Quercetin Bioflavonoids [Discontinued] by Allergy Research Group

POSSIBLY INEFFECTIVE

• Hypercholesterolemia. Oral hesperidin does not seem to reduce cholesterol levels. Details: Clinical studies and a meta-analysis of the available clinical research show that taking hesperidin 400-800 mg daily for 4-12 weeks does not affect total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels when compared with placebo in healthy and obese individuals with or without mild hypercholesterolemia (94539,102315). However, some preliminary clinical research shows that taking glucosyl hesperidin, a soluble hesperidin derivative, 500 mg daily for 24 weeks modestly lowers serum levels of triglycerides and LDL cholesterol when compared with baseline in patients with both hypercholesterolemia and hypertriglyceridemia, but not in those without hypertriglyceridemia (54800). The validity of this finding is limited by the lack of a comparator group.
• Obesity. Oral hesperidin does not seem to be beneficial for weight loss. Details: A meta-analysis of two clinical trials shows that taking hesperidin for 6-12 weeks does not affect body weight or body mass index (BMI) when compared with placebo, although it may modestly improve waist circumference (105280,105281). The studies included in this analysis were short-term and were not designed to evaluate weight as a primary endpoint. Other clinical research conducted in Japan shows that taking glucosyl hesperidin, a soluble hesperidin derivative, 470 mg orally daily for 12 weeks does not reduce body weight, total fat area, or subcutaneous fat area when compared to baseline in modestly overweight patients (94544). Hesperidin has also been evaluated in combination with green tea extract. One clinical study in overweight individuals shows that taking a combination of glucosyl hesperidin 178 mg and green tea extract, providing epigallocatechin gallate (EGCG) 146 mg, daily for 12 weeks modestly attenuates an increase in weight and BMI when compared with placebo. Sub-group analyses suggest that the greatest effects occurred in individuals less than 50 years of age (108152). It is unclear if these effects are due to hesperidin, green tea extract, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. It is unclear if oral hesperidin is beneficial for improving athletic performance. Details: Small clinical studies in healthy male cyclists show that taking a specific form of hesperidin (Cardiose, HealthTech BioActives) has some benefit on athletic performance. One study shows that taking this form of hesperidin 500 mg once, five hours prior to exercise, improves average power, maximum speed, and total energy when compared with placebo. However, it does not improve peak power, time to peak power, or total oxygen consumption (102312). Taking this form of hesperidin 500 mg daily for 8 weeks modestly improves the highest average power output that can be maintained for one hour and the maximal power during an incremental test when compared with placebo. However, there was no effect on the aerobic or anaerobic ventilatory thresholds, oxygen use, or the times to peak power or maximum speed when compared with placebo (105277).
• Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS). Although there is interest in using oral hesperidin for CP/CPPS, there is insufficient reliable information about the clinical effects of hesperidin for this condition. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin. See Diosmin for more information.
• Chronic venous insufficiency (CVI). Oral hesperidin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a specific combination product containing hesperidin methyl chalcone 150 mg, butcher's broom root extract 150 mg, and ascorbic acid 100 mg (Cyclo 3 Fort) usually for 1-3 months may decrease pain, heaviness, cramps, and paresthesia in patients with CVI (37483). There is also research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for CVI. See Diosmin for more information.
• Cognitive function. Although there is interest in using oral hesperidin for improving cognitive function, there is insufficient reliable information about the clinical effects of hesperidin for this condition.
• Coronary artery bypass graft (CABG) surgery. Although there is interest in using oral hesperidin for patients undergoing CABG surgery, there is insufficient reliable information about the clinical effects of hesperidin for this purpose. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin. See Diosmin for more information.
• Coronavirus disease 2019 (COVID-2019). It is unclear if oral hesperidin is beneficial for COVID-19. Details: A large clinical study in unvaccinated outpatients with symptomatic COVID-19 shows that taking hesperidin 1000 mg at bedtime for 14 days after symptom onset does not reduce the proportion of subjects with the most common symptoms (e.g., fever, cough, shortness of breath, and anosmia), number of symptoms after 14 days, or duration of individual symptoms when compared with placebo (112800). However, the study was limited by significant attrition.
