including this study shows that taking flaxseed lignans does not reduce fasting blood glucose or HbA1c (111062).
• Hypercholesterolemia. Oral whole and ground flaxseed modestly reduce lipid levels. Details: Most research shows that taking various flaxseed preparations 30-50 grams daily reduces total cholesterol by 5% to 15% and low-density lipoprotein (LDL) cholesterol by 8% to 18%, but does not seem to affect high-density lipoprotein (HDL) cholesterol, when compared with control (6808,10952,22179,26478,65866,101944,101947,101949,108044,108046)(111064). Apolipoprotein A-1 and apolipoprotein B may be reduced by 6% and 7.5%, respectively (10952). A meta-analysis of clinical studies shows reductions in apolipoprotein A and apolipoprotein B following whole flaxseed supplementation (108046). The cholesterol-lowering effect of flaxseed has been shown in various populations, including those with hypercholesterolemia with/or without diabetes, postmenopausal patients, and patients with chronic kidney disease or cardiovascular risk factors (6808,10952,10978,12910,22180,22181,26478,26480,26488,101944)(101949,101950,111064). One large meta-analysis suggests that the most consistent effect occurs in patients with hypercholesterolemia (101947). Another large meta-analysis suggests that patients with hypercholesterolemia and healthy patients with a body mass index greater than 25 kg/m2 may benefit the most from treatment (108044). Most research shows that flaxseed reduces triglyceride levels (101947,108046,111064). However, there are certain preparations, such as partially defatted flaxseed (which lacks alpha-linolenic acid content) or flaxseed incorporated into bread products, which might increase triglyceride levels by up to 26% (6808,26488).
• Hypertension. Daily oral flaxseed consumption, especially for longer than 12 weeks, seems to modestly reduce blood pressure. Details: Meta-analyses of mainly small clinical studies in patients with and without hypertension show that taking flaxseed reduces systolic and diastolic blood pressure by an average of 1.1 to 1.8 and 1.0 to 1.3 mmHg, respectively, when compared with control (96426,111063). The effect of flaxseed lignan is unclear. One meta-analysis shows that flaxseed lignan does not seem to reduce blood pressure when compared with control (96426). However, a more recent meta-analysis shows that taking flaxseed lignan has a small effect on systolic, but not diastolic, blood pressure (111063). The length of supplementation may play a role as studies lasting longer than 12 weeks seemed to lower blood pressure to a slightly greater degree than studies lasting less than 12 weeks (96426). The validity of these findings is limited due to the short duration of treatment, the variation in study size, the inclusion of patients with and without hypertension, and the range of doses used. Some clinical research also shows that taking flaxseed may be beneficial for blood pressure reduction in patients with hypertension (111063). One individual clinical study in adults with hypertension shows that taking flaxseed 10 grams or 30 grams daily affects blood pressure in a dose-dependent manner when compared with placebo. After 12 weeks of treatment, systolic and diastolic blood pressure decreased by 12 mmHg and 6 mmHg, respectively, in the high-dose group, compared with 10 mmHg and 7 mmHg, respectively, in the low-dose group (108043).
• Mastalgia. Oral flaxseed seems to reduce symptoms of cyclic mastalgia. Details: Clinical research in healthy Iranian women with cyclic mastalgia shows that taking flaxseed powder 25 grams daily for 2 months reduces breast pain intensity from moderate to mild and also reduces duration of pain when compared with placebo (96250). Other preliminary clinical research shows that eating a muffin containing ground flaxseed 25 grams daily for 3 months reduces symptoms of severe cyclic mastalgia (16766).
• Obesity. Oral flaxseed and flaxseed mucilage seem to modestly improve weight loss in patients who are obese or overweight. However, flaxseed lignan extract does not seem to be beneficial. Details: A meta-analysis of 45 clinical studies including 2,561 overweight or obese adults shows that flaxseed consumption reduces body weight by 1.8 kg, body mass index (BMI) by 0.6 kg/m2, and waist circumference by 1.2 cm when compared with control in adults. The most benefit is seen in adults with a baseline BMI greater than or equal to 27 (96427). Flaxseed consumption of at least 30 grams daily for durations of at least 12 weeks demonstrated the greatest efficacy (96427,101949). The soluble fiber, flaxseed mucilage, has also been studied. A clinical trial in overweight or obese adults shows that taking oral flaxseed mucilage 1280 or 2560 mg mixed in water twice daily with meals for 12 weeks decreases body weight, waist circumference, and BMI in a dose-dependent manner when compared with placebo. After 12 weeks, a 5 kg and 4 kg weight reduction was observed in the high- and low-dose groups, respectively, compared to a 1 kg reduction in the placebo group (108047). The validity of this finding is limited due to short duration of treatment and lack of follow-up. Conversely, flaxseed lignan extract does not appear to be effective in reducing weight, BMI, or waist circumference (96427). Some research has investigated whether variants in genes related to satiety and appetite play a role in any effect of flaxseed on weight loss and appetite. A small clinical trial in adults with overweight or obesity shows that taking defatted flaxseed flour in biscuits daily for 8 weeks modestly reduces body weight, BMI, triglycerides, or blood glucose only in those with specific gene variants when compared with control biscuits (111066). More information is needed to determine how these gene variants play a role in the connection between nutrition and obesity.
• Systemic lupus erythematosus (SLE) nephritis. Oral flaxseed might be beneficial for improving kidney function in SLE. Details: Some small clinical studies suggest that taking whole or ground flaxseed orally might improve serum creatinine levels in people with SLE nephritis (6802,8021).

