ResveraCel [Discontinued] by Thorne

EFFECTIVE

• Homocystinuria. Oral betaine anhydrous is effective at reducing plasma homocysteine levels in patients with homocystinuria associated with cystathionine beta-synthase (CBS) deficiency, 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency, or cobalamin cofactor metabolism (cbl) defect. Details: Clinical research shows that taking oral betaine anhydrous reduces plasma homocysteine levels by 20% to 30% when compared with placebo in adults and children with several types of homocystinuria, including CBS deficiency, MTHFR deficiency, and cbl defect (698). Observational studies have also found that betaine anhydrous reduces plasma homocysteine levels as monotherapy, in combination with other treatments, such as pyridoxine, folate, and cobalamin, and in patients refractory to pyridoxine treatment (145,698,34956). A specific betaine anhydrous product (Cystadane, Recordati Rare Diseases Inc.) is approved by the US FDA for homocystinuria. Oral betaine anhydrous is initiated at a dose of 100 mg/kg daily in children under 3 years of age and a dose of 3 grams twice daily in children 3 years and older, then titrated to effect. Although some patients have taken up to 20 grams daily, some clinical research suggests that doses above 150 mg/kg daily do not provide additional benefit (698).

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral betaine anhydrous decreases plasma homocysteine levels in people with hyperhomocysteinemia; however, any effects on cardiovascular sequela and other clinical outcomes are unclear. Details: Most clinical research in adults with normal or mildly elevated plasma homocysteine levels (<25 micromol/L) shows that taking betaine anhydrous 3-6 grams daily orally for up to 12 weeks can modestly decrease plasma homocysteine levels by 5.5% to 15% when compared with control (6810,16451,16452,34894,34896,34902,34904,34925,34936). Some research indicates that oral doses of betaine anhydrous up to 4 grams daily can lower plasma homocysteine levels without an adverse effect on lipid levels (105813). However, it is not clear whether any reduction in plasma levels of homocysteine results in a decreased risk for cardiovascular disease. In patients with kidney failure, clinical research shows that taking betaine anhydrous 4 grams daily lowers levels of plasma homocysteine after methionine loading, but does not affect fasting levels, when compared with control (16455). However, taking this dose of betaine anhydrous in combination with folate 5 mg daily does not seem to have additive homocysteine-lowering effects in patients with kidney failure when compared with folate alone (34885,34957,34963). A very small clinical study in children with hyperhomocysteinemia secondary to pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) or cobalamin C (cblC) deficiencies shows that taking betaine anhydrous 100 or 250 mg/kg daily in divided doses for one month leads to similar reductions in total plasma homocysteine concentrations, suggesting that an increased dose is not beneficial in the setting of pediatric pnrCBS and cblC deficiencies. The researchers noted that increased doses of betaine anhydrous cause proportional increases in methionine concentrations, which can induce severe hypermethioninemia in patients with pnrCBS, possibly leading to increased intracranial pressure and cerebral edema. In contrast, increases in methionine and S-adenosylmethionine concentrations are desirable in patients with cblC deficiency since low concentrations of both are implicated in the pathology of cblC deficiency (111374).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angelman syndrome. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with Angelman syndrome shows that taking betaine anhydrous (Cystadane, Recordati Rare Diseases, Inc.) 100-200 mg/kg daily or betaine anhydrous 6-12 grams daily for 12 months, in combination with folate, folic acid derivatives, creatine, and/or vitamin B12, does not prevent seizures or improve cognitive, motor, or language development, when compared with placebo or baseline (34932,34945).
• Athletic performance. It is unclear if oral betaine anhydrous improves athletic performance; small clinical trials have yielded conflicting findings that may be related to age, training status, and biological sex. Details: Small clinical trials in males with and without strength training experience shows that taking betaine anhydrous 2-2.5 grams daily for 10-15 days, either alone or in combination with resistance training or blood flow restriction, does not improve muscle power, strength, or performance on bench press, leg press, or squat exercises when compared with placebo (34940,34941,34947,34954,111373). In aerobic exercise training, a small clinical study in healthy untrained males shows that taking betaine anhydrous 1.25 grams twice daily with 300 mL of a sports beverage for 2 weeks does not improve aerobic capacity or performance during exhaustive endurance exercise when compared with placebo (105550). Similarly, a small clinical study in trained male runners shows that taking betaine anhydrous 5 grams once with 1000 mL of a sports beverage after becoming dehydrated does not improve long-distance running or sprinting after rehydration when compared with placebo (34916). Additional clinical research in males and females who have undergone at least 6 months of CrossFit training shows that taking betaine anhydrous 1.25 grams twice daily for 6 weeks while continuing to train does not improve muscle strength, body composition, aerobic capacity, or anaerobic performance when compared with placebo (105549). However, other research shows that betaine anhydrous benefits certain aspects of athletic performance in particular subgroups. One small clinical study in healthy, active males shows that taking betaine anhydrous 2.5 grams daily for 2 weeks improves subjective fatigue scores during exercise when compared with placebo (34941). Another small clinical study in active but untrained young females shows that taking betaine anhydrous (BetaPower, Finnfeeds) 2.5 grams daily for 8 weeks in combination with a structured resistance training program reduces body fat percentage and body fat mass, but does not improve muscle strength, when compared with placebo (98525). Another small clinical study in active females shows that taking betaine anhydrous 1.2 grams twice daily for 2 weeks improves power output during sprinting, but not oxygen uptake, when compared with placebo (107950). Betaine anhydrous has also been studied in adolescents. Preliminary clinical research in trained adolescent soccer players shows that taking betaine 1 gram twice daily orally with 300 mL water for 14 weeks improves muscle power, agility, and sprint time, but not muscle strength, when compared with placebo (108654).