• Diabetes. It is unclear if oral hesperidin is beneficial for diabetes. Details: Clinical research in adults with diabetes shows that taking hesperidin (Swanson Health Products) 500 mg once daily for 6 weeks reduces systolic blood pressure and the mean arterial blood pressure by about 3% and 2.5%, respectively, when compared with placebo. Although this improvement is statistically significant, it is unlikely to be considered clinically significant. Also, hesperidin does not modify levels of fasting blood glucose or measures of insulin resistance (98697,105292). A prospective observational study in patients with type 1 or type 2 diabetes has found that taking a specific product (Flebotrofine, AMNOL Chimica Biologica) containing hesperidin for 3 months is not associated with improvements in HbA1c, cholesterol, or triglyceride levels when compared with baseline. Other ingredients in this product included L-arginine, troxerutin, diosmin, black currant extract, and gotu kola extract (108151). There is also research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for diabetes. See Diosmin for more information.
• Diabetic neuropathy. It is unclear if oral hesperidin is beneficial for diabetic neuropathy. Details: A small clinical study in adults with type 2 diabetes, peripheral neuropathy, and metabolic syndrome on oral antidiabetic therapy shows that taking hesperidin 1 gram daily improves diabetic neuropathy as measured by the Michigan Neuropathy Screening Instrument (MNSI) and a physical exam performed by a neurologist when compared with antidiabetic therapy alone. The improvements in measures of diabetic neuropathy were greater when hesperidin was taken with diosmin 1 gram daily compared with either supplement alone or antidiabetic therapy alone, suggesting a synergistic effect (112797).
• Diabetic retinopathy. Although there is interest in using oral hesperidin for diabetic retinopathy, there is insufficient reliable information about the clinical effects of hesperidin for this condition.
• Exercise-induced muscle soreness. It is unclear if oral hesperidin is beneficial for preventing muscle soreness due to exercise. Details: A very small clinical study in sedentary young adults shows that taking hesperidin methyl chalcone 500 mg daily for 3 days prior to intense exercise improves physical performance and postural balance and relieves impaired strength and muscle soreness upon palpation but does not relieve muscle soreness during active movement when compared with placebo (112801).
• Hemorrhoids. Oral hesperidin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with acute hemorrhoidal crisis shows that taking a specific supplement (Triade H, Omikron Italia Srl) containing hesperidin, diosmin, and troxerutin daily for 43 days results in significantly less pain, bleeding, anal itching, and medication use when compared with placebo (93885). This product was given as one sachet of powdered diosmin 300 mg, troxerutin 300 mg, hesperidin 300 mg, and vitamin C 12 mg mixed in water orally three times daily for 3 days, then two sachets daily for 2 days, then one sachet daily for seven days, followed by one tablet containing hesperidin 100 mg, diosmin 300 mg, and troxerutin 300 mg daily for one month (93885). There is also research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for hemorrhoids. See Diosmin for more information.
• Hypertension. It is unclear if oral hesperidin is beneficial for hypertension. Details: Preliminary clinical research in overweight males with or without hypertension shows that taking hesperidin 136 mg or drinking 250 mL of orange juice containing hesperidin 136 mg twice daily for 4 weeks lowers diastolic, but not systolic, blood pressure by around 5 mmHg when compared with placebo (94543). However, a meta-analysis of the available clinical research shows that taking hesperidin supplements 400-800 mg daily for 4-12 weeks does not reduce systolic or diastolic blood pressure when compared with placebo in healthy and obese individuals with or without hypertension (102315). Due to the mixed populations evaluated in this research, the effect of hesperidin in patients with diagnosed hypertension is unclear.
• Hypertriglyceridemia. It is unclear if oral hesperidin is beneficial for hypertriglyceridemia. Details: Preliminary clinical research in patients with hypercholesterolemia shows that taking glucosyl hesperidin, a soluble hesperidin derivative, 500 mg daily for 6 weeks modestly lowers triglyceride levels when compared with baseline in patients who also have hypertriglyceridemia, but not in those without hypertriglyceridemia. However, glucosyl hesperidin did not lower cholesterol levels; a lower dose of 100 mg daily had no effect on either outcome (105290). Clinical research in a similar population shows that taking glucosyl hesperidin 500 mg daily for 24 weeks reduces triglyceride levels by up to 34% from baseline and modestly reduces levels of low-density lipoprotein cholesterol (54800). The validity of the findings in these studies is limited by the lack of a comparator group.