POSSIBLY INEFFECTIVE

• Osteoporosis. Oral flaxseed does not seem to be beneficial in osteoporosis. Details: Clinical research shows that consuming ground flaxseed 40 grams daily for up to one year does not affect markers of bone metabolism or improve bone mineral density in healthy, postmenopausal adults (10952,12910). Similarly, taking flaxseed extract 550 mg three times daily for 6 months does not appear to improve bone mineral density when compared with placebo in older adults (21197).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral flaxseed for acne, there is insufficient reliable information about the clinical effects of flaxseed for this purpose.
• Benign prostatic hyperplasia (BPH). It is unclear if oral flaxseed lignan improves symptoms of BPH. Details: A small clinical study in patients with BPH shows that taking a specific flaxseed lignan extract (BeneFlax, Archer Daniels Midland Co.) 300 mg or 600 mg daily for 4 months improves lower urinary tract symptom scores when compared with placebo. Additionally, the 600 mg dose was associated with improved quality of life when compared with placebo (21193).
• Breast cancer. It is unclear if oral flaxseed reduces the risk for breast cancer or the progression of breast cancer. Details: A small clinical study in females newly diagnosed with breast cancer shows that consuming a muffin containing ground flaxseed 25 grams daily for about 40 days reduces markers of tumor cell proliferation when compared with baseline, but not when compared with placebo (16765). The effect of flaxseed intake on breast cancer outcomes was not assessed. Dietary lignans, which occur in flaxseed, have been linked with a lower risk of developing breast cancer. Most large-scale population studies have found that high intake of dietary lignans and serum levels of the lignan enterolactone are associated with a reduced risk of developing breast cancer (16775,16776,16777,16779,16781,16782,16783,16785). It is unclear if flaxseed lignan, specifically, is beneficial for reducing the risk of breast cancer.
• Burning mouth syndrome. Flaxseed has only been evaluated in a mouthwash in combination with German chamomile; its effect when used alone is unclear. Details: A small clinical study in female patients with burning mouth syndrome shows that using a homemade mouthwash containing boiled whole flaxseed 10 grams and German chamomile 1 gram in 200 mL of water 3-4 times daily for 3 months decreases subjective burning and dry mouth symptoms, increases salivary flow rate, and decreases saliva viscosity when compared with baseline (104807). However, the validity of these results is limited by the lack of a control group and product standardization, as the mouthwash was prepared by each patient from ingredients they purchased.
• Cardiovascular disease (CVD). It is unclear if oral flaxseed or flaxseed lignans reduce the development or progression of CVD. Details: A small clinical study in older adults that were also given dietary advice shows that taking flaxseed 30 grams daily for 12 weeks, starting 4 weeks after percutaneous coronary intervention (PCI), more than doubles flow mediated dilation when compared with a group not taking flaxseed (101945). However, population research has found that total dietary intake of lignans, including flaxseed lignans, is not associated with a reduced risk of coronary heart disease or all-cause mortality (16787). This research did not specifically assess the effect of flaxseed intake on CVD.
• Chronic kidney disease (CKD). Although there is interest in using oral flaxseed for CKD, there is insufficient reliable information about the clinical effects of flaxseed for this condition.
• Colorectal cancer. It is unclear if oral flaxseed reduces the risk of colorectal cancer. Details: Flaxseed is one source of dietary lignans. Population research has found that serum levels of lignans are not associated with risk of developing colorectal cancer (16778). However, other population research has found that high dietary intake of lignans is associated with a reduced risk of colorectal cancer (16784), and that higher serum levels of dietary lignans are associated with a reduced risk of colorectal adenomas (16788). It is unclear if flaxseed lignan, specifically, is beneficial for reducing the risk of colorectal cancer.
• Endometrial cancer. It is unclear if oral flaxseed reduces the risk of endometrial cancer. Details: Flaxseed is one source of dietary lignans. A large-scale population study has found that serum levels of lignans are not associated with risk of developing endometrial cancer (16786).This research did not specifically assess the effect of flaxseed intake on endometrial cancer risk.
• Fatigue. It is unclear if oral ground flaxseed reduces fatigue in overweight children. Details: A small non-blinded clinical study in overweight healthy children ages 7-18 shows that consuming ground flaxseed 20 grams in divided doses with food daily for 4 weeks seems to modestly reduce mental fatigue but not physical fatigue when compared with puffed wheat 25 grams daily (105473).
• Impaired glucose tolerance (prediabetes). It is unclear if oral flaxseed is beneficial in prediabetes. Details: A small clinical study in adults with prediabetes shows that consuming milled flaxseed 20 grams or 40 grams daily for 12 weeks does not improve glycemic control, but modestly reduces systolic blood pressure, when compared with no intervention (96434).
• Irritable bowel syndrome (IBS). It is unclear if oral flaxseed improves IBS symptoms. Details: A small open-label clinical study in patients with IBS suggests that consuming whole or ground flaxseed 24 grams daily for 4 weeks does not improve quality of life, severity of IBS symptoms, or number of bowel movements when compared with no intervention (21198).
• Lung cancer. It is unclear if oral flaxseed reduces the risk of lung cancer. Details: Observational research has found that consuming a higher amount of dietary phytoestrogens, such as the lignan metabolites and precursors found in flaxseed, is associated with a lower risk of developing lung cancer when compared to those who consume smaller amounts (13190). It is unclear if flaxseed, specifically, is beneficial for reducing the risk of lung cancer.
• Menopausal symptoms. There is contradictory evidence about the effects of flaxseed for reducing menopausal symptoms. Details: Some preliminary clinical research in postmenopausal adults shows that taking either flaxseed meal 90 grams daily or a specific flaxseed extract (Biogalenica, Medicinal Compounding Pharmacy) 1000 mg daily for 6 months reduces menopausal symptoms and the frequency of hot flashes when compared to baseline (21200). Other small clinical studies in postmenopausal adults show that consuming ground flaxseed orally 40 grams daily reduces symptoms of hot flashes by about 35% and night sweats by about 44% when compared to baseline (10978,12910). However, similar reductions have been observed with placebos, such as wheat germ (12910,18224). Higher quality studies of flaxseed used in food products have yielded negative results. One clinical trial in postmenopausal adults shows that taking a specific flaxseed-containing bar (Glambia Nutritionals) providing 7 grams of flaxseed and 410 mg of lignans reduces hot flash frequency by 28% and hot flash scores by 50% when compared to baseline, but not when compared with placebo (18224). In another small clinical study, consuming muffins containing flaxseed 25 grams daily providing 50 mg lignans did not improve hot flashes or measures of quality of life when compared with placebo in a similar patient population (16762). Eating flaxseed-enriched bread providing 25 grams of flaxseed daily for 12 weeks also did not improve menopausal symptoms or reduce the frequency of hot flashes when compared to control (22176).
