Resveratrol Plus by Nora Ross

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Amenorrhea. Although there has been interest in using oral cassia cinnamon for amenorrhea, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Angina. Although there has been interest in using oral cassia cinnamon for angina, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Common cold. Although there has been interest in using oral cassia cinnamon for the common cold, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Diabetes. Several clinical trials have evaluated oral cassia cinnamon for type 2 diabetes, but results are conflicting. Details: Some clinical studies and meta-analyses of cassia cinnamon have found significant benefits in patients with diabetes (11347,17011,21914,21918,89646,89649), while others have not (14344,16010,17689,21915,21916,89650). Results from meta-analyses are also mixed with respect to lowering fasting blood glucose and lipid levels (89647,108264). A meta-analysis including more than 500 adults with type 2 diabetes show that taking cassia cinnamon 120 mg To 14.4 grams daily for 4-18 weeks reduces fasting blood glucose by an average of 25 mg/dL, total cholesterol by 16 mg/dL, low-density lipoprotein (LDL) cholesterol by 9 mg/dL, and triglycerides by 30 mg/dL, and increases high-density lipoprotein (HDL) cholesterol by 2 mg/dL (89647). Analyses included studies examining either extract or powder, and two of the studies included used an unspecified type of cinnamon. In contrast, a more recent meta-analysis of studies limited to cassia cinnamon ground bark powder 1-2 grams daily for 40-90 days shows no benefit on fasting blood glucose or lipid levels (108264). Evidence regarding cassia cinnamon's effect on glycated hemoglobin (HbA1c) is mixed. In patients with type 2 diabetes, a meta-analysis of 18 low-quality clinical studies shows that cassia cinnamon lowers HbA1c by about 0.6% when compared with placebo (113675). However, other studies suggest that cassia cinnamon does not change HbA1c, although some of the studies were too short to detect a change (89647,108264). The individual studies included in the meta-analyses were also small, and very heterogenous in relation to dose, duration, use of conventional medications, and diabetes control at baseline (89647,108264). Cassia cinnamon has also been evaluated in combination with other ingredients. A study in treatment-naïve adults newly diagnosed with type 2 diabetes shows that taking a combination product containing cassia cinnamon extract 100 mg, black seed extract, and ficin extract (NW Low-Glu) 4-5 times daily for 12 weeks reduces HbA1c by 0.6-0.8% and 2-hour postprandial glucose by 25-35 mg/dl when compared to baseline, with similar findings when compared with metformin. However, there were no notable differences in fasting blood glucose, insulin resistance, and beta cell function (111710). It is unclear if these effects are due to cassia cinnamon, other ingredients, or the combination. In patients with type 1 diabetes, clinical research shows that taking cassia cinnamon daily does not improve fasting blood glucose, HbA1c, insulin sensitivity, or the rate of hypoglycemic episodes (16010,89648).
• Diarrhea. It is unclear if oral cassia cinnamon is beneficial for diarrhea. Details: A moderate-sized clinical study in adults with diarrhea shows that taking cinnamon water extract 1200 mg twice daily for 8 weeks increases colonic transit time by about 10 hours but does not improve other symptoms of diarrhea including percentage of bowel movements with diarrhea, Bristol stool scale score, abdominal pain, bowel urgency, or abdominal distension when compared with placebo (111712).
• Dyslipidemia. It is unclear if oral cassia cinnamon is beneficial for dyslipidemia. Details: A meta-analysis of 12 clinical studies in adults with metabolic syndrome, polycystic ovary syndrome (PCOS), nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, prediabetes, and overweight or obesity shows that taking cassia cinnamon daily for 2-4 months reduces total cholesterol by 7 mg/dL, triglycerides by 9 mg/dL, and low-density lipoprotein (LDL) cholesterol by 6 mg/dL but does not increase high-density lipoprotein (HDL) cholesterol. Subgroup analysis suggests that cassia cinnamon improves lipid profiles of Asian patients but not European or American patients. Additionally, higher doses appear to regulate lipid profiles better, and cassia cinnamon doses above 1.5 grams daily increase high-density lipoprotein cholesterol by about 2.5 mg/dL. Subgroup analysis also shows that cassia cinnamon only reduces triglycerides for patients with metabolic syndrome and increases HDL cholesterol for patients with PCOS but does not impact total cholesterol for those with type 2 diabetes (111709).