• Lymphedema. Oral hesperidin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females with lymphedema due to breast cancer surgery shows that taking three capsules of a specific combination product (Cyclo 3 Fort), which contains hesperidin methyl chalcone 150 mg, butcher's broom root extract 150 mg, and ascorbic acid 100 mg per capsule, three times daily orally for 90 days reduces swelling in the upper arm and forearm and improves mobility and heaviness when compared with placebo (37494). There is also research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for lymphedema. See Diosmin for more information.
• Metabolic syndrome. It is unclear if oral hesperidin is beneficial for metabolic syndrome. Details: A small clinical study in adults with metabolic syndrome shows that taking hesperidin (Shaanxi Yuantai Biological Technology Co., Ltd) 500 mg twice daily for 12 weeks increases the number of patients who no longer have defined metabolic syndrome by almost two-fold when compared with placebo. There were also modest reductions in fasting blood glucose, triglycerides, and systolic blood pressure, as well as the total number of patients with abdominal obesity, elevated blood pressure, and elevated fasting blood sugar. However, there were no differences in levels of high-density lipoprotein (HDL) cholesterol, diastolic blood pressure, or waist circumference (105288). In another preliminary clinical study using the same product, there were modest reductions in systolic blood pressure and triglyceride levels when compared with no treatment. However, there were no effects on other measures of metabolic syndrome or the overall number of patients with defined metabolic syndrome. This study also shows that when hesperidin is taken in combination with flaxseed 15 grams twice daily, serum concentrations of triglycerides and glucose, as well as systolic blood pressure, were modestly improved when compared with control. The prevalence of individuals with defined metabolic syndrome at the end of treatment was reduced by approximately 77%, which was significant when compared with the control group (105276). Another small clinical study in adults with metabolic syndrome, type 2 diabetes, and peripheral neuropathy on oral antidiabetic therapy shows that taking hesperidin 1 gram daily reduces body mass index, fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol but not systolic blood pressure, diastolic blood pressure, or HDL cholesterol when compared with control. These effects are enhanced when hesperidin is combined with diosmin 1 gram daily (112797).
• Minor bleeding. Although there is interest in using oral hesperidin for minor bleeding, there is insufficient reliable information about the clinical effects of hesperidin for this purpose. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin. See Diosmin for more information.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral hesperidin is beneficial for NAFLD; the available evidence is conflicting. Details: A small clinical trial in adults with NAFLD shows that taking hesperidin 1 gram daily for 12 weeks along with lifestyle modification improves hepatic steatosis as measured by transient elastography when compared with placebo and lifestyle modification. Taking hesperidin also modestly improves total cholesterol, triglyceride, alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) levels. However, there were no effects on liver fibrosis or levels of aspartate aminotransferase (AST), fasting blood glucose, insulin, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol (102313). Other preliminary clinical research using the same treatment protocol shows that although there were modest reductions in ALT, there was no effect on liver steatosis, liver fibrosis, or other metabolic measures. When used in combination with flaxseed 30 grams daily, levels of fasting blood glucose and a measure of insulin resistance were modestly improved (105275). These studies may have been too small to detect differences in most endpoints.
• Rheumatoid arthritis (RA). It is unclear if oral hesperidin is beneficial for RA. Details: A small clinical study shows that drinking a 100 mL beverage containing alpha-glucosyl hesperidin 3 grams daily orally for 12 weeks might improve symptoms of RA when compared with placebo (54850).
• Varicose veins. Although there is interest in using oral hesperidin for varicose veins, there is insufficient reliable information about the clinical effects of hesperidin for this condition. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for this purpose. See Diosmin for more information.
• Venous leg ulcers. Although there is interest in using oral hesperidin for venous leg ulcers, there is insufficient reliable information about the clinical effects of hesperidin for this condition. There is research evaluating the use of micronized purified flavonoid fraction, which contains small amounts of hesperidin, for this purpose. See Diosmin for more information. More evidence is needed to rate hesperidin for these uses.