• Metabolic syndrome. Small studies suggest that oral flaxseed is beneficial for metabolic syndrome. Details: One small clinical study in older adults shows that taking a specific flaxseed lignan extract (BeneFlax, Archer Daniels Midland Co.) 550 mg three times daily for 6 months reduces metabolic syndrome risk scores when compared with placebo in males, but not females (21197). Another small open-label clinical trial in patients with metabolic syndrome suggests that taking flaxseed powder 30 grams daily for 12 weeks modestly reduces the number of people meeting the criteria for metabolic syndrome when compared with no supplementation (105276). However, food containing flaxseed does not seem to be as beneficial. Some clinical research in Asian Americans with metabolic syndrome shows that eating bread containing flaxseed 30 grams daily plus lifestyle counseling for 12 weeks does not improve markers of metabolic syndrome when compared with lifestyle counseling alone (21199).
• Nonalcoholic fatty liver disease (NAFLD). Small clinical studies suggest that oral flaxseed may modestly reduce markers of liver disease progression in patients with NAFLD. Details: A small clinical pilot study in adults with NAFLD shows that taking brown milled flaxseed 30 grams daily for 12 weeks along with lifestyle modification reduces fibrosis by 21% and steatosis by about 15.3%, compared with reductions of 9.7% and 5.5%, respectively, in those following lifestyle modifications alone (96249). A larger follow-up clinical study in patients with NAFLD shows that taking brown milled flaxseed 30 grams daily for 12 weeks in addition to lifestyle modification reduces steatosis by about 28%, compared with a 16% reduction in the lifestyle modification group (105275).
• Osteoarthritis. It is unclear if topical flaxseed is beneficial in patients with osteoarthritis. Details: A small clinical study in patients with hand osteoarthritis who are using routine treatments shows that using a flaxseed poultice compress once daily for 7 days improves pain by 63% and hand function by 66% when compared with a hot compress or no compress in combination with routine treatments. Some of the benefit was maintained for at least a week following treatment (101946).
• Peripheral arterial disease (PAD). It is unclear if oral flaxseed is beneficial in patients with PAD. Details: Clinical research in patients with PAD shows that taking milled flaxseed 30 grams daily mixed with a variety of foods for one year does not reduce the incidence of cardiac arrhythmias or improve the distance walked until claudication when compared with placebo (101942). This study may have been inadequately powered to detect differences between groups.
• Pharyngitis. Although there is interest in using oral flaxseed for pharyngitis, there is insufficient reliable information about the clinical effects of flaxseed for this purpose.
• Polycystic ovary syndrome (PCOS). It is unclear if oral flaxseed is beneficial in patients with PCOS. Details: A small open-label clinical study in patients with PCOS shows that taking flaxseed 30 grams daily for 12 weeks in conjunction with receiving lifestyle modification advice reduces triglyceride and insulin levels and improves insulin resistance when compared with lifestyle modification advice alone. About 69% of those in the treatment group who had irregular menstrual cycles at baseline had a regular cycle at the end of treatment, compared with no significant improvement in the control group. Flaxseed did not affect body weight, low-density lipoprotein (LDL) cholesterol, or blood glucose when compared with control (101943).
• Prostate cancer. Small clinical studies suggest that oral flaxseed may modestly improve biomarkers of prostate cancer. Details: A very small clinical trial in patients with prostatic intraepithelial neoplasia (PIN), a precancerous proliferation of prostatic epithelial cells, shows that adding ground flaxseed (Alena, Enreco) 30 grams daily to a fat-restricted diet for 6 months lowers prostate specific antigen (PSA) levels and slows prostate epithelium proliferation when compared with baseline (12908). This finding is limited by the lack of a placebo group. A clinical study in patients with prostate cancer awaiting prostatectomy shows that taking ground flaxseed (Alena, Enreco) 30 grams daily with or without a fat-restricted diet for about 30 days reduces tissue proliferation rate, but does not reduce PSA, when compared with control (16761).
• Radiation-induced pneumonitis. It is unclear if oral flaxseed is beneficial for preventing radiation-induced pneumonitis in patients with non-small cell lung cancer (NSCLC). Details: A very small, clinical trial in adults with locally advanced or metastatic NSCLC currently undergoing chemoradiation therapy shows that taking ground flaxseed (Golden Valley Flax; Hylden Farms) 40 grams daily, starting one week prior to radiotherapy and continuing until completion of treatment, may reduce the risk of radiation-induced pneumonitis when compared with baseline, with only 1 patient (5%) developing a grade ≥3 event and no cases of grade 2 events (108042). The validity of these findings is limited by the lack of a comparator group and a low adherence rate due to tolerability issues.
• Rheumatoid arthritis (RA). It is unclear if oral flaxseed is beneficial in patents with RA. Details: A clinical study in adults with RA shows that following either a regular or anti-inflammatory diet supplemented with oral flaxseed 30 grams daily for 12 weeks improves disease activity score 28-joint (DAS28-ESR), as well as pain and quality of life outcomes, such as emotional well-being and vitality, when compared with baseline (108048). The validity of these findings is limited by the lack of a comparator group.
• Ulcerative colitis. It is unclear if oral flaxseed is beneficial in patients with ulcerative colitis. Details: A small open-label clinical study in patients with ulcerative colitis shows that taking ground flaxseed 30 grams daily for 12 weeks seems to modestly reduce inflammatory markers and disease severity and improve quality of life when compared with control (101941). A nonblinded, clinical study in adults with mild to moderate ulcerative colitis shows that taking brown milled flaxseed 15 grams twice daily for 12 weeks improves disease severity scores when compared with placebo (108045). The validity of these findings is limited by the lack of blinding and short duration of treatment. More evidence is needed to rate flaxseed for these uses.

