Table 2.

Published Clinical Trials Dealing with the Effects of Resveratrol on Human Health

Cohort and sample size (n)	Trial design, resveratrol dose and time of intervention	Objective	Main outcome	Reference
Subjects with established disease and/or under medication
Patients with colon cancer (n=8).	Four parallel arms, randomized trial. Placebo-uncontrolled. Unblinded. Daily ingestion (for 19 days) of: 80 g grape powder (GP) with 0.07 mg RES, n=3; or 120 g GP with 0.11 mg RES, n=2; or 3.9 mg RES + 120 mg quercetin, n=2; or 15.5 mg RES + 480 mg quercetin, n=1. GP was dissolved in water. RES+quercetin in capsules. Registration number: NCT00256334a.	Changes in Wnt pathway in normal and cancer colon tissues after surgery.	Inhibition of some genes from Wnt pathway only in normal tissue.	[264]
Patients with colorectal cancer (n=20).	Two parallel arms, non-randomized, placebo uncontrolled. Blinded-analysis was performed. Daily ingestion (for 8 days) of 0.5 g, n=10; or 1 g micronized RES, n=10. RES in capsules.	Detection of RES and derived metabolites in colorectal tissue, and effect on proliferation marker Ki-67.	Ki-67 level was reduced by 5% and 7% in cancer and normal tissue, respectively.	[260]
Patients with colorectal cancer and hepatic metastasis (n=6).	Two parallel arms, randomized, placebo-controlled trial. Preoperative daily ingestion (from 10 to 21 days) of a sachet containing 5 g of micronized RES or placebo. Registration number: NCT00920803	Pharmacokinetics, tissue disposition and effect on apoptosis marker (cleaved caspase-3).	Detection of RES in hepatic tissue and increased (39%) content of cleaved caspase-3 in this tissue. RES was well tolerated. Higher RES bioavailability than that reported for standard RES.	[263]
Type 2 male diabetics (n=19).	Two parallel arms, randomized, double-blind, placebo-controlled trial. Follow-up: 4 weeks. Daily ingestion of 10 mg RES, n=10 or placebo, n=9. RES in capsules.	Effect on insulin sensitivity and explore the possible related mechanisms.	Decrease of insulin resistance possibly due to a decrease of oxidative stress and improvement of insulin signaling via the Akt pathway.	[267]
Patients with metabolic syndrome (n=34).	Randomized, cross-over, unblinded, and placebo- uncontrolled. Follow-up for 6 months but effective treatment with RES was for 3 months and then discontinued, i.e. first 3 months group A, n=17, daily ingested 100 mg RES and for the second 3 months did not. The inverse pattern in group B, n=17. RES in capsules	Improvement of endothelial function in medicated patients with metabolic syndrome.	In both groups, FMD increased approximately from 4% to 9% and returned to baseline values after discontinuation of RES treatment. No effects were observed on some inflammatory and atherogenic markers.	[269]
Patients on statin treatment and at high risk of CVD (n=75).	Three parallel arms, randomized, triple-blind, placebo-controlled trial. Follow-up: 6 months daily ingestion of 350 mg placebo (n=25), resveratrol-containing grape extract (GE-RES, grape phenolics + 8 mg RES, n=25) or conventional grape extract lacking RES (GE). Study products in capsules. Registration number: NCT01449110.	Effects on atherogenic makers, i.e. serum lipid profile, ApoB and LDLox.	GE-RES nutraceutical decreased ApoB (-9.8%) and LDLox (-20%) in patients beyond their treatment according to standard guidelines for primary prevention of CVD. No drug interactions were detected. No adverse effects on hematological profile, hepatic, thyroid and renal functions.	[270]
Type 2 diabetics (n=62).	Randomized, 2 parallel arms trial. Placebo uncontrolled. Unblinded. Follow up: 3 months daily ingestion of hypoglucemic drugs + 250 mg RES (n=28) or only hypoglucemic drugs in control group (n=29). Study products in capsules. Registration number (India): CTRI/2011/05/001731.	Effects on glycemic control and associated risk markers.	RES improved systolic and diastolic blood pressures, HbA1c (-5%), total cholesterol and LDLc concentrations.	[274]
Overweight/obese and moderately insulin resistant older adults (n=10).	Randomized assignment to take RES capsules for 4 weeks in one of the three doses: 1, 1.5, and 2 g/day, taken in divided doses. Open-label, uncontrolled study design. Registration number: NCT01375959.	Glucose metabolism and vascular function.	Improved insulin sensitivity and postmeal plasma glucose. Results did not differ by dose. No drug interactions were observed during the study.	[276]