• Colorectal adenoma. It is unclear if oral betaine anhydrous reduces the risk of colorectal adenoma. Details: Preliminary population research has found that high dietary betaine intake is not associated with a reduced risk of colorectal adenoma when compared with low dietary betaine intake (14845).
• Depression. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with major depression shows that taking a specific combination product (DDM Metile, Omeopiacenza) containing betaine anhydrous 125 mg and S-adenosyl-L-methionine (SAMe) 250 mg orally twice daily for 12 months improves depression symptoms when compared with amitriptyline 75 mg daily. After 12 months, patients treated with the combination product showed an average improvement in depression scores of 38%, compared with 18% in patients treated with amitriptyline (90107). It is unclear if this effect is due to betaine anhydrous, SAMe, or the combination.
• Dry mouth. It is unclear if topical betaine anhydrous is beneficial in patients with dry mouth. Details: Applying betaine anhydrous 4% topically twice daily in a toothpaste for 2 weeks reduces symptoms of dry mouth when compared with baseline (6812). Other preliminary clinical research in adults with dry mouth shows that using a specific mouthwash product (Xeros Dentaid) that contains betaine anhydrous 1.33%, xylitol 3.3%, and sodium fluoride 0.05%, each evening for 4 weeks improves dry mouth symptoms when compared with baseline (34944). It is unclear if this effect is due to betaine anhydrous, other ingredients, or the combination. Additionally, the validity of the findings from these studies is limited by the lack of a comparator group.
• Fibrocystic breast disease. Although there has been interest in using oral betaine anhydrous for fibrocystic breast disease, there is insufficient reliable information about the clinical effects of betaine anhydrous for this purpose.
• Gastroesophageal reflux disease (GERD). Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of betaine anhydrous 100 mg, melatonin 6 mg, L-tryptophan 200 mg, vitamin B6 25 mg, folic acid 10 mg, vitamin B12 50 mcg, and methionine 100 mg daily for 40 days reduces symptoms of GERD in more patients when compared with omeprazole 20 mg daily. Symptom improvement occurred in 100% of patients who took this combination supplement, compared with only 66% of patients taking omeprazole (16011). It is unclear if this effect is due to betaine anhydrous, other ingredients, or the combination.
• Gingivitis. Topical betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of patients with gingivitis shows that brushing with a toothpaste containing a combination of extra virgin olive oil, xylitol, and betaine anhydrous daily for 4 months decreases gingival bleeding and improves markers associated with gingival health when compared with placebo and commercial toothpaste (111372).
• Hepatitis C. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking pegylated interferon alpha and ribavirin in combination with betaine anhydrous (Cystadane, Recordati Rare Diseases, Inc.) and S-adenosyl-L-methionine (SAMe) daily for 12 months induces early virological response in approximately 60% of patients with hepatitis C who were previously unresponsive to treatment with pegylated interferon alpha and ribavirin. However, sustained virological response only occurred in 10% of these patients (20465). The validity of this study is limited by the lack of a comparator group. Also, it is unclear if this effect is due to betaine anhydrous, SAMe, or the combination.
• Metabolic Syndrome. It is unclear if oral betaine anhydrous is beneficial in patients with metabolic syndrome. Details: A large observational study in older adults with overweight or obesity and metabolic syndrome has found that increased dietary intake of betaine for 1 year is associated with reduced body weight, waist circumference, glycated hemoglobin (HbA1c), body weight, and triglycerides and increased levels of high-density lipoprotein (HDL) cholesterol (111375).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral betaine anhydrous is beneficial in patients with NASH. Details: Preliminary clinical research shows that taking betaine anhydrous 10 grams twice daily orally for 12 months improves NASH scores when compared with placebo (34928). Taking betaine anhydrous also normalizes liver enzyme levels and reduces inflammation and fibrosis when compared with baseline (10631,34928).
• Obesity. It is unclear if oral betaine anhydrous is beneficial in patients with obesity. Details: Preliminary clinic research in obese adults on a reduced-calorie diet shows that taking betaine anhydrous 3 grams orally twice daily for 12 weeks does not reduce body weight or fat mass or improve resting energy expenditure when compared with placebo (16452). A meta-analysis of small randomized controlled trials that studied the effects of betaine anhydrous on body composition also shows that taking betaine 1.5-20 grams daily for 2-52 weeks does not reduce body mass, fat mass, or fat-free mass when compared with control. However, the validity of this study is limited by inclusion of obese, non-obese, and healthy patients (108653).
• Osteoarthritis. Although there has been interest in using oral betaine anhydrous for osteoarthritis, there is insufficient reliable information about the clinical effects of betaine anhydrous for this purpose.
• Rett syndrome. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in female children with Rett syndrome shows that taking a combination of folate 15 mg and betaine anhydrous 6-12 grams orally daily for 12 months does not improve motor function, growth, or development when compared with placebo. In addition, one subgroup analysis suggests that taking the combination product may reduce head circumference growth rate (34922).
• Sunburn. Topical betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy adults shows that applying a specific cream (Physiogel AI), which contains betaine anhydrous 0.36%, N-palmitoylethanolamine 0.3%, N-acetylethanolamine 0.21%, and sarcosine 0.24%, daily for one month prior to ultraviolet (UV) light exposure can reduce UV-induced redness when compared with placebo. However, application of this cream only once 20 minutes prior to UV exposure does not have any effect (34905). It is unclear if any benefits are due to betaine anhydrous, other ingredients, or the combination. More evidence is needed to rate betaine anhydrous for these uses.