(Read more about FLAXSEED)

POSSIBLY INEFFECTIVE

• Athletic performance. Oral quercetin does not seem to improve athletic performance. Details: A pooled analysis of data from seven clinical trials shows that intake of quercetin does not improve maximal oxygen consumption or capacity to perform prolonged exercise in trained or untrained athletes when compared with placebo (91577). Additionally, one small clinical study in male soldiers shows that taking quercetin 500 mg twice daily for 8.5 days before a loaded treadmill marching test and a cycling time trial test does not affect ratings of perceived exertion, cycling time, or peak oxygen consumption during treadmill testing when compared with placebo (91578).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral quercetin is beneficial in older adults with age-related cognitive decline. Details: Preliminary research in healthy adults aged 60 to 80 years with age-related forgetfulness shows that drinking 500 mL of a barley-based beverage containing 110 mg quercetin glycoside calculated as isoquercitrin, daily for 40 weeks seems to improve reaction times when compared with placebo. However, increase in score on the mini-mental state examination (MMSE), reduction in accumulation of amyloid beta in the brain, and prevention of reduction in cerebral blood flow occur to a similar extent with quercetin and placebo (110008).
• Allergic rhinitis (hay fever). It is unclear if oral quercetin is beneficial in patients with allergic rhinitis. Details: A small clinical study in Japanese adults with allergic rhinitis shows that taking a specific quercetin product (Quercetin Phytosome, Indena SpA) 100 mg twice daily for 4 weeks does not improve scores related to quality of life, activities of daily living, nasal symptoms, or ocular symptoms on the Japanese Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ). However, scores related to fatigue and sleep quality improved when compared with placebo. Additionally, sneezing, rhinorrhea, and activities of daily living scores improved when another scale was used to assess the severity of allergic rhinitis (109620). Quercetin has also been evaluated in combination with other ingredients. A small clinical study in children aged 6-12 years with allergic rhinitis who had gone through a treatment phase with antihistamines and a specific combination of quercetin, perilla, and vitamin D3 (Lertal) 1 tablet daily for 4 weeks shows that taking this specific combination for an additional 4-12 weeks reduces the chance of having symptom exacerbations by approximately 50% when compared with no further treatment past the first 4 weeks. The number of days requiring rescue medication was also reduced from 28.5 days to an average of 9.6 days (104676).
• Alzheimer disease. Although there has been interest in using oral quercetin for Alzheimer disease, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Asthma. It is unclear if oral quercetin is beneficial in patients with asthma. Details: Preliminary clinical research in patients with mild-to-moderate asthma shows that taking a specific quercetin product (QFit, Indena SpA) 250 mg or 500 mg daily for 30 days along with conventional therapy reduces daytime and nighttime asthma symptoms, improves spirometry measures, and decreases the use of rescue inhalers when compared to baseline. Significant improvements in these outcomes were lacking in patients receiving conventional therapy alone (102540).
• Atherosclerosis. Although there has been interest in using oral quercetin for atherosclerosis, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Autism spectrum disorder. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children aged 4-10 years with autism shows that taking a combination of luteolin 10 mg/kg, quercetin 7 mg/kg, and rutin 3 mg/kg in olive oil for 26 weeks improves hyperactivity, irritability, and lethargy by a moderate to large amount, and improves some indices of functioning, such as daily living and social behavior, by a small amount when compared with baseline. The validity of these findings is limited by the lack of a comparator group (96765).
• Benign prostatic hyperplasia (BPH). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking one tablet of a specific combination product (Difaprost) containing quercetin, beta-sitosterol, and saw palmetto daily for 3 months does not improve general symptoms of BPH when compared to baseline (96784). The validity of these findings is limited by the lack of a comparator group.
• Beta-thalassemia. It is unclear if oral quercetin is beneficial in patients with beta-thalassemia. Details: Preliminary clinical research in transfusion-dependent patients with beta-thalassemia shows that taking quercetin 500 mg daily for 12 weeks reduces iron and ferritin levels, increases transferrin levels, and decreases transferrin saturation when compared with placebo. However, total iron binding capacity was not improved. These results suggest that quercetin might reduce iron overload, which is a complication of frequent blood transfusions in these patients (102541).
• Cancer. Although there has been interest in using intravenous or intraperitoneal quercetin for cancer, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Canker sores. Topical quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a cream containing quercetin, glycol, zinc, and Myristica (Rootage skin cream, Elsi-Si) three times daily results in complete healing of minor canker sores and reduces pain in 100% of patients within 7-10 days, compared with only 60% of patients using a benzydamine hydrochloride mouthwash three times daily (104677).
• Cardiovascular disease (CVD). It is unclear if oral quercetin is beneficial for CVD prevention. Details: Population research has found that increasing dietary intake of quercetin from food sources such as tea, onions, and apples is associated with a significantly reduced risk of heart disease-related mortality in elderly males (7726). However, preliminary clinical research shows that quercetin 1 gram daily for 28 days does not significantly improve platelet aggregation, thromboxane B2 production, blood pressure, heart rate, or serum lipid levels when compared with placebo in healthy people (1998).
• Cataracts. Although there has been interest in using oral quercetin for cataracts, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Chemotherapy-induced cystitis. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with bladder cancer undergoing intravesical chemotherapy shows that taking a specific combination product (Ialuril, IBSA Farmaceutici) containing quercetin 400 mg, hyaluronic acid 40 mg, chondroitin sulfate 400 mg, and curcumin 400 mg every morning, starting 7 days before the first instillation and ending 30 days after the last instillation, improves lower urinary tract symptoms as measured using a visual analog scale and the International Prostate Symptom Score (IPSS) at 13 months when compared with placebo (109622).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral quercetin for CFS, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Chronic venous insufficiency (CVI). Although there has been interest in using oral quercetin for CVI, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Colorectal cancer. Although there has been interest in using oral quercetin for colorectal cancer prevention, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Contrast induced nephropathy. It is unclear if oral quercetin is beneficial for the prevention of contrast induced nephropathy. Details: Preliminary clinical research in patients undergoing coronary catheterization shows that taking quercetin 500 mg every 8 hours, starting two days prior to contrast imaging and continuing for two days after, does not appear to prevent contrast induced nephropathy when compared with a control group not receiving quercetin (102539). Given its small size, this study may have been inadequately powered to detect significant differences for this outcome.
• Coronavirus disease 2019 (COVID-19). Analysis of several small, open-label clinical studies suggest that oral quercetin may modestly reduce hospitalizations and intensive care unit (ICU) admissions in patients with COVID-19. Whether quercetin is beneficial in patients with severe COVID-19 is unclear. Details: A meta-analysis of 6 open-label clinical studies in patients with COVID-19 shows that taking quercetin 260-1000 mg daily for 7-30 days along with standard therapy with analgesics, antipyretics, antibiotics, remdesivir, or favipiravir reduces the odds of intensive care unit (ICU) admission by 69% and the odds of hospitalization by 75% but does not decrease the rate of all-cause mortality or the rate of recovery upon follow-up when compared with standard care (111412). However, the interpretation of these findings is limited by differences in the severity of COVID-19, doses and durations of quercetin therapy, and standard of care regimens used across the included studies. In outpatients in the early stages of COVID-19, two small, open-label clinical studies included in the meta-analysis above show that taking quercetin 200 mg two or three times daily for 14-30 days along with standard care reduces time to symptom resolution when compared with standard care alone. However, these studies show mixed results with respect to prevention of hospitalization, ICU admission, and death (106498,106499). More recent research in patients with early-stage, mild to moderate COVID-19 symptoms shows that taking quercetin 500 mg three times daily for 1 week, followed by 500 mg twice daily for 1 week, increases the rate of symptom resolution and achieving a negative COVID-19 test at 1 week by 116% and 183%, respectively, when compared with placebo (110009). Quercetin has also been evaluated in patients with severe COVID-19. A small, open-label clinical study of patients with severe COVID-19 who have not been admitted to the ICU shows that taking quercetin 500 mg twice daily for 7 days along with remdesivir or favipiravir shortens the time to discharge by around 1.5 days and improves symptoms of weakness and lethargy, but does not improve other symptoms of COVID-19 or reduce the risk of ICU admission or death, when compared with remdesivir or favipiravir alone (107450).
• Depression. It is unclear if oral quercetin is beneficial for depression in patients with a recent myocardial infarction (MI). Details: A moderate-sized clinical study in adults 6-8 weeks post-MI conducted in Iran shows that taking quercetin 500 mg daily for 8 weeks does not improve self-reported depression scores when compared with placebo (112228). However, the severity of patients' depression was minimal at baseline, which limits the power to detect a difference between groups.