(Read more about HESPERIDIN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Lemon has only been evaluated in combination with quince in a nasal spray for hay fever; its effect when used alone is unclear. Details: A small clinical study in patients with grass pollen allergy shows that using a specific nasal spray (Gencydo, Weleda AG) containing lemon and quince three times daily for 7 days does not improve the symptoms of allergic rhinitis when compared with placebo. In this study, using the nasal spray reduced airway resistance during inspiration at 10 and 20 minutes after pollen exposure, and reduced airway resistance during expiration at 20 minutes after pollen exposure (98826).
• Anxiety. It is unclear if aromatherapy with lemon essential oil reduces test anxiety. Details: A small clinical study in first year nursing students in Turkey shows that administering aromatherapy with lemon essential oil for 15 minutes prior to an exam reduces test anxiety scores when compared with control students (110779). However, it is unclear whether any improvements are clinically significant or lead to improved test scores.
• Halitosis. Lemon essential oil has only been evaluated in combination with other essential oils; its effect when used alone is unclear. Details: Preliminary research in males with dementia in a long-term care facility shows that cleaning the tongue, gums, and teeth with a solution of lemon, peppermint, and tea tree essential oils twice daily for 7 days improves oral condition, measured on the Korean Oral Assessment Guide scale, increases salivary pH into the normal range, and decreases halitosis score when compared with saline control. On a scale of 0 to 5, the essential oil mixture reduced the halitosis score by 1.24 points, compared with 0.2 points for the control (112957).
• Hypertension. It is unclear if oral lemon is beneficial in patients with high blood pressure. Details: A small, prospective, population study in middle-aged Japanese women has found that increased lemon intake is associated with a modest reduction in systolic, but not diastolic, blood pressure (93471).
• Kidney stones (nephrolithiasis). It is unclear if oral lemon juice is beneficial for recurrent idiopathic calcium oxalate nephrolithiasis. Details: A randomized, controlled trial in patients with recurrent idiopathic calcium oxalate nephrolithiasis shows that taking fresh lemon juice 60 mL orally twice daily for 2 years with a standard diet does not improve the time to stone recurrence when compared with no supplementation. The validity of these findings is limited due to poor patient adherence, which declined from 79% at 6 months, to 68% at 1 year, and 48% at 2 years. When restricted to a 1-year follow-up, stone recurrence occurred in 10% of patients taking lemon juice, compared with 21% of patients in the control group; this difference was statistically significant (107489).
• Meniere disease. Although there is interest in using lemon orally for Meniere disease, there is insufficient reliable information about the clinical effects of lemon for this condition.
• Myocardial infarction (MI). It is unclear if aromatherapy with lemon essential oil is beneficial in patients with acute MI. Details: A small clinical study in hospitalized patients with acute MI shows that administering aromatherapy with lemon essential oil over 3 days moderately reduces systolic blood pressure, but not diastolic blood pressure, when compared with a paraffin control. Heart rate and anxiety were reduced by a small amount the day following the completion of lemon aromatherapy (103455).