(Read more about BETAINE ANHYDROUS)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Although there is interest in using oral nicotinamide riboside for AMD, there is insufficient reliable information about the clinical effects of nicotinamide riboside for this condition.
• Alzheimer disease. Although there is interest in using oral nicotinamide riboside for Alzheimer disease, there is insufficient reliable information about the clinical effects of nicotinamide riboside for this condition.
• Ataxia telangiectasia. It is unclear if oral nicotinamide riboside improves ataxia telangiectasia. Details: Preliminary clinical research in adults and children with ataxia telangiectasia shows that taking nicotinamide riboside orally 25 mg/kg daily for 4 months improves ataxia scores by 11% to 17% when compared with baseline. Ataxia scores also worsened after treatment withdrawal. The validity of this study is limited by the lack of a comparator group (107703).
• Athletic performance. It is unclear if oral nicotinamide riboside improves athletic performance in healthy adults. Details: One small study in young, healthy males shows that taking a specific nicotinamide riboside product (NAD+ Cell Regenerator, Life Extension) 500 mg two hours before exercise does not improve measures of muscle strength, muscle fatigue, or oxygen consumption when compared with placebo (102036). Given the small sample size, this study is limited by a lack of adequate power to detect significant differences between groups.
• Diabetes. Although there is interest in using oral nicotinamide riboside for diabetes, there is insufficient reliable information about the clinical effects of nicotinamide riboside for this condition.
• Heart failure. It is unclear if oral nicotinamide riboside is beneficial for heart failure. Details: Preliminary clinical research in patients with heart failure and a left ventricle ejection fraction of less than 40% shows that taking nicotinamide riboside 250 mg orally twice daily, titrated weekly by 250 mg to a final dose of 1000 mg orally twice daily, for 12 weeks does not improve 6-minute walk test distance or quality of life scores when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110506).
• Hyperlipidemia. It is unclear if oral nicotinamide riboside improves lipid levels. Details: One small clinical study in sedentary males with obesity and elevated blood lipids shows that taking nicotinamide riboside (Niagen, ChromaDex) 1000 mg twice daily for 12 weeks does not improve total cholesterol or low-density lipoprotein (LDL) cholesterol when compared with placebo (94745).
• Hypertension. It is unclear if oral nicotinamide riboside reduces blood pressure. Details: One small clinical study in patients with and without hypertension shows that taking nicotinamide riboside (Niagen, ChromaDex) 500 mg twice daily for 6 weeks non-significantly reduces systolic and diastolic blood pressure by around 4 mmHg and 2 mmHg, respectively, when compared with placebo. The effect seems to be more pronounced in patients with elevated blood pressure at baseline (94744).
• Nonalcoholic fatty liver disease (NAFLD). Oral nicotinamide riboside has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with NAFLD shows that taking a combination product containing nicotinamide riboside 125 mg and pterostilbene 25 mg (Basis, Elysium Health), 2-4 tablets orally daily for 26 weeks does not improve liver function test levels or liver fat content when compared with placebo (110508).
• Obesity. It is unclear if oral nicotinamide riboside improves weight loss. Details: Two small clinical studies in adults with obesity shows that taking nicotinamide riboside (Niagen, ChromaDex) 1000 mg once or twice daily for 6-12 weeks does not reduce body weight or improve insulin sensitivity, glucose metabolism, or lipid levels when compared with placebo (94745,104935).
• Parkinson disease. It is unclear if oral nicotinamide riboside improves Parkinson disease. Details: Very preliminary clinical research in adults with newly diagnosed Parkinson disease shows that taking nicotinamide riboside 500 mg orally twice daily for 4 weeks does not improve Parkinson disease scores when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110504).
• Physical performance. It is unclear if oral nicotinamide riboside improves physical performance in older adults. Details: One small clinical study in healthy, elderly males shows that taking a specific nicotinamide riboside product (NAD+ Cell Regenerator, Life Extension) 500 mg two hours before exercise seems to improve some measures of muscle strength and fatigue, but not oxygen consumption, when compared with placebo. Additionally, muscle strength, as measured by isometric peak torque, was improved in these older patients when compared with younger males taking the same product (102036). More evidence is needed to rate nicotinamide riboside for these uses.

(Read more about NICOTINAMIDE RIBOSIDE)

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). Quercetin has also been evaluated in combination with another ingredient. A small clinical study in trained athletes shows that taking a single dose of quercetin (Quercetin Powder from Sophora Japonica Flower, Aki Organics) 140 mg and mangiferin 84 mg, a mango constituent, one hour prior to an intermittent high-intensity exercise test improves performance as measured by circuit time and reduces perceived exertion, but does not improve heart rate, sprint time, or subjective muscle soreness when compared with placebo (113077). It is unclear whether these effects are due to quercetin, mangiferin, or the combination.

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.

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POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Intranasal resveratrol seems to be beneficial for reducing allergic rhinitis symptoms in adults and children. Details: Some clinical research shows that intranasal resveratrol with carboxymethyl-beta-glucan can improve symptoms of allergic rhinitis (91332,97339). One clinical study in adults with allergic rhinitis shows that using an intranasal spray containing resveratrol 0.1% three times daily for 4 weeks reduces nasal symptoms and improves quality of life scores when compared with placebo (97339). A study in children aged 4-17 years with pollen-induced allergic rhinitis shows that using an intranasal spray containing resveratrol 0.05% three times daily for 2 months improves itching, sneezing, runny nose, and nasal obstruction and reduces use of rescue medication when compared with placebo (91332).
• Obesity. Oral resveratrol seems to be beneficial for weight loss in individuals with overweight or obesity. However, it is unlikely to be beneficial for improving most metabolic parameters in this population. Details: A meta-analysis of 28 clinical trials shows that taking resveratrol modestly decreases body weight by 0.5 kg, body mass index (BMI) by 0.17 kg/m2, and waist circumference by 0.8 cm when compared with placebo or no intervention. This analysis included studies of individuals with normal weight, overweight, and obesity, with or without type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, or other chronic conditions. A subgroup analysis suggests that individuals with obesity have a greater response to resveratrol. In these individuals, taking resveratrol 8-3000 mg daily resulted in an average weight reduction of 1.15 kg and a BMI reduction of 0.3 kg/m2 when compared with placebo. The greatest impact on body weight and BMI occurred with resveratrol doses of no more than 500 mg daily and treatment durations of at least 3 months (100696). However, it is unclear whether any improvements are clinically significant.