• Diabetes. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with type 2 diabetes who are not using hypoglycemic agents shows that taking a specific combination of quercetin, myricetin, and chlorogenic acid (Emulin, Anderson Global Group LLC) 250 mg daily for 7 days reduces levels of fasting and postprandial glucose by about 5% when compared to baseline. These changes were significantly different than the slight increases seen in the placebo group. In patients taking metformin along with the combination supplement, fasting blood glucose levels decreased by about 20%, compared with a decrease of less than 1% with metformin alone (96779).
• Exercise-induced muscle damage. It is unclear if oral quercetin is beneficial for preventing muscle damage associated with exercise. Details: Some clinical research shows that taking quercetin 500 mg twice daily for 3 weeks prior to and during an endurance run or cycling event does not attenuate exercise-induced muscle damage, soreness, or inflammation (16429,16431). However, a series of two small clinical trials show that taking quercetin 1000 mg daily for 14 days prior to eccentric exercise modestly attenuates the decline in the maximal intensity of a contraction when compared with placebo (99236,104226). Additionally, this dosing regimen appears to modestly accelerate the recovery of muscle strength and neuromuscular function after exercise when compared with placebo (104226).
• Exercise-induced respiratory infections. It is unclear if oral quercetin is beneficial for prevention of respiratory infections induced by exercise. Details: Preliminary clinical research shows that taking quercetin 500 mg twice daily for 3 weeks before, and continuing during 3 days of prolonged, intense cycling, reduces the incidence of upper respiratory infections in the 14 days following the heavy exercise (16430).
• Gout. Although there has been interest in using oral quercetin for gout, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Herpes labialis (cold sores). Although there has been interest in using oral quercetin for herpes labialis, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Hypercholesterolemia. It is unclear if oral quercetin is beneficial for improving cholesterol levels. Details: Multiple meta-analyses show that taking quercetin does not affect total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides (TG) when compared with placebo (96783,104229). However, a subgroup analysis shows that taking quercetin for at least 8 weeks seems to reduce TG levels by 13 mg/dL and increase HDL levels by 3 mg/dL, compared with no change in patients who took quercetin for less than 8 weeks (104229). It is unclear these patients had elevated cholesterol levels at baseline.
• Hypertension. It is unclear if oral quercetin is beneficial for reducing blood pressure. Details: Three meta-analyses show that taking quercetin 100-1000 mg daily for 4-12 weeks decreases systolic and diastolic blood pressure by 2-4 mmHg and 2-3 mmHg, respectively, when compared with placebo. However, only two of the studies included in these analyses evaluated patients with hypertension (16424,96775,104229,109617). Additional clinical research in patients with mild hypertension shows that taking a single dose of quercetin 1095 mg can lower systolic and diastolic blood pressure by 7 mmHg and 3 mmHg, respectively, when measured 10 hours later (96780). Overall, the benefit of quercetin on blood pressure seems modest; it is unclear whether the improvement is clinically significant for patients with hypertension.
• Kidney transplant. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific product containing a combination of quercetin 20 mg and curcumin 480 mg (Oxy-Q, Farr Labs) taken once or twice daily in combination with anti-rejection medications, starting within 24 hours of a kidney transplant and continuing for one month, improves early function of the graft and reduces serum creatinine when compared with taking placebo in combination with anti-rejection medications (16420).
• Lung cancer. It is unclear if oral quercetin is beneficial in lung cancer prevention. Details: Epidemiologic research has found that increasing dietary intake of quercetin is associated with a reduced risk of lung cancer in smokers (96778).
• Metabolic syndrome. It is unclear if oral quercetin is beneficial in patients with metabolic syndrome. Details: A meta-analysis of small clinical studies shows that taking quercetin 100-1000 mg daily for 4-12 weeks does not improve fasting blood glucose, glycated hemoglobin, or insulin levels when compared with placebo in patients with risk factors for metabolic syndrome, such as type 2 diabetes, prehypertension, polycystic ovary syndrome, and/or obesity (100967). Additional research is needed to determine if quercetin is beneficial in patients with existing metabolic syndrome.
• Niacin-induced flushing. Although there has been interest in using oral quercetin for niacin-induced flushing, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Obesity. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking quercetin 500 or 1000 mg daily for 12 weeks, in addition to niacin 5 mg or 10 mg and vitamin C 125 mg or 250 mg, does not reduce body weight or fat mass when compared with placebo in adults considered overweight or obese based on body mass index (BMI) (104678).
• Oral mucositis. It is unclear if oral quercetin is beneficial in patients with oral mucositis. Details: One small clinical study shows that taking quercetin 250 mg twice daily for 4 weeks does not prevent oral mucositis associated with chemotherapy when compared with placebo (96776).
• Ovarian cancer. It is unclear if oral quercetin is beneficial for ovarian cancer prevention. Details: One epidemiologic study found no association between dietary intake of quercetin and related flavonols and the risk of ovarian cancer (16428).
• Pancreatic cancer. It is unclear if oral quercetin is beneficial for pancreatic cancer prevention. Details: Epidemiologic studies have found that a high dietary intake of quercetin and related flavonols might reduce the risk of pancreatic cancer, especially in male smokers (16426,16427).
• Peptic ulcers. Although there has been interest in using oral quercetin for peptic ulcers, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Physical performance. It is unclear if oral quercetin is effective for improving physical performance in older adults. Details: A small clinical study in Japanese individuals 50-74 years of age shows that taking quercetin glycosides 200 mg or 500 mg daily along with low-intensity resistance training 3 days weekly for 24 weeks does not improve muscle size or lean body mass, but may reduce muscle stiffness, when compared with placebo (109621).
• Polycystic ovary syndrome (PCOS). It is unclear if oral quercetin is beneficial for improving hormone levels or pregnancy rates in patients with PCOS. Details: Clinical research in patients with PCOS shows that taking quercetin 1000 mg daily for 12 weeks reduces testosterone and luteinizing hormone (LH) levels by 9% and 3%, respectively, when compared to baseline; both of these improvements were significant when compared with placebo. Insulin resistance also improved by 18% when compared to baseline, which was significant when compared with placebo (96782). In a similar group of patients with higher levels of insulin resistance at baseline, taking the same dose of quercetin modestly reduced testosterone and LH levels when compared with placebo; however, there was no improvement in insulin resistance (99237). These disparate outcomes might be due to different baseline levels of insulin resistance. Also, it is unclear if these changes are associated with an improvement in the clinical symptoms of PCOS. Quercetin has also been evaluated for improving pregnancy rates in adults with PCOS and infertility. A small clinical study shows that taking quercetin 500 mg daily for 40 days increases pregnancy rates when compared with placebo. Quercetin supplementation also improves the grading of oocytes, but not the quality of embryos, in those undergoing in vitro fertilization (IVF). Nearly 84% of patients taking quercetin became pregnant spontaneously or via IVF in the 6 months following initiation of quercetin supplementation. Only 11% of patients taking placebo became pregnant during the study, all through IVF (109618). Due to a short duration of follow-up, it is unclear whether quercetin improves live birth rates.
• Prostatitis. It is unclear if oral quercetin is beneficial in patients with prostatitis. Details: Preliminary clinical research shows that taking quercetin 500 mg twice daily for one month reduces pain and improves quality of life, but does not seem to affect voiding dysfunction, in patients with chronic, nonbacterial prostatitis when compared with placebo (481).
• Rheumatoid arthritis (RA). It is unclear if oral quercetin is beneficial in patients with RA. Details: In patients with RA, clinical research shows that taking quercetin 500 mg daily for 8 weeks improves morning stiffness, morning pain, and after-activity pain when compared with placebo. However, taking quercetin does not seem to improve the number of swollen or tender joints or the disease activity score when compared with placebo (96774).
• Schizophrenia. Although there has been interest in using oral quercetin for schizophrenia, there is insufficient reliable information about the clinical effects of quercetin for this condition.
• Upper respiratory tract infection (URTI). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking quercetin 500 mg or 1000 mg daily for 12 weeks, in combination with vitamin C 500 mg or 1000 mg daily or niacin 20 mg or 40 mg daily, does not reduce the frequency or severity of URTIs. However, in a subgroup analysis of physically fit individuals 40 years and older, the severity of URTIs and the number of sick days related to URTIs were reduced by 36% and 31%, respectively, when quercetin 1000 mg was compared with placebo (104679).
• Urethral syndrome. Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking one tablet daily of a specific formulation containing quercetin, bromelain, chondroitin sulfate, gotu kola, rhodiola, and barbed skullcap (Cistiquer, Deakos) for 7 weeks reduces urinary urgency by 91% when compared with baseline. Also, 55% of patients reported no discomfort associated with urination. This combination product was reported to be at least as effective as intravesical administration of betamethasone 8 mg plus gentamicin 80 mg twice weekly (96777).
• Urinary tract infections (UTIs). Oral quercetin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking 1-2 capsules of a combination of hyaluronic acid, chondroitin sulfate, curcumin, and quercetin daily for 15 days each month, in combination with the use of local topical estrogen therapy (0.005% estriol vaginal gel) for up to 12 months, increases the number of women cured of recurrent UTIs to 66%, compared with only 34% of those taking the oral combination product or the vaginal estrogen product alone (96781). More evidence is needed to rate quercetin for these uses.

