Table 1. Summary of peer reviewed published clinical trials*.
| Authors | Participants (n) | Objective | Form and dose of resveratrol | Duration | Outcome |
|---|---|---|---|---|---|
| Bioavailability from resveratrol supplement (as capsules or in another matrix) | |||||
| Almeida et al. 2009 [24] | Healthy men (20) and women (20) |
Bioavailability from resveratrol supplement | 25, 50, 100, or 150 mg capsules | Multiple, 6x/day at 4h intervals for 13 doses | Peak plasma concentrations of trans-resveratrol were reached at 0.8-1.5 h post dose. Following the 13th dose of trans-resveratrol 25, 50, 100 and 150 mg, mean peak plasma concentration (C(max)) was 3.89, 7.39, 23.1 and 63.8 ng/mL. Interindividual variability was high. Bioavailability was higher after morning administration. Resveratrol was well-tolerated, but with some mild adverse events reported. |
| Boocock et al. 2007 [25] | Healthy men (18) and women (22) |
Bioavailability from resveratrol supplement | 0.5, 1, 2.5, or 5 g capsules | Single dose | Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 ng/mL, which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The AUC values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. |
| Brown et al. 2010 [56] | Healthy men (22) and women (18) |
Bioavailability from resveratrol supplement | 0.5, 1, 2.5, or 5 g caplets | Multiple, once daily for 29 days | Plasma Cmax was 958.6 μg/L following 29 days of 5 g. Cmax and total AUC for the metabolites dramatically exceeded those for resveratrol. 2.5 g and 5 g caused mild to moderate gastrointestinal symptoms. |
| Burkon et al. 2008 [57] | Healthy males (9) | Bioavailability from resveratrol supplement | 85.5 mg of peceid per 70 kg of body weight | Single dose, dissolved in 100 mL of 15% ethanol and made up with a low-fat milk (1.5%) to a total volume of 500 ml | Trans-resveratrol metabolites formed in the plasma and urine were identified and quantified. The metabolites were trans-resveratrol-3-sulfate, trans-resveratrol-3,4-disulfate, trans-resveratrol-3,5-disulfate, trans-resveratrol-3-glucuronide and trans-resveratrol-4-glucuronide. Up to 50% of the plasma trans-resveratrol-3-sulfate, trans-resveratrol-disulfates and trans-resveratrol-glucuronides were bound to proteins. |
| La Porte et al. 2010 [58] | Healthy men (3) and women (5) |
Bioavailability of resveratrol supplement | 2000 mg capsules; taken with standard breakfast or high-fat breakfast, quercetin (500 mg) or 100 mL 5% alcohol | Multiple, twice daily | Resveratrol in combination with a high-fat breakfast reduced the area under the plasma concentration-time curve and the Cmax compared to a standard breakfast. Quercetin, or 5% alcohol (100 mL) did not influence trans-resveratrol pharmacokinetics. Resveratrol was well tolerated, although diarrhea was frequently observed. |
| Meng et al. 2004 [59] | Healthy men (3) | Bioavailability of resveratrol supplement | 0.03, 0.5, or 1 mg/kg dissolved in 5 mL whisky mixed with 50 mL water | Single | Resveratrol levels were readily detected in the plasma and the urine. The recovery of resveratrol in the plasma suggested a rapid absorption of resveratrol in the gastrointestinal tract. |
| Meng et al. 2004 [59] | Healthy men (3) | Bioavailability of resveratrol supplement | 0.32, 0.64, 0.96, or 1.92 mg delivered in grape juice (200, 400, 600, or 1200 mL) | Single | Resveratrol was only detected in the urine at when 600 and 1200 mL of grape juice were given. In grape juice, the level of free resveratrol is rather low. Cis- and trans-Piceid are the major resveratrol derivatives in grape juice. |
| Nunes et al. 2009 [60] | Healthy young men (6) and healthy young women (6) and elderly men (6) and elderly women (6) |
Bioavailability of resveratrol supplement | 200 mg capsules | Single, followed by multiple doses at 8-hour intervals for 3 days followed by a last single dose at day 4 (total of eight doses of 200 mg) | Pharmacokinetic and metabolite profile. Resveratrol was well tolerated by young and elderly subjects and the kinetic profile was independent of age and gender. |
| Patel et al. 2010 [61] | Colon cancer patients (20) | Bioavailability of resveratrol supplement | 0.5, or 1 g/ day | Single dose for 8 days | Trans-resveratrol (674 nmol/g) and resveratrol-3-O-glucuronide (86 nmol/g) were recovered from colonic tissue. |