POSSIBLY INEFFECTIVE

• Cardiovascular disease (CVD). Oral resveratrol does not seem to be beneficial for CVD prevention. Details: Population research suggests that a higher dietary intake of resveratrol is not associated with a reduced risk of CVD when compared with a lower dietary intake (91334). Also, a meta-analysis of clinical research shows that taking resveratrol for up to 6 months does not improve any measures of plasma lipids, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides in patients at high risk for CVD (91333). While one preliminary clinical study shows that taking resveratrol 10 mg daily for 3 months improves left ventricular function by about 1% and endothelial function when compared to baseline in patients with a history of myocardial infarction and coronary artery disease, the improvements are very small and blood pressure and markers of inflammation do not appear to be improved (91330).
• Hypercholesterolemia. Oral resveratrol does not seem to be beneficial for hypercholesterolemia. Details: A meta-analysis of clinical research shows that resveratrol is unlikely to be beneficial for improving blood lipids when compared with placebo in patients with hypercholesterolemia. In the meta-analysis, studied populations included people who are overweight or obese, as well as patients with hypertension, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), angina, and dyslipidemia (105181). Although there was a small reduction in total cholesterol levels of approximately 7 mg/dL, resveratrol did not improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides (105181). Also, an analysis of results from clinical research shows that taking resveratrol for up to 6 months does not improve any measures of plasma lipids, including total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides in patients at high risk for cardiovascular disease (91333). Also, clinical research in healthy humans shows that taking resveratrol 500 mg orally daily for 30 days increases levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B (112944). Another meta-analysis identified more promising results; however, any effect on blood lipids may not be considered clinically significant. This meta-analysis included 17 clinical studies enrolling 968 participants with dyslipidemia, type 2 diabetes, coronary artery disease, overweight or obesity, or stroke. Resveratrol reduced total cholesterol by approximately 10 mg/dL, LDL by approximately 6 mg/dL, and triglycerides by approximately 9 mg/dL, but did not improve HDL, when compared with placebo. However, most of the included studies were small and utilized heterogenous dosing regimens, with doses ranging from 10-3000 mg daily for 4-48 weeks (110020).
• Metabolic syndrome. Oral resveratrol does not seem to be beneficial for metabolic syndrome. Details: A meta-analysis of clinical research shows that taking resveratrol does not improve blood pressure when compared with placebo in patients with metabolic syndrome or related disorders (102513). A similar meta-analysis shows that taking resveratrol does not improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, or liver enzymes. There was a small reduction in total cholesterol levels of approximately 7 mg/dL (105181). However, only 3-4 of the papers included in these meta-analyses, which included 28-31 publications, evaluated patients with metabolic syndrome. The remainder included patients with related conditions, such as overweight/obesity, type 2 diabetes, or nonalcoholic fatty liver disease (NAFLD). The mainly small or preliminary clinical studies that did evaluate patients with metabolic syndrome all show that taking resveratrol 100-1000 mg daily for 12-16 weeks does not improve blood pressure, glucose control, or plasma lipids (91331,95828,102513,105181). However, one preliminary clinical trial shows that taking resveratrol 500 mg three times daily for 3 months reduces body weight by about 4 kg, body mass index (BMI) by 1.3 kg/m2, fat mass by 2.4 kg, and waist circumference by 4 cm when compared to baseline (91331). The validity of these findings is limited by the lack of a comparator group. Also, a moderate-sized clinical trial of adults with metabolic syndrome shows that taking resveratrol 300 mg and delta-tocotrienols 500 mg daily for 24 weeks improves body weight, waist circumference, blood pressure, fasting blood glucose, triglycerides, total and HDL cholesterol, and markers of inflammation and oxidative stress when compared with placebo (112144). It is unclear if these effects are due to resveratrol, delta-tocotrienols, or the combination.
• Nonalcoholic fatty liver disease (NAFLD). Oral resveratrol does not seem to be beneficial for most metabolic symptoms of NAFLD. It is unclear if oral resveratrol is beneficial for improving steatosis. Details: Although some individual studies disagree, meta-analyses reviewing 4-6 preliminary clinical studies show that taking resveratrol does not affect liver enzyme levels, insulin resistance, blood pressure, blood lipids, body mass index (BMI), or abdominal size when compared with placebo in patients with NAFLD (95826,99048,105184). Most trials have studied doses of 300-3000 mg daily for 2-3 months; one study used resveratrol 500 mg 3 times daily for 6 months (95826,98911,99048,105184). However, one meta-analysis shows that taking resveratrol might have a small effect on levels of the inflammatory mediators C-reactive protein and tumor necrosis factor (TNF)-alpha (105184). It is not clear if resveratrol might reduce steatosis in patients with NAFLD. One preliminary clinical study shows that taking resveratrol 3000 mg daily in two divided doses for 8 weeks does not improve steatosis when compared to baseline in males with NAFLD (91327). However, another preliminary clinical study in adults with NAFLD shows that taking resveratrol 500 mg daily for 3 months, while following an energy-balanced diet and exercising, improves steatosis, but not fibrosis, insulin resistance, lipid levels, or body composition, when compared with lifestyle modifications alone (91328). The difference in these findings might be due to small study sizes, the duration of therapy, or the gender of the included patients.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical resveratrol is beneficial for acne. Details: Preliminary clinical research shows that applying a gel containing trans-resveratrol 1 mcg per gram to facial skin for 60 days reduces the severity of acne by about 54%, compared to only 6% for control gel (71064).
• Age-related cognitive decline. It is unclear if oral resveratrol is beneficial for age-related cognitive decline. Details: One small clinical study shows that taking resveratrol 75 mg twice daily for 14 weeks modestly improves cognitive performance and memory after menopause, but not executive function or learning, when compared with placebo (95827). Another small clinical study in healthy, older adults shows that taking resveratrol 200 mg daily for 26 weeks improves memory retention, but not delayed recall or word recognition, when compared with placebo. In this study, resveratrol capsules were formulated to also contain 320 mg of quercetin to enhance the absorption of resveratrol (102511). It is unclear if resveratrol alone would result in similar effects. Despite these positive results, conflicting research exists. A small clinical study in sedentary, overweight, elderly adults shows that taking resveratrol 300 mg daily for 90 days does not improve measures of cognitive function such as psychomotor speed, attention, executive function, learning, or memory when compared with placebo. Taking a higher dose of 1000 mg daily for 90 days modestly improves psychomotor speed, but no other cognitive measures, in these patients (98907). Another small clinical study in healthy elderly adults shows that taking resveratrol 200 mg daily for 26 weeks does not improve verbal memory when compared with placebo (98909).