(Read more about QUERCETIN)

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 ground flaxseed is used orally and appropriately. Ground flaxseed has been safely used in numerous clinical trials in doses up to 30-60 grams daily for up to 1 year (6803,6808,8020,10952,10978,12908,12910) (16760,16761,16762,16765,16766,18224,21191,21194,21196,21198) (21199,21200,22176,22179,22180,22181,65866,66065) (101943,101949,101950).

POSSIBLY SAFE ...when flaxseed lignan extract or mucilage is used orally and appropriately. Some clinical research shows that a specific flaxseed lignan extract (Flax Essence, Jarrow Formulas) 600 mg daily can be used with apparent safety for up to 12 weeks (16768). Additional clinical research shows that other flaxseed lignin extracts can be used with apparent safety for up to 6 months (21193,21197,21200). In one clinical trial, flaxseed mucilage was used with apparent safety at a dose of up to 5120 mg daily for up to 12 weeks (108047)....when flaxseed is used topically in a warm poultice (101946).

POSSIBLY UNSAFE ...when raw or unripe flaxseed is used orally. Raw flaxseed contains potentially toxic cyanogenic glycosides (linustatin, neolinustatin, and linamarin); however, these glycosides have not been detected after flaxseed is baked (5899). Unripe flaxseeds are also thought to be poisonous when consumed due to cyanide content.

PREGNANCY: POSSIBLY UNSAFE
when used orally. Flaxseed can have mild estrogenic effects. Theoretically, this might adversely affect pregnancy (9592,12907); however, there is no reliable clinical evidence about the effects of flaxseed on pregnancy outcomes.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about FLAXSEED)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Quercetin has been used with apparent safety in doses up to 1 gram daily for up to 12 weeks (481,1998,1999,16418,16429,16430,16431,96774,96775,96782)(99237,102539,102540,102541,104229,104679,106498,106499,107450,109620)(109621). ...when used intravenously and appropriately. Quercetin has been used with apparent safety in doses less than 945 mg/m2. Higher doses have been reported to cause nephrotoxicity (9564,16418). There is insufficient reliable information available about the safety of quercetin when used topically.

POSSIBLY UNSAFE ...when used intravenously in large amounts. Doses greater than 945 mg/m2 have been reported to cause nephrotoxicity (9564,16418).

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

(Read more about QUERCETIN)

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.