| Ortuno et al. 2010 [62] | Healthy men (11) | Bioavailability of resveratrol | Randomized, crossover, controlled trial 14 μg/ kg of resveratrol in different matrices: 250 mL red wine, 1 L grape juice, or 10 tablets (red wine extracts enriched with trans-resveratrol) |
Single | Plasma trans-resveratrol increased as a response to all grape products and that of cis-resveratrol after wine and grape juice. Despite similar doses of trans-resveratrol being administered, the bioavailability of resveratrol from wine and grape juice is six fold higher than that from tablets. |
| Walle et al. 2004 [20] | Healthy men (3) and healthy women (3) |
Bioavailability from 14C-resveratrol supplement | 25 mg taken orally and intravenously | Single | Absorption is at least 70% with peak plasma levels of resveratrol and metabolites of around 491 ng/ml and a plasma half-life of 9.2 h. Most of the oral dose was recovered in the urine. Three main metabolic pathways were identified: sulfate and glucuronic acid conjugation of the phenolic goups, and hydrogenation of the aliphatic double bond. |
| Goldberg et al. 2003 [19] | Healthy men (12) | Bioavailability from three different matrices | 25 mg/ 70 kg body weight dissolved in 100 mL of white wine (11.5% ethanol), white grape juice, or V8 vegetable juice/ homogenate | Single | Efficient absorption of resveratrol but significant differences in bioavailability pattern between matrices, with plasma resveratrol concentration decreasing most rapidly with V8 and least rapidly using grape juice. |
| Gresele et al. 2008 [63] | Healthy men (9) and women (11) |
Bioavailability from moderate wine consumption | 300 mL/d intake of red of white wine. Total polyphenolic concentration: Red wine 1.8 g/L; white wine 0.25 g/L |
15 days | Plasma resveratrol concentrations increased form 0.72 to 1.33 μmol/L for white wine and from 0.71 to 1.72 μmol/L for red wine. |
| Urpi-Sarda et al. 2005 [64] | Healthy men (11) | Bioavailability from wine consumption | 5.38 mg from 250 mL red wine | Single | Resveratrol metabolites were incorporated into low-density lipoproteins after a moderate intake of red wine. The metabolites identified in low-density lipoproteins were trans-resveratrol-3-O-glucuronide, cis-resveratrol-3-O-glucuronide, cis-resveratrol-3-O-glucoside, and free trans-resveratrol. |
| Vitaglione et al. 2005 [65] | Healthy men (14) and women (11) |
Bioavailability from wine consumption | 3.4, 7.5, or 33 μg/ kg from 300 or 600 mL red wine with three different dietary approaches: fasting, a standard meal, a meal with high and low amounts of lipids | Single | Free trans-resveratrol was found in trace amounts, only in some serum samples collected 30 minutes after red wine ingestion while after longer times resveratrol glucuronides predominated. Trans-resveratrol bioavailability was shown to be independent from the meal or its lipid content. However, Wide the wide variation in subject responses combined with low bioavailability suggests that the combination of polyphenols may account for the French paradox. |
| Zamora-Ros et al. 2006 [66] | Healthy men (10) and healthy women (10) |
Bioavailability from wine consumption | 0.357, 0.398, or 2.56 mg/day from 300 mL sparkling wine or 200 mL either white wine or red wine | Multiple; once daily, for 28 days | Significant increases in total resveratrol metabolites were observed in the urine after consumption of sparkling, white or red wine. Resveratrol metabolites in urine may be useful biomarkers of wine intake in epidemiological and intervention studies. |
| Oxidative stress and inflammation | |||||
| Ghanim et al. 2010 [53] | Healthy adults (20) | Oxidative stress and inflammation | Polygonum cupsidatum extract contain 40 mg of resveratrol Randomized, placebo controlled |
Daily for 6 weeks | The extract induced a significant reduction in reactive oxygen species generation as shown by a decrease in the expression of P47 (phox), NFκB, JNK-1, PTP-1B, SOCS-3 in mononuclear cells, when compared to placebo and baseline. The extract also suppressed plasma concentrations of TNF-α, IL-6 and CRP. |
| Ghanim et al. 2011 [67] | Healthy men (4) and women (6) |
Markers of oxidative stress, inflammation, Nrf-2 binding activity, the concentrations of endotoxin (lipopolysaccharide) and lipoprotein binding protein | Crossover, placebo controlled. - High-fat high-carbohydrate meal with placebo - High-fat high-carbohydrate meal with 100 mg resveratrol and 75 mg grapeskin polyphenols |