• Erectile dysfunction (ED). Although there has been interest in using oral cassia cinnamon for ED, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Hypertension. Although there has been interest in using oral cassia cinnamon for hypertension, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Impaired glucose tolerance (prediabetes). The effects of cassia cinnamon in patients with impaired glucose tolerance are unclear; results from clinical research are conflicting. Details: A small clinical study in patients with impaired glucose tolerance shows that taking cassia cinnamon powder 6 grams twice daily for 12 weeks does not improve fasting plasma glucose or insulin sensitivity when compared with placebo (96280). However, another clinical study in overweight or obese patients with impaired fasting blood glucose shows that taking a dried aqueous extract of cassia cinnamon 250 mg twice daily for 12 weeks reduces fasting blood glucose by about 12 mg/dL when compared with baseline, but does not affect fasting insulin levels (93118). Another preliminary clinical trial in overweight or obese patients with impaired glucose tolerance shows that taking two capsules of a specific combination product, (Glycabiane, PiLeJe) containing cassia cinnamon extract 228 mg, chromium chloride 10 mcg, and carnosine 100 mg per capsule, daily for 4 months decreases fasting blood glucose by 6.5 mg/dL but has no effect on glycated hemoglobin (HbA1c), insulin sensitivity, or body weight, when compared with placebo (94234). It is unclear whether these effects are due to cassia cinnamon, ingredients, or the combination.
• Mosquito repellent. It is unclear if topical cassia cinnamon is beneficial as a mosquito repellent. Details: Preliminary clinical research suggests that applying a cream containing cassia cinnamon oil 5% to the skin provides protection from mosquito bites. However, the repellency of this cream appears to decrease more quickly over time compared to MeiMei cream (containing citronella and geranium oils) and Repellan S aerosol (containing 19% N,N-diethyl-m-toluamide (DEET)) (59580).
• Muscle cramps. Although there has been interest in using oral cassia cinnamon for muscle cramps, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Nausea and vomiting. Although there has been interest in using oral cassia cinnamon for nausea and vomiting, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Obesity. It is unclear if oral cassia cinnamon is beneficial for weight loss. Details: Preliminary clinical research in a small number of patients with overweight or obesity and impaired glucose tolerance shows that taking two capsules of a specific combination product (Glycabiane, PiLeJe) containing cassia cinnamon extract 228 mg, chromium chloride 10 mcg, and carnosine 100 mg per capsule, daily for 4 months does not decrease body weight, BMI, fat mass, or lipid levels when compared with placebo (94234). A very small clinical study in healthy adults shows that drinking a single dose of cinnamon infusion containing 2 grams of powdered cinnamon served along with breakfast does not increase energy expenditure, diet-induced thermogenesis, respiratory quotient, or lipid and carbohydrate oxidation and does not affect appetite responses including hunger, fullness, desire to eat, macronutrient intake, and food intake throughout the day when compared with control. Furthermore, cassia cinnamon intake reduces feelings of satiety and increases energy intake in the first meal after the intervention when compared with control (111707). The validity of these findings is limited by a lack of blinding.
• Polycystic ovary syndrome (PCOS). It is unclear if oral cassia cinnamon is beneficial for patients with PCOS. Details: A small observational study in adults with PCOS suggests that taking cinnamon 500 mg three times daily for 8 weeks is associated with decreased body weight, body mass index, insulin resistance, and testosterone but does not appear to alter levels of luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone (DHEA), insulin, or lipids when compared with placebo (113514).
• Stroke. It is unclear if oral cassia cinnamon is beneficial for stroke prevention. Details: Preliminary clinical research in patients with a mild ischemic stroke or transient ischemic attack shows that taking cinnamon (Chinese herbal formula granules, Guangdong Yifang Pharmaceutical Co, Ltd) 5 grams with aspirin 100 mg daily for 90 days, starting within 24 hours of the ischemia, reduces the percentage of patients with a recurrent stroke to 3%, compared with 15% of those taking aspirin plus placebo. There were also modest improvements in levels of plasma lipids, glucose, and glycated hemoglobin, as well as a reduced likelihood of identifying unstable or severe plaques on carotid ultrasound (108265). The use of cassia cinnamon, specifically, was not confirmed; however, this species of cinnamon is commonly used in traditional Chinese medicine, as indicated in the study.
• Urinary incontinence. Although there has been interest in using oral cassia cinnamon for urinary incontinence, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose. More evidence is needed to rate cassia cinnamon for these uses.