(Read more about DIINDOLYLMETHANE)

ANTIBIOTIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, antibiotics might interfere with the metabolism of flaxseed constituents, which could potentially alter the effects of flaxseed.  Details Some potential benefits of flaxseed are thought to be due to its lignan content. Secoisolariciresinol diglucoside (SDG), a major lignan precursor, is found in high concentrations in flaxseed. SDG is converted by bacteria in the colon to the lignans enterolactone and enterodiol (5897,8022,8023,9592). Antibiotics alter the flora of the colon, which could theoretically alter the metabolism of flaxseed.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, using flaxseed in combination with anticoagulant or antiplatelet drugs might have additive effects and increase the risk of bleeding.  Details Some clinical evidence suggests that the oil contained in flaxseed can decrease platelet aggregation (5898,21912).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, flaxseed might have additive effects when used with antidiabetes drugs and increase the risk for hypoglycemia.  Details Some clinical research suggests that flaxseed can lower blood glucose levels (5899,10978,21194,21196,111061).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, flaxseed might have additive effects when used with antihypertensive drugs and increase the risk of hypotension.  Details Clinical research shows that daily flaxseed consumption, especially for longer than 12 weeks, modestly reduces blood pressure (21197,26487,96426,96428,111063).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking flaxseed might decrease the effects of estrogens.  Details Flaxseed contains lignans with mild estrogenic and possible antiestrogenic effects. The lignans seem to compete with circulating endogenous estrogen and might reduce estrogen binding to estrogen receptors, resulting in an anti-estrogen effect (8868,9593). It is unclear if this effect transfers to exogenously administered estrogens.

(Read more about FLAXSEED)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of quercetin and antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research suggests that a combination of quercetin, myricetin, and chlorogenic acid reduce levels of fasting glucose in patients with type 2 diabetes, including those already taking antidiabetes agents (96779). The effect of quercetin alone is unknown.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking quercetin with antihypertensive drugs might increase the risk of hypotension.  Details Quercetin can modestly decrease blood pressure in people with mild hypertension (16424,96780). Theoretically, it might have additive blood pressure lowering effects when used with antihypertensive drugs.

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of cyclosporine.  Details A small study in healthy volunteers shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of a single dose of cyclosporine, possibly due to inhibition of p-glycoprotein or cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporin (16434).

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of CYP2C8 substrates.  Details In vitro research shows that quercetin inhibits CYP2C8 (16432,16435). Inhibition of paclitaxel (Taxol) metabolism via CYP2C8 has been reported in vitro (16436). However, a small study in humans found no effect of quercetin on rosiglitazone (Avandia), which is also a CYP2C8 substrate (16432).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of CYP2C9 substrates.  Details A small clinical study in healthy volunteers shows that taking quercetin 500 mg twice daily for 10 days prior to taking diclofenac, a CYP2C9 substrate, increases diclofenac plasma levels by 75% and prolongs the half-life by 32.5% (97931). Animal research also shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar), a substrate of CYP2C9 (100968). Furthermore, laboratory research shows that quercetin inhibits CYP2C9 (15549,16433).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of CYP2D6 substrates.  Details In vitro research show that quercetin inhibits CYP2D6 (15549,16433). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might alter the effects and adverse effects of CYP3A4 substrates.  Details A small clinical study in healthy volunteers shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of a single dose of cyclosporine (Neoral, Sandimmune), a substrate of CYP3A4 (16434). Animal research also shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar) and quetiapine (Seroquel), substrates of CYP3A4 (100968,104228). Other laboratory research also shows that quercetin inhibits CYP3A4 (15549,16433,16435). However, one clinical study shows that quercetin can increase the metabolism of midazolam, a substrate of CYP3A4, and decrease serum concentrations of midazolam by about 24% in some healthy individuals, suggesting possible induction of CYP3A4 (91573).

DICLOFENAC (Voltaren, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, concomitant use might increase the levels and adverse effects of diclofenac.  Details A small clinical study in healthy volunteers shows that taking quercetin 500 mg twice daily for 10 days prior to taking diclofenac increases diclofenac plasma levels by 75% and prolongs the half-life by 32.5%. This is thought to be due to inhibition of CYP2C9 by quercetin (97931).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of losartan and decrease the effects of its active metabolite.  Details Animal research shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of losartan (Cozaar) while decreasing plasma levels of losartan's active metabolite. This metabolite, which is around 10-fold more potent than losartan, is the result of cytochrome P450 (CYP) 2C9- and CYP3A4-mediated transformation of losartan. Additionally, in vitro research shows that quercetin may inhibit P-glycoprotein-mediated efflux of losartan from the intestines, resulting in increased absorption of losartan (100968). These results suggest that concomitant use of quercetin and losartan might increase systemic exposure to losartan while also decreasing plasma concentrations of losartan's active and more potent metabolite.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might decrease the levels and effects of midazolam.  Details A small clinical study in healthy volunteers shows that quercetin can increase the metabolism of midazolam, with a decrease in AUC of about 24% (91573).

MITOXANTRONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of mitoxantrone.  Details In vitro research shows that quercetin increases the intracellular accumulation and cytotoxicity of mitoxantrone, possibly through inhibition of breast cancer resistance protein (BCRP), of which mitoxantrone is a substrate (107897). So far, this interaction has not been reported in humans.

ORGANIC ANION TRANSPORTER 1 (OAT1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of OAT1 substrates.  Details In vitro research shows that quercetin is a strong non-competitive inhibitor of OAT1, with half-maximal inhibitory concentration (IC50) values less than 10 mcM (104454). So far, this interaction has not been reported in humans.

ORGANIC ANION TRANSPORTER 3 (OAT3) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of OAT3 substrates.  Details In vitro research shows that quercetin is a strong non-competitive inhibitor of OAT3, with half-maximal inhibitory concentration (IC50) values as low as 0.75 mcM (104453,104454). So far, this interaction has not been reported in humans.