Stable CAD patients (n=40).	Randomized, 2 parallel arms, double-blind, placebo-controlled trial. Follow up: 3 months daily ingestion of 10 mg RES in one of the groups. RES in capsules.	Cardioprotective effects after myocardial infarction.	RES decreased versus baseline LDLc (8%) and improved endothelial function (50%), left ventricular diastolic function (2%), and protected from unfavorable hemorheological changes. No effect on CRP and TNFa.	[275]
Patients on statin treatment and at high risk of CVD (n=75). (Same cohort as in Tomé-Carneiro et al. 2012a).	Three parallel arms, randomized, triple-blind, dose-response, placebo-controlled trial. Follow-up: 12 months daily ingestion of 350 mg placebo (n=25), resveratrol-containing grape extract (GE-RES, grape phenolics + 8 mg RES, n=25) or conventional grape extract lacking RES (GE) for 6 months and the double dose for the following 6 months. Study products in capsules. Registration number: NCT01449110.	Effect on inflammatory and fibrinolytic status of patients.	GE-RES nutraceutical decreased hsCRP (-26%), TNFa (-19.8%), PAI-1 (-16.8%) and IL-6/IL-10 ratio (-24%), and increased IL-10 (19.8%). No drug interactions were detected. No adverse effects on hematological profile, hepatic, thyroid and renal functions.	[273]
Patients taking an oral contraceptive (n=12 + n=42).	Unmasked and unrandomized trial. Two separate experiments: 1) Follow-up: 2 months with 30 mg of RES in addition to oral contraceptive (containing 3 mg drospiredone plus 30 ug ethinylestardiol) previously taken for 6 months; 2) Follow-up: After submittion to laparoscopy and hysteroscopy for the management of endometriosis. Sixteen patients on oral contraceptives alone for at least 2 months prior to hospital admission, while 26 were using them in combination with RES.	Experiment 1: Effect on the management of endometriosis-related pain in patients who failed to obtain pain relief during the use of an oral contraceptive drospiredone + ethinylestardiol. Experiment 2: Effect on aromatase and cyclo-oxygenase-2 expression in endometrial tissue.	RES significant reduced pain scores (82% of patients reporting complete resolution of dysmenorrhea and pelvic pain after 2 months of use). Inhibition of both aromatase and cyclo-oxygenase-2 expression was significantly greater in the eutopic endometrium of patients taking RES compared with oral contraceptives alone.	[277]
Patients with multiple myeloma (n=24).	Two-arm, unrandomized and unmarked phase 2 clinical trial. Follow up: 5g of SRT501 following breakfast for 20 days in a 21-day cycle up to 12 cycles. Registration number: NCT00920556.	Effect of SRT501 with or without bortezomib in multiple myeloma patients who had relapsed or were refractory to at least one prior therapy.	Unacceptable safety profile and minimal efficacy in patients with relapsed/refractory MM highlighting the risks of novel drug development in such populations.	[278]
Patients with stable angina pectoris (n=116)	Randomized, double-blinded, active-controlled, and parallel trial with 3 groups of subjects who received the test drugs and 1 control group of subjects who were not randomized. Follow up: inclusion, 30 and 60 days of oral supplementation with calcium fructoborate (CF) (112 mg/day), RES (20mg/day), and their combination. Registration number: ISRCTN02337806.	Effect on inflammation biomarkers (hsCRP), left ventricular function markers (N-terminal prohormone of brain natriuretic peptide (BNP)), and lipid markers (total cholesterol, LDL-c, HDL-c, and triacylglycerols).	Significant hsCRP decrease in all groups at the 30-d and 60-d visits: 39.7% at 60 d for the CF group and 30.3% RES plus CF, at 60 d. The N-terminal prohormone of BNP was significantly lowered by RES (59.7% at 60 d) and by CF (52.6% at 60 d). However, their combination was the most effective and induced a decrease of 65.5%. Lipid markers showed slight changes from baseline in all groups.	[279]