• Nausea and vomiting. It is unclear if aromatherapy with lemon oil is beneficial in palliative care patients with nausea and vomiting. Details: A small observational study in hospitalized palliative care patients with advanced cancer has found that administering aromatherapy with lemon oil pads relieves nausea and vomiting in 73% of applications (110778). The interpretation of these findings is limited by the use of a retrospective chart review and the lack of a comparator group.
• Obesity. Although there is interest in using lemon orally for obesity, there is insufficient reliable information about the clinical effects of lemon for this condition.
• Oral mucositis. Lemon has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A randomized, controlled trial in patients with head and neck cancer receiving external beam radiotherapy 5 days weekly shows that using a 2:1 oral honey-lemon throat spray four to eight times daily, beginning 1 day prior to radiotherapy initiation and continuing for 5 weeks, does not improve severity of mucositis when compared with oral benzydamine hydrochloride throat spray applied four to eight times daily. The actual rate of oral mucositis occurrence is 65% in those receiving the honey-lemon spray, compared with 35% with the benzydamine hydrochloride spray; however, this difference was not statistically significant (107487). This study may have been inadequately powered to detect a difference between groups. Also, the validity of these findings is limited due to the lack of objective outcome measures.
• Postoperative nausea and vomiting (PONV). It is unclear if aromatherapy with lemon essential oil is beneficial in patients with PONV. Details: Preliminary research in patients undergoing lower extremity fracture surgery shows that aromatherapy with lemon essential oil started the morning of surgery, then every 2 hours to the end of surgery, in the recovery room, and 16 hours after surgery reduces the frequency, severity, and amount of PONV, and the frequency of anti-emetic drug administration after surgery, when compared with control. The intensity of pain is also reduced, but not the amount of post-operative opioid needed (112956).
• Pregnancy-induced nausea and vomiting. It is unclear if aromatherapy with lemon essential oil is beneficial in patients with nausea and vomiting due to pregnancy. Details: A small clinical study in pregnant patients shows that practicing aromatherapy with 2 drops of lemon essential oil placed on a cotton ball as needed modestly reduces pregnancy-induced nausea and vomiting on 2 of 4 days of the study when compared with placebo (93475).
• Radiation-induced sialadenitis. Aromatherapy with lemon essential oil has only been evaluated in combination with other essential oils; its effect when used alone is unclear. Details: A small clinical study in patients with thyroid cancer shows that receiving 10-minute aromatherapy baths with lemon and ginger essential oils prior to meals for 2 weeks before treatment with radioactive iodine therapy attenuates damage to the salivary gland when compared with distilled water baths (98129).
• Respiratory tract infections. Although there is interest in using lemon orally for respiratory tract infections such as cold and flu, there is insufficient reliable information about the clinical effects of lemon for these conditions. More evidence is needed to rate lemon for these uses.