2 visits, 1 week apart | The supplement containing resveratrol and muscadine polyphenols suppresses the increase in oxidative stress, lipopolysaccharide and lipoprotein binding protein concentrations, and expression of TLR-4, CD14, IL-1β and SOCS-3 in mononuclear cells after a high-fat high-carbohydrate meal. It also stimulates specific Nrf-2 activity and induces the expression of the related antioxidant genes NQO-1 and GST-P1. |
| Cardiovascular effects | |||||
| Kennedy et al. 2010 [68] | Young healthy men (4) and women (20) |
Cognitive performance and localized cerebral blood flow | Double-blind, placebo-controlled, crossover 250 or 500 mg capsules |
Single; once daily on 3 separate days | Resveratrol dose-dependently increased cerebral blood flow during task performance, as indicated by total concentrations of haemoglobin. Resveratrol did not enhance cognitive function. |
| Wong et al. 2010 [69] | Overweight/ obese men (14) and post-menopausal women (5) with borderline hypertension | Endothelial function and cardiovascular health | 30, 90, or 270 mg in a randomized double-blind crossover design | Each dose for 6 days | Flow-mediated dilation of the brachial artery increased 45 min following 30, 90, and 270 mg doses of resveratrol. |
| Cancer | |||||
| Nguyen et al. 2009 [70] | Colorectal cancer patients (8) | A phase-I pilot study in which the effects of resveratrol are examined on Wnt signalling in the normal colonic mucosa and colon cancer tissue | 4 groups: - N=3: 80 g of grape powder dissolved in water - N=2 120 g of grape powder dissolved in water - N=2 20 mg of resveratrol (capsule containing also quercetin) - N=1 80 mg of resveratrol (capsule containing also quercetin |
Daily for two weeks | Grape powder (80 g), which contains low doses of resveratrol in combination with other bioactive components, can inhibit the Wnt pathway in colonic cancer patients but this effect is confined to the normal colonic mucosa. |
| Patel et al. 2010 [61] | Colon cancer patients (20) | Chemo preventive activity | 0.5, or 1 g/ day | Single dose for 8 days | Resveratrol reduced tumour cell proliferation by 5%. |
| Chow et al. 2010 [71] | Healthy men (11) and women (31) |
Effect on drug- and carcinogen-metabolizing enzymes | 1 g caplets | Once daily for 28 days | Resveratrol intervention inhibited the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and induced the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-π level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. |
| Brown et al. 2010 [56] | Healthy men (22) and women (18) |
Chemo preventive properties | 0.5, 1, 2.5, or 5 g caplets | Multiple, once daily for 29 days | Resveratrol decreased circulating IGF-1 and IGFBP-3 in circulating plasma. The decrease was most marked at 2.5 g. The observed decrease might contribute to cancer chemo preventive activity. |
| Diabetes, obesity, and metabolism | |||||
| Elliot et al. 2009 [51] | Type 2 diabetics | Insulin sensitivity | 2.5, or 5 g | Daily for 28 days | Decreased fasting and postprandial glucose and insulin at 5 g. |
| Brasnyo et al. 2011 [52] | Diabetic men (19) | Insulin sensitivity | 5 mg capsules | Twice daily for 4 weeks | Resveratrol significantly decreased insulin resistance (as measured by HOMA index), while it increased the pAkt:Akt ratio in platelets. Urinary ortho-tyrosine excretion (a measure of oxidative stress) decreased by resveratrol. |
| Timmers et al. 2011 [18] | Healthy obese men (11) | Metabolic effects | 75 mg of resveratrol in a randomized double-blind, placebo-controlled crossover design | Twice daily, for 30 days | Resveratrol improved the metabolic profile: resveratrol reduced sleeping and resting metabolic rate. In muscle, resveratrol activated the AMPK-SIRT1-PGC1α axis. Resveratrol reduced blood glucose and insulin levels, reduced liver fat storage, improved muscle mitochondrial function and reduced inflammation markers in the blood. |
| Crandall et al. 2012 [17] | Older men (3) and women (7) with impaired glucose tolerance | Glucose tolerance and vascular function | 1, 1.5, or 2 g | Daily for 4 weeks | Decreased peak glucose and 3-h glucose AUC following a meal at 1.5 and 2 g. Matsuda index for insulin sensitivity improved at 1.5 and 2 g. Trend towards improved hyperemia index. |