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of OATP substrates.  Details In vitro evidence shows that quercetin can inhibit organic anion-transporting peptide (OATP) 1B1-mediated uptake of estrone-3-sulfate and pravastatin (91581). Furthermore, clinical research in healthy males shows that intake of quercetin along with pravastatin increases the AUC of pravastatin by 24%, prolongs its half-life by 14%, and decreases its apparent clearance by 18%, suggesting that quercetin modestly inhibits the uptake of pravastatin in hepatic cells (91581).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might alter the effects and adverse effects of P-glycoprotein substrates.  Details There is preliminary evidence that quercetin inhibits the gastrointestinal P-glycoprotein efflux pump, which might increase the bioavailability and serum levels of drugs transported by the pump (16433,16434,16435,100968,104228). A small study in healthy volunteers reported that pretreatment with quercetin increased bioavailability and plasma levels after a single dose of cyclosporine (Neoral, Sandimmune) (16434). Also, two small studies have shown that quercetin might decrease the absorption of talinolol, a substrate transported by the gastrointestinal P-glycoprotein efflux pump (91579,91580). However, in another small study, several days of quercetin treatment did not significantly affect the pharmacokinetics of saquinavir (Invirase) (16433). The reason for these discrepancies is not entirely clear (91580). Until more is known, use quercetin cautiously in combination with P-glycoprotein substrates.

PRAVASTATIN (Pravachol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might increase the effects and adverse effects of pravastatin.  Details In vitro evidence shows that quercetin can inhibit OATP 1B1-mediated uptake of pravastatin (91581). Also, preliminary clinical research in healthy males shows that intake of quercetin along with pravastatin increases the maximum concentration of pravastatin by 24%, prolongs its half-life by 14%, and decreases its apparent clearance by 18%, suggesting that quercetin modestly inhibits the uptake of pravastatin in hepatic cells (91581).

PRAZOSIN (Minipress) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of prazosin.  Details In vitro research shows that quercetin inhibits the transcellular efflux of prazosin, possibly through inhibition of breast cancer resistance protein (BCRP), of which prazosin is a substrate. BCRP is an ATP-binding cassette efflux transporter in the intestines, kidneys, and liver (107897). So far, this interaction has not been reported in humans.

QUETIAPINE (Seroquel) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the effects and adverse effects of quetiapine.  Details Animal research shows that pretreatment with quercetin can increase plasma levels of quetiapine and prolong its clearance, possibly due to inhibition of cytochrome P450 3A4 (CYP3A4) by quercetin. Additionally, the brain-to-plasma ratio of quetiapine concentrations increased, possibly due to inhibition of P-glycoprotein at the blood-brain barrier (104228). This interaction has not been reported in humans.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use might inhibit the effects of quinolone antibiotics.  Details In vitro, quercetin binds to the DNA gyrase site on bacteria (481), which may interfere with the activity of quinolone antibiotics.

SULFASALAZINE (Azulfidine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin might increase the effects and adverse effects of sulfasalazine.  Details Animal research shows that quercetin increases the maximum serum concentration (Cmax) and area under the curve (AUC) of sulfasalazine, possibly through inhibition of breast cancer resistance protein (BCRP), of which sulfasalazine is a substrate (107897). So far, this interaction has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, quercetin may increase the risk of bleeding if used with warfarin.  Details Animal and in vitro studies show that quercetin might increase serum levels of warfarin (17213,109619). Quercetin and warfarin have the same human serum albumin (HSA) binding site, and in vitro research shows that quercetin has stronger affinity for the HSA binding site and can theoretically displace warfarin, causing higher serum levels of warfarin (17213). Animal research shows that taking quercetin for 2 weeks before initiating warfarin increases the maximum serum level of warfarin by 30%, the half-life by 10%, and the overall exposure by 63% when compared with control. Concomitant administration of quercetin and warfarin, without quercetin pre-treatment, also increased these measures, but to a lesser degree. Researchers theorize that inhibition of CYP3A4 by quercetin may explain these effects (109619). So far, 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, flaxseed is usually well-tolerated.
Most Common Adverse Effects:
Orally: Bloating, diarrhea, gastrointestinal complaints.
Serious Adverse Effects (Rare):
Orally: Severe allergic reactions such as and anaphylaxis.

Gastrointestinal ...Integrating flaxseed in the diet can cause digestive symptoms similar to other sources of dietary fiber including bloating, fullness, flatulence, abdominal pain, diarrhea, constipation, dyspepsia, and nausea (12910,16761,16765,21198,21200,22176,22179,65866,101943). Higher doses are likely to cause more gastrointestinal side effects. Flaxseed can significantly increase the number of bowel movements and the risk for diarrhea (6803,8021,16765). Doses greater than 45 grams per day may not be tolerated for this reason (6802). Metallic aftertaste and bowel habit deterioration have also been reported in a clinical trial (21198).
There is some concern that taking large amounts of flaxseed could result in bowel obstruction due to the bulk forming laxative effects of flaxseed. Bowel obstruction occurred in one patient in a clinical trial (65866). However, this is not likely to occur if flaxseed is consumed with an adequate amount of fluids.

Immunologic ...Occasionally, allergic and anaphylactic reactions have been reported after ingestion of flaxseed (16761). Handling and processing flaxseed products might increase the risk of developing a positive antigen test to flaxseed and hypersensitivity (6809,12911,26471,26482).

Oncologic ...Flaxseed contains alpha-linolenic acid (ALA). High dietary intake of ALA has been associated with increased risk for prostate cancer (1337,2558,7823,7147,12978). However, ALA from plant sources, such as flaxseed, does not seem to increase this risk (12909).

Other ...Orally, partially defatted flaxseed, which is flaxseed with less alpha-linolenic acid, might increase triglyceride levels (6808). Raw or unripe flaxseed contains potentially toxic cyanogenic glycosides (linustatin, neolinustatin, and linamarin). These chemicals can increase blood levels and urinary excretion of thiocyanate in humans. However, these glycosides have not been detected after flaxseed is baked (5899).

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General ...Orally and intravenously, quercetin seems to be well tolerated in appropriate doses. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

Gastrointestinal ...Intravenous administration of quercetin is associated with nausea and vomiting (9564).

Neurologic/CNS ...Orally, quercetin may cause headache and tingling of the extremities (481,111500). Intravenously, quercetin may cause pain at the injection site. Injection pain can be minimized by premedicating patients with 10 mg of morphine and administering amounts greater than 945 mg/m² over 5 minutes (9564). In addition, intravenous administration of quercetin is associated with flushing and sweating (9564).

Pulmonary/Respiratory ...Intravenous administration of quercetin at doses as high as 2000 mg/m² is associated with dyspnea that may persist for up to 5 minutes (9564).

Renal ...Intravenously, nephrotoxicity has been reported with quercetin in amounts greater than 945 mg/m² (9563,9564,70304).

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