• Aging skin. Although there has been interest in using oral resveratrol for aging skin, there is insufficient reliable information about the clinical effects of resveratrol for this purpose.
• Alzheimer disease. It is unclear if oral resveratrol is beneficial for improving symptoms of Alzheimer disease. Details: A meta-analysis of small clinical studies in patients with Alzheimer disease shows that taking resveratrol or trans-resveratrol up to 500 mg daily for 12 to 52 weeks improves the ability to perform activities of daily living but does not change cognitive function when compared with placebo (114517).
• Beta-thalassemia. It is unclear if oral resveratrol is beneficial for beta-thalassemia. Details: A small clinical study in patients with beta-thalassemia intermedia shows that taking micronized trans-resveratrol (Xian Tianxingjian Natural Bio-Products CO., LTD) 2000 mg with piperine (Bioprex Co.) 40 mg, with or without hydroxyurea 8-15 mg/kg, daily for 6 months does not improve hemoglobin levels or affect the need for blood transfusion when compared with taking placebo with or without hydroxyurea (98908).
• Cancer. It is unclear if dietary resveratrol is beneficial for cancer prevention. Details: Population research has found that a higher dietary intake of resveratrol is not associated with a reduced risk of cancer when compared to lower dietary intake (91334).
• Chronic obstructive pulmonary disease (COPD). Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of resveratrol 10 mg, vitamin C 180 mg, zinc 15 mg, and flavonoids 160 mg daily for 20 days followed by 10 days without supplementation, repeated for three cycles, modestly reduces symptoms of cough and sputum production in patients with mild-to-moderate COPD when compared with control (71130). It is not clear if these effects are due to resveratrol, the other ingredients, or the combination.
• Cognitive function. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy young adults shows that taking a specific supplement (Transmax by BiotiviaTM) containing trans-resveratrol 500 mg and piperine 10 mg daily for 28 days does not improve most measures of cognitive performance when compared with placebo (95834).
• Cognitive impairment. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in a small number of patients with mild cognitive impairment shows that taking resveratrol 200 mg and quercetin 350 mg daily for 26 weeks does not improve learning and memory performance when compared with placebo (102512). However, given the small sample size, it is possible this study was inadequately powered to detect significant changes in these cognitive measures.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral resveratrol is beneficial for COVID-19. Details: A small clinical trial in outpatients with COVID-19 shows that taking resveratrol (Vita-Age) 1 gram four times daily, for 7-15 days based on symptom duration, does not reduce the rate of hospitalization, emergency room visits, or pneumonia when compared with placebo. All patients also received a single dose of Vitamin D3 (109164). This study may have been inadequately powered to detect differences between groups.
• Diabetes. Some research shows that oral resveratrol is beneficial for improving glycemic indices in patients with type 2 diabetes. However, more research is needed to determine the most effective dose or the patient population most likely to benefit. Details: Although results from individual clinical studies have been mixed (91329,95825,95832,100695,109165,109167,109170), meta-analyses of clinical research show that resveratrol modestly reduces blood glucose and glycated hemoglobin (HbA1c) levels in patients with diabetes. Studies lasted 4-24 weeks and many included patients treated with antidiabetes medications, including metformin. However, these meta-analyses have yielded differing findings regarding effective doses (91329,109165,109167,109170). One meta-analysis of clinical research in individuals aged 45 years and older shows that doses of 250-1000 mg daily modestly reduce levels of fasting blood glucose, insulin, and HbA1c, as well as insulin resistance, when compared with placebo. Doses of up to 250 mg daily are generally ineffective, and only one study used doses greater than 1000 mg daily. Although sub-analyses suggest that these benefits may be limited to individuals aged 45-59 years, the number of studies in older individuals is small and findings are unclear (109165). A second meta-analysis in adults with type 2 diabetes suggests that resveratrol doses of at least 500 mg daily were necessary for reducing levels of fasting blood glucose and insulin, as well as insulin resistance (109167). A third meta-analysis, which also included Chinese language publications, shows that doses of resveratrol of at least 1000 mg daily are needed for improved glycemic control (109170). Some studies have used a specific resveratrol product (Biotivia Bioceuticals, International SrL) (95825). Although the reasons for discrepancies between individual clinical trials are not clear, it is possible that conflicting results are related to baseline blood glucose control. Resveratrol has shown benefit in patients with diabetes that is not well-controlled at baseline (HbA1c of 8% or higher) (91329), while results are mixed in patients with diabetes that is at least moderately well-controlled prior to supplementation (HbA1c of 7% or lower) (95825,100695). It is also possible that the differences may relate to the technique used to measure outcomes. For instance, resveratrol appears to improve insulin resistance when measured by the Stumvoll insulin sensitivity index, but not by the gold-standard hyperinsulinemic-euglycemic clamp technique (95832). Resveratrol has also been evaluated for improving blood pressure, blood lipid, and liver transaminase levels in patients with type 2 diabetes. Meta-analyses of clinical trials show that resveratrol has a small, but likely clinically insignificant, effect on systolic blood pressure when compared with placebo. Two meta-analyses show similar findings for diastolic blood pressure; however, some research suggests that any benefits are limited to doses of at least 500 mg daily (102513,109167,109170). Most meta-analyses of clinical research show that resveratrol does not improve blood lipid levels (105181,109167,109170) or liver transaminase levels (105181) when compared with placebo. Other clinical research in patients with overweight and type 2 diabetes shows that taking resveratrol 1000 mg daily for 8 weeks does not affect hepatic steatosis or cardiovascular risk indices when compared with placebo (109169).