(Read more about LEMON)

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)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if topical rutin is beneficial for aging skin. Details: Preliminary clinical research shows that topical application of a cream containing rutin 2% twice daily for 4 weeks reduces signs of skin aging around the eye in females aged 30-50 years. Skin dermal density is improved by 20%, area of crow's feet is reduced by 26%, and the number of wrinkles under the eye is reduced by 53% when compared with placebo (92236).
• Autism spectrum disorder. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children 4-10 years-old with autism spectrum disorder shows that taking a product containing rutin 3 mg/kg, luteolin 10 mg/kg, and quercetin 7 mg/kg daily for 26 weeks improves aspects of behavior, such as hyperactivity, irritability, and lethargy, by a moderate to large amount when compared to baseline. It also seems to improve some indices of functioning, such as daily living and social behavior, by a small amount. These improvements were considered to be greater than expected when taking aging into consideration; however, no placebo was used in this study (96765).
• Diabetes. It is unclear if oral rutin is beneficial for diabetes. Details: A small clinical study in adults with type 2 diabetes conducted in Iran shows that taking rutin 500 mg twice daily for 3 months reduces fasting blood glucose and glycated hemoglobin by approximately 40 mg/dL and 1%, respectively, and modestly reduces triglycerides and total and low-density lipoprotein cholesterol when compared with placebo (112182). The interpretation of these findings is limited by the omission of data regarding concurrent diabetes medications. A small observational study in patients with a family history of type 1 diabetes shows that taking a specific product (Mucos Pharma) containing rutin 100 mg, trypsin 48 mg, and bromelain 90 mg daily for 24 months is not associated with reduced incidence of type 1 diabetes at 8 years (99472).
• Exercise-induced respiratory infections. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in non-elite male runners shows that taking a combination product (Wobenzym Plus, Mucos Pharma) providing rutin 600-1200 mg, trypsin 288-576 mg, and bromelain 540-1080 mg daily for 3 weeks, starting one week before a marathon, does not reduce the risk of a post-race respiratory tract infection when compared with placebo (96766).
• Hemorrhoids. Although there is interest in using oral rutin for hemorrhoids, there is insufficient reliable information about the clinical effects of rutin for this condition.
• Inflammatory bowel disease (IBD). Although there is interest in using oral rutin for IBD, there is insufficient reliable information about the clinical effects of rutin for these conditions.
• Lymphedema. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research in patients who have undergone a mastectomy shows that taking a specific combination product containing rutin, pancreatin, papain, bromelain, trypsin, and chymotrypsin (Wobenzym N, Mucos Pharma) daily for 7 weeks reduces arm swelling associated with lymphedema when compared with diuretics (24560). Also, preliminary clinical research in patients with primary or secondary lymphedema of the upper or lower limbs shows that taking a combination product containing rutin 300 mg, bromelain 100 mg, and sweet clover 100 mg daily for 6 months decreases pitting, limb volume, pain, and quality of life when compared to baseline (103298). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear if these effects are due to rutin, other ingredients, or the combination.
• Multiple sclerosis (MS). Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with relapsing-remitting MS shows that taking an enzyme combination containing rutin 100 mg, trypsin 48 mg, and bromelain 90 mg per tablet for at least 3 months does not affect the progression of disability, relapse rate, or central nervous system lesions when compared with placebo (99468). The validity of these results are limited by the short duration of treatment.
• Obesity. It is unclear if oral rutin is beneficial for obesity. Details: In Japanese adults with a body mass index (BMI) of 23-30 kg/m2, a small clinical trial shows that taking a specific monoglucosyl rutin ( αG Rutin PS) 200 mg or 400 mg daily for 8 weeks reduces the area of visceral fat by 2.4 cm and 3.5 cm, respectively, compared with an increase of 5.2 cm in those taking placebo. However, there were no differences between groups in the actual value of visceral fat, changes in total fat or subcutaneous fat, BMI, body weight, abdominal circumference, or cholesterol or triglyceride levels (105298).
• Oral mucositis. Although there is interest in using oral rutin for oral mucositis, there is insufficient reliable information about the clinical effects of rutin for this condition.
• Osteoarthritis. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a specific combination product (Wobenzym PS, formerly Phlogenzym, Mucos Pharma) at a dose providing up to 600 mg rutin, 288 mg trypsin, and 540 mg bromelain daily for 3-12 weeks, is as effective as diclofenac for relieving pain and improving knee function in patients with painful osteoarthritis of the knee. This product also reduces the need for rescue medication by 95% when compared with placebo (6252,91104,99467,99477).
• Postoperative swelling. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical study in patients undergoing surgery of the jaw shows that taking an enzyme combination of rutin 200 mg, trypsin 96 mg, and bromelain 180 mg twice daily for 5 days in addition to standard treatment reduces soft-tissue thickness (indicating the amount of swelling) at most of the nine assessed facial points when compared to control (99476).
• Sprains. Oral rutin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in patients with a sprained ankle shows that taking a specific enzyme combination (Phlogenzym, Mucos Pharma) containing rutin 100 mg, trypsin 48 mg, and bromelain 90 mg, or taking different combinations of the individual enzymes three times daily for 10 days, is no more effective for relieving pain than placebo (99473).
• Stroke. Although there is interest in using oral rutin for stroke prevention, there is insufficient reliable information about the clinical effects of rutin for this purpose.
• Sunburn. Although there is interest in using topical rutin for sunburn prevention, there is insufficient reliable information about the clinical effects of rutin for this purpose.
• Varicose veins. Although there is interest in using oral rutin for varicose veins, there is insufficient reliable information about the clinical effects of rutin for this condition. More evidence is needed to rate rutin for these uses.