(Read more about CASSIA CINNAMON)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Gingivitis. Preliminary clinical research shows that using a mouth rinse containing 1 mg/mL of a knotweed root extract twice daily for 14 days, without any brushing, might reduce bleeding and inflammation of the gums associated with gingivitis, and make plaque easier to remove (9347). More evidence is needed to rate knotweed for this use.

(Read more about KNOTWEED)

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 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). One clinical trial also shows that taking resveratrol 150 mg daily for 6 months reduces glycated hemoglobin (HbA1c) by a small amount when compared with placebo in individuals with overweight or obesity but has no effect on insulin sensitivity, fat mass, or levels of fasting blood glucose, lipids, or liver enzymes (105183). Also, meta-analyses of clinical research show that resveratrol is unlikely to be beneficial for improving blood pressure or blood lipids when compared with placebo in individuals with overweight or obesity (102513,105181).

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.
• 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). More evidence is needed to rate resveratrol for these uses.

(Read more about RESVERATROL)

LIKELY SAFE ...when consumed in amounts commonly found in foods. Cassia cinnamon has Generally Recognized As Safe (GRAS) status in the US for use as a spice or flavoring agent (4912) ...when used orally and appropriately, short-term. Cassia cinnamon 1-2 grams daily has been used safely for up to 3 months (17011,21914). Cassia cinnamon 3-6 grams daily has been used safely for up to 6 weeks (11347,14344). Cassia cinnamon extract corresponding to 3 grams daily of cassia cinnamon powder has also been used safely for up to 4 months (21916).

POSSIBLY SAFE ...when used topically, short-term. Cassia cinnamon oil 5% cream applied topically to the legs has been used safely in one clinical trial (59580).

POSSIBLY UNSAFE ...when used orally in high doses, long-term. Some cassia cinnamon products contain high levels of coumarin. Coumarin can cause hepatotoxicity in animal models (15299,21920). In humans, very high doses of coumarin from 50-7000 mg daily can result in hepatotoxicity that resolves when coumarin use is discontinued (15302). In most cases, ingestion of cassia cinnamon will not provide a high enough amount of coumarin to cause significant toxicity; however, in especially sensitive people, such as those with liver disease, prolonged ingestion of large amounts of cassia cinnamon might exacerbate the condition.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Cassia cinnamon 1 gram daily has been used safely in adolescents 13-18 years of age for up to 3 months (89648).

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods (4912). There is insufficient reliable information available about the safety of cassia cinnamon when used in medicinal amounts during pregnancy and breast-feeding. Stay on the safe side and stick to food amounts.

(Read more about CASSIA CINNAMON)

POSSIBLY SAFE ...when knotweed is used as a tea in doses up to 6 grams daily of dried plant (2,18) . ...when used topically twice daily for 14 days as a dental rinse containing 1mg/mL knotweed root extract (9347).