• Diabetic nephropathy. It is unclear if oral resveratrol is beneficial for diabetic nephropathy. Details: Preliminary clinical research in patients with diabetic nephropathy shows that taking resveratrol 500 mg plus losartan 12.5 mg daily for 90 days can reduce urinary albumin-to-creatinine ratios, but not serum creatinine levels or glomerular filtration rates, when compared with taking placebo and losartan. When compared to baseline, the urinary albumin-to-creatinine ratio decreased by 46 mg/gram with resveratrol and increased by 25 mg/gram with placebo (100695).
• Hypertension. It is unclear if oral resveratrol is beneficial for lowering blood pressure. Details: A meta-analysis of clinical research shows that resveratrol is unlikely to be beneficial for improving systolic or diastolic blood pressure when compared with placebo in patients with hypertension. In the meta-analysis, studied populations included people who are overweight or obese, as well as patients with hypertension, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), stroke, and dyslipidemia (102513). More research is needed in patients with hypertension.
• Migraine headache. It is unclear if oral resveratrol is beneficial for treating migraine headache. Details: A small clinical crossover study in patients with hormonal migraine headaches shows that taking resveratrol (Veri-te Resveratrol, Evolva SA) 75 mg twice daily for 3 months does not affect headache frequency, severity, or disability when compared with placebo (109166). However, this study did not include a wash-out period between treatments, introducing the potential for carry-over effects.
• Mitochondrial myopathies. It is unclear if oral resveratrol is beneficial for increasing exercise tolerance in patients with mitochondrial myopathies. Details: A very small clinical trial in adults with mitochondrial myopathies shows that taking resveratrol (Veri-te resveratrol) 500 mg twice daily for 8 weeks does not improve exercise capacity when compared with placebo (109162). This study may have been inadequately powered to detect differences between groups.
• Osteoarthritis. It is unclear if oral resveratrol is beneficial for osteoarthritis. Details: A small clinical study in patients with mild or moderate knee osteoarthritis receiving physical therapy and meloxicam 15 mg daily shows that adding resveratrol 500 mg daily for 90 days improves pain, function, and stiffness when compared with adding placebo (98910).
• Osteopenia. It is unclear if oral resveratrol is beneficial for improving bone mineral density (BMD). Details: A meta-analysis of clinical research shows that taking resveratrol at doses of up to 1500 mg daily for 1-12 months does not increase BMD or alter bone biomarkers when compared with placebo (109163). The studies in this meta-analysis included various populations, such as postmenopausal or overweight individuals, or patients with type 2 diabetes or metabolic syndrome. However, a clinical study in healthy, postmenopausal females shows that taking fermented soy 200 mg, containing resveratrol 25 mg and equol 10mg, orally daily for 12 months increases whole-body BMD when compared with placebo. Levels of markers of bone formation, including osteocalcin and bone-specific alkaline phosphatase, are increased, and the level of deoxypyridinoline, a marker of bone resorption, is decreased (112942).
• Periodontitis. It is unclear if oral resveratrol is beneficial for periodontitis. Details: A small clinical study in individuals with chronic moderate-to-severe periodontitis who recently received non-surgical treatment for periodontitis shows that taking resveratrol 480 mg daily for 4 weeks improves plaque index when compared with placebo, but resveratrol does not seem to improve other markers of periodontitis, including pocket depth, bleeding index, clinical attachment loss, or salivary markers of inflammation (112135). The study may have been inadequately powered and too short in duration to detect a difference between the groups.
• Peritoneal dialysis. It is unclear if oral resveratrol can improve outcomes with peritoneal dialysis. Details: One clinical study shows that taking trans-resveratrol 150 mg or 450 mg daily for 12 weeks increases ultrafiltration rate and volume when compared with placebo in patients on peritoneal dialysis. The effect appears to be dose-dependent (95830).
• Polycystic ovary syndrome (PCOS). It is unclear if oral resveratrol is beneficial for PCOS. Details: Clinical research in patients with PCOS shows that taking resveratrol 1000 mg daily for 3 months results in a regular menstruation cycle length in 77% of individuals, compared with 52% of those taking placebo. The occurrence of hair loss was reduced by about 50%; however, there was no effect on hormone, metabolic, or lipid profiles. There was also a small increase in fat mass and decrease in fat-free mass, although the clinical relevance of these changes is unclear (109131). A small clinical trial in adults with PCOS shows that taking micronized trans-resveratrol (RevGenetics) 1500 mg daily for 3 months decreases levels of testosterone, but does not improve weight, lipid levels, insulin sensitivity, acne, or hirsutism, when compared with placebo (95823). A meta-analysis of 4 controlled trials of resveratrol, taken orally in doses of 800-1500 mg daily for 40 days to 3 months, shows reductions in levels of testosterone, luteinizing hormone, and dehydroepiandrosterone sulfate when compared with placebo, but no effect on follicle stimulating hormone, prolactin, thyroid stimulating hormone, C-reactive protein, insulin, sex hormone binding globulin, lipids, acne, or pregnancy rates (112943).
• Rheumatoid arthritis (RA). It is unclear if oral resveratrol is beneficial for RA. Details: A small clinical study shows that adding resveratrol 1 gram orally once daily as adjunct therapy to antirheumatic drugs for 2 months reduces the number of tender and swollen joints, as well as biomarkers of inflammation. It is not known whether resveratrol reduces joint damage when assessed using conventional radiography. Also, the most effective combination of resveratrol and antirheumatic drug is not known, since the patients in this study were taking different antirheumatic drugs at variable doses (95706).
• Sciatica. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with sciatica secondary to a herniated disk shows that taking a combination of resveratrol 50 mg with alpha-lipoic acid, acetyl-L-carnitine, and cholecalciferol orally once daily for 30 days, concurrently with a physiotherapy protocol, reduces pain and disability, and improves quality of life when compared with the physiotherapy protocol alone (112933). It is unclear if the effects are due to resveratrol, other ingredients, or the combination.
• Ulcerative colitis. It is unclear if oral resveratrol is beneficial for ulcerative colitis. Details: Preliminary clinical research shows that taking trans-resveratrol (Sumabe Company) 500 mg daily for 6 weeks reduces subjective measures of disease activity and improves quality of life measures when compared with placebo in patients with mild to moderate active ulcerative colitis (95831). However, a small clinical trial in patients with mild to moderate active ulcerative colitis shows that taking resveratrol (VeNatura Resveratrol Supplement) 250 mg twice daily for 8 weeks, while following the Mediterranean diet, is not more effective for improving ulcerative colitis symptom severity than following the Mediterranean diet without supplemental resveratrol (113339). More evidence is needed to rate resveratrol for these uses.