(Read more about RUTIN)

LIKELY SAFE ...when used orally in amounts found in foods.

POSSIBLY SAFE ...when supplements are used orally and appropriately, short-term. Doses of up to 3 grams daily have been used with apparent safety for up to 3 months (37494,54850,94544,105275,105276).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods.

PREGNANCY AND LACTATION: POSSIBLY SAFE
when used orally in doses of up to 100 mg daily for 30 days in combination with diosmin. Some evidence suggests that taking this combination may be associated with placental insufficiency when used during the third trimester of pregnancy; however, the combination does not seem to induce fetal abnormalities, retard fetal growth, increase the risk of intrauterine death, or affect birth weight. Also, when breastfeeding, this combination does not seem to affect infant growth or feeding (54970).

(Read more about HESPERIDIN)

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

POSSIBLY SAFE ...when inhaled in amounts used for aromatherapy, short-term. Lemon essential oil has been used with apparent safety as aromatherapy for up to 2 weeks in clinical research (93475,98128,98129). There is insufficient reliable information available about the safety of lemon when used topically, or when used orally or intranasally in medicinal amounts.

PREGNANCY AND LACTATION:
Insufficient reliable information available. Avoid using in amounts greater than those typically found in foods.

(Read more about LEMON)

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)

LIKELY SAFE ...when used orally in amounts found in foods, such as fruits and vegetables.

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. Rutin has been used with apparent safety at doses of up to 600 mg daily for up to 12 weeks (6252,24560,91104,96766,105298). ...when applied topically as a cream (92236,99258,99260).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the use of supplemental rutin; avoid amounts greater than those found in foods.

(Read more about RUTIN)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Animal research suggests that hesperetin, a bioflavonoid aglycone derivative of hesperidin, may have antiplatelet activity (54822).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking hesperidin with antihypertensive drugs might increase the risk of hypotension.  Details Some clinical and animal research shows that hesperidin can decrease blood pressure (54851,94543,98697,105278). However, other clinical research shows that hesperidin does not affect blood pressure (102315).

CELIPROLOL (Celicard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin may decrease the levels and clinical effects of celiprolol.  Details Animal research shows that concomitant use of hesperidin may reduce the plasma area under the curve of celiprolol by up to 75% (91760). This effect has not been reported in humans.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use with CNS depressants may cause additive sedative effects.  Details Animal studies show that hesperidin has sedative effects, due to opioid receptor activity (54841) and can increase sedation when used with diazepam (54789). This effect has not been reported in humans.

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin may increase the levels and clinical effects of diltiazem.  Details Animal research suggests that hesperidin may enhance the bioavailability of diltiazem, increasing the plasma area under the curve of diltiazem by up to 65.3% (91761). This effect has not been reported in humans.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin might inhibit P-glycoprotein-mediated drug efflux and potentially increase levels of drugs that are substrates of P-glycoprotein.  Details In vitro research shows that hesperidin can inhibit P-glycoprotein efflux (54908). This effect has not been reported in humans.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hesperidin might increase the levels and clinical effects of verapamil.  Details Animal research suggests that hesperidin may enhance the bioavailability of verapamil, increasing the plasma area under the curve of verapamil by 96.8% (91762). This effect has not been reported in humans

(Read more about HESPERIDIN)

ITRACONAZOLE (Sporanox) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking itraconazole capsules or tablets with a beverage containing lemon might increase the levels and clinical effects of itraconazole.  Details In one case report, dissolving itraconazole tablets in a small amount of specific beverages containing lemon prior to administration increased the level of itraconazole in a lung transplant patient. In this case, the increased bioavailability was desirable and was likely due to improved tablet dissolution in the acidic beverage (110781).

(Read more about LEMON)

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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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rutin with antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research suggests that rutin has hypoglycemic effects (105299).

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General ...Orally, hesperidin is generally well tolerated.

Dermatologic ...A case of recurrent allergic dermatitis was reported in a 70-year-old female with no known allergies who applied topical hesperidin methyl chalchone (94538).

Immunologic ...A case of recurrent allergic dermatitis was reported in a 70-year-old female with no known allergies who applied topical hesperidin methyl chalchone (94538).

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General ...Orally, lemon is well tolerated in amounts commonly found in foods. A thorough evaluation of safety outcomes has not been conducted on the use of larger amounts.
Most Common Adverse Effects:
Orally: Epigastralgia and heartburn with the regular consumption of fresh lemon juice.

Dermatologic ...Topically, the application of lemon oil might cause photosensitivity, due to furocoumarin derivative content. This occurs most often in fair-skinned people (11019).

Gastrointestinal ...Orally, fresh lemon juice, taken as 60 mL twice daily, has been reported to cause gastrointestinal disturbances in 37% of patients in one clinical trial, compared with 8% of patients in the placebo group. Specifically, of the patients consuming lemon juice, 21% experienced heartburn and 8% experienced epigastralgia, compared to 1% and 3%, respectively, in the placebo group (107489).

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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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General ...Orally, rutin is generally well tolerated.

Dermatologic ...Orally, rutin may cause flushing and rashes in some people (313).

Gastrointestinal ...Orally, rutin may cause gastrointestinal disturbance in some people (313).

Neurologic/CNS ...Orally, rutin may cause headache in some people (313).

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