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

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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.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cassia cinnamon may have additive effects with antidiabetes drugs.  Details Cassia cinnamon may lower blood glucose levels, and have additive effects in patients treated with antidiabetic agents (11347,17011,21914,21918,89649). Dose adjustments to diabetes medications might be necessary.

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, large doses of cassia cinnamon might cause additive effects when used with hepatotoxic drugs.  Details There is some concern that ingesting large amounts of cassia cinnamon for an extended duration might cause hepatotoxicity in some people. Cassia cinnamon contains coumarin, which can cause hepatotoxicity in animal models (15299,21920). In humans, very high doses of coumarin from 50-7000 mg/day can result in hepatotoxicity that resolves when coumarin use is discontinued (15302,97249). Lower amounts might also cause liver problems in sensitive people, such as those with liver disease or those taking potentially hepatotoxic agents.

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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, cassia cinnamon appears to be well-tolerated. Significant side effects have not been reported in most patients.
Most Common Adverse Effects:
Topically: Burning mouth, stomatitis.

Dermatologic ...In one clinical trial, a rash was reported in one patient taking cassia cinnamon 1 gram daily for 90 days (17011).
In one case, a 58-year-old female with a documented allergy to topically applied cinnamic alcohol presented with eyelid dermatitis, which was found to be a manifestation of systemic contact dermatitis to cinnamon in the diet. Symptoms improved in two days and completely cleared five days after discontinuing the addition of cinnamon to food products (95599). In other case reports, two adults presented with allergic contact cheilitis following the ingestion of chai tea with cinnamon and yogurt with cinnamon. Cinnamon components were confirmed as the causative allergic agents with patch tests, and both cases of allergic contact cheilitis completely resolved upon cessation of the cinnamon-containing products (113516,113515).
Topically, allergic skin reactions and stomatitis from toothpaste flavored with cassia cinnamon have been reported (11915,11920). Intraoral allergic reactions with symptoms of tenderness and burning sensations of the oral mucosa have also been reported in patients using breath fresheners, toothpaste, mouthwash, candy, or chewing gum containing cinnamon, cinnamic aldehyde or cinnamic alcohol as flavoring agents. Glossodynia, or burning mouth syndrome, has also been reported in a 62-year-old female who ate apples dipped in cinnamon nightly (95598), and allergic contact dermatitis has been reported in a teenage female using a homemade cinnamon sugar face scrub (95596).

Endocrine ...In one clinical trial, a hypoglycemic seizure was reported in one patient taking cassia cinnamon 1 gram daily for 3 months. The event occurred one day after enrolling in the study (89648). It is unclear if cassia cinnamon caused this event.

Hepatic ...There is some concern about the safety of ingesting large amounts of cassia cinnamon for extended durations due to its coumarin content. Coumarin can cause hepatotoxicity in animal models (15299). In humans, very high doses of coumarin from 50-7000 mg/day can result in hepatotoxicity that resolves when coumarin is discontinued (15302). In clinical trials, taking cassia cinnamon 360 mg to 12 grams daily for 3 months did not significantly increase levels of aspartate transaminase (AST) or alanine transaminase (ALT) (21918,96280,108259). However, in one case report, acute hepatitis with elevated AST and ALT occurred in a 73-year-old female who started taking a cinnamon supplement (dose unknown) one week prior to admission. The cinnamon supplement was added on to high-dose rosuvastatin, which may have led to additive adverse hepatic effects. After discontinuing both products, liver function returned to normal, and the patient was able to restart rosuvastati without further complications (97249). In most cases, ingestion of cassia cinnamon won't provide a high enough amount of coumarin to cause significant toxicity; however, in especially sensitive people, such as those with liver disease or taking potentially hepatotoxic agents, prolonged ingestion of large amounts of cassia cinnamon might exacerbate the condition.

Immunologic ...An unspecified allergic reaction was reported in one patient taking cassia cinnamon 1 gram daily for 3 months (89648).

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General ...No adverse effects have been reported. However, a high-quality assessment of safety has not been conducted.

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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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