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LIKELY SAFE ...when used orally and appropriately in doses of up to 6 grams daily (698,10631). However, some patients have used up to 20 grams daily with apparent safety (698). Betaine anhydrous is available as an FDA-approved prescription product (Cystadane) (698), and also as a supplement. The European Food Safety Authority states that betaine anhydrous is safe to use in doses up to 6 mg/kg daily, in addition to usual dietary intake (105548). There is insufficient reliable information available about the safety of topical betaine anhydrous.

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses up to 150 mg/kg daily (698). However, some patients have used up to 20 grams daily with apparent safety (698). Prescription betaine anhydrous (Cystadane) is approved by the US FDA for use in infants and children (698).

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

(Read more about BETAINE ANHYDROUS)

POSSIBLY SAFE ...when nicotinamide riboside chloride is used orally and appropriately. The European Food Safety Authority has set a tolerable upper intake level (UL) of 300 mg daily for nicotinamide riboside chloride (104937,107706). In clinical research, higher doses have been used for up to 12 weeks (110504,110506). A specific nicotinamide riboside branded ingredient (Niagen, ChromaDex) 1000 mg has been used twice daily for 12 weeks with apparent safety (94744,94745,94746,102035).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when nicotinamide riboside chloride is used orally and appropriately. The European Food Safety Authority has determined that taking nicotinamide riboside chloride in doses of up to 230 mg daily is safe when pregnant or breastfeeding (104937,107706).

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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 in amounts found in foods (2030).

POSSIBLY SAFE ...when taken orally in doses of up to 1500 mg daily for up to 3 months (71066,71097,91328,91331,95825,95833,98910,100695,105183,109163,109167). Higher doses of 2000-3000 mg daily have been well tolerated when taken for 2-6 months, but are more likely to cause gastrointestinal side effects (91327,98908). ...when used topically for up to 30 days (71064). ...when used as an intranasal spray for up to 4 weeks (97339).

CHILDREN: LIKELY SAFE
when used in amounts found in foods.

CHILDREN: POSSIBLY SAFE
when used as an intranasal spray for up to 2 months in children 4 years of age and older (91332). There is insufficient reliable information available about the safety of resveratrol when used by mouth in larger amounts as medicine.

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts found in foods (2030). Resveratrol is found in grape skins, grape juice, wine, and other food sources. However, wine should not be used as a source of resveratrol during pregnancy and lactation.

(Read more about RESVERATROL)

(Read more about BETAINE ANHYDROUS)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, nicotinamide riboside may have additive effects with antihypertensive drugs, potentially increasing the risk for hypotension.  Details One small clinical study suggests that nicotinamide riboside can modestly reduce blood pressure in hypertensive patients (94744). However, other clinical research did not find a reduction in blood pressure when compared with control (104935).

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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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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Resveratrol may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Resveratrol seems to have antiplatelet effects (2949,2950,2951,2952,2961,70813,70828,70831,70892,70968,71106).