Patients with stable CAD (n=75).	Three parallel arms, randomized, triple-blind, dose-response, placebo-controlled trial. Follow-up: 12 months daily ingestion of 350 mg placebo (n=25), resveratrol-containing grape extract (GE-RES, grape phenolics + 8 mg RES, n=25) or conventional grape extract lacking RES (GE) for 6 months and the double dose for the following 6 months. Study products in capsules. Registration number: NCT01449110.	Effect on inflammatory and fibrinolytic status of patients.	Significant increase in adiponectin levels (10%) in GE-RES group in addition to a decrease in PAI-1 levels. Non-HDL cholesterol decreased significantly in both GE and GE-RES groups. Downregulation of pro-inflammatory genes expression in PBMCs isolated from GE-RES group patients. No drug interactions were found and no adverse effects were observed on the hematological profile or on the hepatic, thyroid and renal functions.	[280]
Healthy subjects (no medication)
Healthy subjects (n=20).	Two parallel arms, randomized, placebo-controlled trial. Unmasked. Follow-up: 6 weeks daily ingestion of 200 mg P. cuspidatum extract (containing 40 mg RES, n=10) or placebo (n=10). Study products in capsules.	Effects on oxidative stress and inflammatory status.	RES-containing extract decreased ROS, p47phox, INFKB, IKKb and JNK, PTP-1B and SOCS-3 in PBMCs. In addition, plasma concentrations of TNFa (-33%) and CRP (-29%) also decreased.	[284]
Healthy subjects (n=42).	Placebo-uncontrolled, non-randomized, unblinded. Cohort with a single arm to evaluate effects after 4 weeks upon daily ingestion of 1 g RES (capsules).	Effect of RES on CYPs and phase II enzymes.	RES inhibited the activity of CYP3A4, CYP2D6, and CYP2C9 and induced CYP1A2.	[288]
Healthy subjects (n=40).	Four parallel arms, non-randomized, placebo uncontrolled. Blinded for analysis. Daily ingestion of 0.5 g (n=10), 1 g (n=10), 2.5 g (n=10) and 5 g (n=10) micronized RES for 29 days. RES in capsules.	Safety, pharmacokinetics and effects on circulating IGF-1 and IGFBP-3.	IGF-1 levels were decreased on the 2.5 g dose and IGFBP-3 on the 1 and 2.5 g doses. No linear dose-response was observed between RES plasma AUC values and effects on IGF-1 and IGFBP-3.	[30]
Healthy subjects (n=10).	2-arms, crossover, placebo-controlled, non-randomized, unblinded. Ingestion of a single dose of either a nutraceutical containing 100 mg RES from P. cuspidatum and 75 mg muscadine grape phenolics or placebo 10 min before a high-fat, high carbohydrate (HFHC) meal. Effects were measured for 5 hours after meal. Study products in capsules.	Effects on HFHC meal-induced oxidative and inflammatory stress.	The nutraceutical reduced meal-induced elevations of plasma LPS, and improved the expression of different oxidative and inflammatory-related genes in PBMNCs (p47phox, Nrf-2, TLR-4, CD14, IL-1b, SOCS-3, Keap-1, NQO-1 and GST-P1). The highest effects occurred from 3 to 5 hours after meal.	[290]
Healthy overweight/obese men or postmenopausal women with mildly elevated blood pressure (n=19).	Randomized, crossover, double-blind trial, single dose, placebo-uncontrolled. Single ingestion of 30, 90, 270 mg synthetic RES or placebo at weekly intervals. Analyses were performed 1 h after consumption of study products (capsules).	Acute, dose-dependent effect of RES on FMD.	FMD improved by 65% 1 h after consuming 30 or 90 mg RES and by 88% with 270 mg RES.	[293]
Obese men (n=11).	Randomized, crossover, double-blind, placebo-controlled trial. Daily ingestion of 150 mg synthetic RES for 1 month. RES in capsules. Registration number: NCT00998504.	To assess whether RES induce metabolic changes in obese men.	RES induced modest but consistent metabolic changes that mimic calorie restriction. A number of effects and mechanisms were reported such as reduction of sleeping and resting metabolic rate, activation of AMPK and increase of SIRT1 and PGC-1α in muscle, among others.	[294]
Healthy subjects (n=22).	Randomized, crossover, double-blind, dose-response, placebo-controlled trial. Single intake of placebo, 250 mg or 500 mg RES. Analyses were performed 45 min after the ingestion. RES in capsules. Registration number: NCT01010009.	Acute effect on brain functions by improving blood flow.	RES increased dose-dependently cerebral blood flow. Cognitive function was not affected.	[289]
Women at increased breast cancer risk (n=31).	Randomized, 3-arm, double-blind, placebo-controlled trial. Daily ingestion of placebo, 5 mg RES or 50 mg RES for 3 months. Study products in capsules.	Effect on DNA methylation and prostaglandin E2	No significant effect was found on the 4 genes studies (RASSF-1a, APC, CCND2 and p16). A correlation was found between the decrease of RASSSF-1a methylation and serum RES concentration.	[298]