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1A1.  Details In vitro research shows that resveratrol can inhibit CYP1A1 enzymes (70811,70862). However, this interaction has not been reported in humans.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that resveratrol can inhibit CYP1A2 enzymes (21733). However, this interaction has not been reported in humans.

CYTOCHROME P450 1B1 (CYP1B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1B1.  Details In vitro research shows that resveratrol can inhibit CYP1B1 enzymes (70834). However, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP2C19.  Details In vitro research shows that resveratrol can inhibit CYP2C19 enzymes (70896). However, this interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Resveratrol might increase levels of drugs metabolized by CYP2E1.  Details In vitro research suggests that resveratrol inhibits CYP2E1 isoenzyme (7864,70896). Also, a pharmacokinetic study shows that taking resveratrol 500 mg daily for 10 days prior to taking a single dose of chlorzoxazone 250 mg increases the maximum concentration of chlorzoxazone by about 54%, the area under the curve of chlorzoxazone by about 72%, and the half-life of chlorzoxazone by about 35% (95824). Chlorzoxazone is used as a probe drug for CYP2E1.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that resveratrol can inhibit the CYP3A4 enzyme (7864,70896). However, clinical research shows that taking resveratrol 3000 mg daily for 8 weeks does not necessitate dose adjustments to medications metabolized by CYP3A4 (91327).

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General ...Orally, betaine anhydrous is generally well tolerated.
Most Common Adverse Effects:
Orally: Body odor, diarrhea, elevated cholesterol levels, GI distress, nausea, vomiting.
Serious Adverse Effects (Rare):
Orally: Cerebral edema.

Cardiovascular ...Betaine anhydrous might have adverse effects on the plasma lipid profile. Some studies have reported a 3% to 4% increase in total and low-density lipoprotein (LDL) cholesterol levels with betaine anhydrous 6 grams daily (16452,16455,16456,34904). A meta-analysis of 6 studies in adults, some with obesity and/or prediabetes, shows that taking betaine anhydrous 4-6 grams daily for 6-24 weeks is associated with a mean increase in total cholesterol of 4 mg/dL, with no significant change in LDL cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels (105814). Another meta-analysis of 12 studies, some in healthy adults and others in adults with various disease states, shows that taking betaine anhydrous 1.5-20 grams daily for 2-52 weeks is associated with a mean increase in total cholesterol of 14 mg/dL, and a mean increase in LDL cholesterol of 10 mg/dL, with no change in triglyceride or HDL cholesterol levels (105813).

Gastrointestinal ...Orally, betaine anhydrous can cause vomiting, nausea, GI distress, and diarrhea (698,10631,34888,34928,111374).

Neurologic/CNS ...When used orally to treat homocystinuria due to cystathionine beta-synthase deficiency, elevated plasma methionine concentrations can occur following use of betaine anhydrous, which might lead to cerebral edema (698,111374).

Other ...Orally, betaine anhydrous can cause body odor (698,10631).

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General ...Orally, nicotinamide riboside seems to be well tolerated.
Most Common Adverse Effects:
Orally: Bloating, muscle pain, nausea, pruritus, sweating, and transient changes in stools.

Dermatologic ...Orally, mild cases of flushing, skin rash, pruritus, and excessive sweating have been reported in clinical trials for some patients taking nicotinamide riboside (Niagen, ChromaDex) (94744,94745). However, flushing and skin rash were reported at the same rate in patients receiving placebo (94744).

Gastrointestinal ...Orally, mild cases of nausea, bloating, and transient changes in stools have been reported in clinical trials for some patients taking nicotinamide riboside (Niagen, ChromaDex) (94744,94745,102035).
Other gastrointestinal adverse effects such as abdominal discomfort, diarrhea, and dyspepsia have been reported with oral use of a combination product (Basis, Elysium Health) containing nicotinamide riboside and pterostilbene (94747). It is unclear if these effects were due to nicotinamide riboside, pterostilbene, or the combination.

Hematologic ...Orally, increased bruising was reported in one clinical trial for one patient taking nicotinamide riboside (Niagen, ChromaDex) (94744).

Musculoskeletal ...Orally, leg cramps were reported in one clinical trial for one patient taking nicotinamide riboside (Niagen, ChromaDex) (94744). Some patients taking this specific nicotinamide riboside product in another clinical trial have reported mild muscle pain or soreness (102035).

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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 ...In foods, resveratrol is well tolerated. When used orally in higher doses, as well as topically or intranasally, resveratrol seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal discomfort, and loose stools.

Dermatologic ...Orally, there is one case of a pruritic skin rash that occurred in a clinical trial. The rash resolved two weeks after stopping resveratrol (109163).
Topically, a case of allergic contact dermatitis has been reported after applying a facial cream (Resveratrol BE, Skinceuticals) containing aqueous resveratrol 1% in combination with Baikal skullcap root extract 0.5%. Patch testing identified a positive reaction to both ingredients (110024).

Gastrointestinal ...Orally, mild gastrointestinal discomfort with increased diarrhea or loose stools has been reported, especially when resveratrol is taken in doses of 2. 5-5 grams daily (71042,71052,91327,95830,109163,109164,109167).

Hematologic ...In one clinical study, a patient developed severe febrile leukopenia and thrombocytopenia after taking oral resveratrol 500 mg three times daily for 10 days. Upon re-exposure to resveratrol, febrile leukopenia recurred (109163).

Musculoskeletal ...Orally, resveratrol has been associated with muscle cramps in patients on peritoneal dialysis. The causality of this adverse effect has not been established (95830).

Neurologic/CNS ...Orally, resveratrol has been associated with headache, fatigue, and memory loss in patients on peritoneal dialysis. The causality of these adverse effects has not been established (95830).

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