Obese subjects (n=32).	Randomized, 3-arm, single-blind, placebo controlled trial. Daily ingestion of 150 mg RES (n=10), 300 mg catechin-rich grape seed extract (CGSE, n=12) or 400 mg RES phosphate (RTP, n=10) for 28 days. Study products in capsules.	Comparison of study products on oxidative stress in obese subjects.	Low density microarrays in whole blood showed preliminary changes in some genes related to oxidative stress, mainly affected by CGSE and RTP. However, data were not validated by RT-PCR. Serum oxidative stress markers were mainly improved by RTP and CGSE.	[295]
Healthy subjects (n=12).	Non-randomized, placebo-uncontrolled, unblinded. Daily consumption of 3 capsules to provide a total content of 6 mg RES, 300 mg dried grape extract, 150 mg of dried extract from olive oil, 9 mg lycopene, 300 mg vitamin C and 90 mg bioflavonoids from citrus fruits. Follow-up: 5 days.	Effects on against oxidative DNA-damage and alters their redox status.	No significant effects were found on lymphocytes DNA-stability parameters, and serum CRP and LDLox values after 5 days.	[296]
Nonobese, postmenopausal women (n=45).	Randomized, double-blind, placebo-controlled trial. Follow up: 12 weeks of RES supplementation (75 mg/day). Registration number: NCT00823381.	Evaluate the metabolic effects in nonobese, postmenopausal women with normal glucose tolerance.	No change in body composition, resting metabolic rate, plasma lipids, or inflammatory markers. No increase in liver, skeletal muscle, or adipose tissue insulin sensitivity. No affect in RES putative molecular targets, including AMPK, SIRT1, NAMPT, and PPARGC1A, in either skeletal muscle or adipose tissue.	[299]
Obese healthy men (n=24).	Randomized, placebo-controlled, double-blinded, and 2-arm parallel. Follow up: either RES or placebo treatment for 4 weeks.	Metabolic effects of high-dose RES in obese human subjects.	Insulin sensitivity deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. No effect on blood pressure, resting energy expenditure, oxidation rates of lipid, ectopic or visceral fat content, or in inflammatory and metabolic biomarkers.	[300]
Healthy adult smokers (n=50).	Randomized, double-blind, cross-over trial. Follow up: patients were allocated to either "resveratrol-first" group (30 days of 500 mg RES/day, 30 days wash-out, 30-days placebo) or to "placebo-first" group (30 days placebo, 30 days wash-out, 30 days 500 mg RES/day). Registration number: NCT01492114.	Effects on markers of inflammation and oxidative stress in smokers.	Significant CRP and triglyceride concentrations reduction, and increased Total Antioxidant Status values. Uric acid, glucose, insulin, cholesterol, liver enzyme concentrations, and weight, waist circumference, and blood pressure values did not change significantly.	[301]
Volunteers with acne vulgaris (n=20).	Single-blind, vehicle-controlled, 1-arm trial. Non-randomized. Daily administration of hydrogel-containing RES and only vehicle in each face’s volunteer for 2 months.	Therapeutic effects of RES on acneic skin.	Global acne grading system (GAGS) score decreased by 53.7% on the RES-treated sides of the face. Histological analyses showed a decrease of 66.7% in the area of micromedones. No adverse effects were observed.	[302]
Healthy females (n=15).	1-arm, vehicle-controlled, trial. Non-randomized. Topical application of 4 different moisturizing cream formulations on six sites on the non-exposed dorsal skin for 4 days. RES triphosphate (RTP), RTP+antioxidant blend, antioxidant blend alone and vehicle alone were applied to each participant. Histological analyses were blinded to the investigators.	Effects of RTP on UV-induced skin damage.	UV-induced erythema was mainly prevented by RTP and inhibited sunburn cell formation and melanin content.	[303]
Healthy subjects (n=50).	Randomized, unmasked, placebo-controlled trial. Follow up: 1 capsule of either placebo or a grape extract supplement (133 mg) containing 8 mg RES for 60 days.	Topical and systemic effects on age-related alterations to the skin, the skin antioxidant pool, and systemic oxidative stress levels.	Systemic oxidative stress, plasmatic antioxidant capacity, and skin antioxidant power increased significantly. Skin moisturization and elasticity improved, while skin roughness and depth of wrinkles diminished. Intensity of age spots decreased significantly.	[304]