RESVERATROL

Resveratrol, a common polyphenol in berries, grape skin and more has, so far, failed to deliver evidence of sustained benefits to patients in the few clinical trials published. There are tendiencies to protective actions found in at least one study in women at high firsk of breast cancer. (Highlight 1). Similarly in otherwise healty individuals resveratrol at somewhat elevated doses is seen suppressing insuling growth factor, which appears to increase progression in some cancer types.

Where resveratrol has more consistent clinical evidence is metabolic health benefits in control of insulin and glucose levels, but those are mainly in type 2 diabetic patients ( Highlight 2). Several trials report benefits in BMI reduction for obesity improvement. Evidence that resveratrol can reliably decrease systemic markers of inflammation are mixed and trial results vary considerably, its likely effects are more significant in with high BMI (see References)

There are quite often reports of gastrointestinal discomfort at higher doses, leading some studies to suggest up to 1g daily.

TYPICAL ABSORPTION LEVELS

10 – 20%

EXAMPLES OF IMPROVED OUTCOMES

NO

PRE-DIAGNOSIS OR PREVENTION

NO

Highlighted Studies

The predominant resveratrol species in serum was the glucuronide metabolite. Total trans-resveratrol and glucuronide metabolite serum levels increased after consuming both trans-resveratrol doses (P < .001 for both). RASSF-1α methylation decreased with increasing levels of serum trans-resveratrol (P = .047). The change in RASSF-1α methylation was directly related to the change in PGE2 (P = .045). This work provides novel insights into the effects of trans-resveratrol on the breast of wom...

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..ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3……most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma…. Circulating levels of IGFBP-3 are now thought to be directly associated with an increased risk of common cancers, albeit associations are modest and vary between ...

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Resveratrol supplementation [in type 2 diabetes] improves glycemic control by showing a maximum decrease in HOMA-IR and insulin levels. Change in FPG and HbA1c was although significant but percentage reduction was very less. Resveratrol also shows a significant decline in inflammation and oxidative stress…after 24 weeks was resulted in significant reduction of plasma glucose, insulin, homeostatic model assessment of insulin resistance,  malondialdehyde, high sensitive-C-reactive protei...

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Available evidence from RCTs suggests that resveratrol supplementation significantly reduced TNF-α and hs-CRP levels. Significant improvement in inflammatory markers support resveratrol as an adjunct to pharmacologic management of metabolic diseases…results of meta-analysis found significant reductions in the level of TNF-α and hs-CRP after supplementation with resveratrol. Resveratrol supplementation had no significant effect on the level of IL-6

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TABLE OF REFERENCES

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392022/3In conclusion, we demonstrate that the trans isomer and the glucuronide metabolite predominate in the circulation after chronic administration of trans-resveratrol, with a dose- dependent increase in both. RASSF-1a methylation decreased with increasing levels of trans-resveratrol and resveratrol-glucuronide in the circulation, and with decreasing PGE2 expression in the breast. Our preliminary observations suggest a novel mechanism for the chemopreventive effect of trans-resveratrol in the breast of high-risk womenthere was a significant decrease in PGE2 expression in NAF in association with a decrease in RASSF-1a (but not APC, p16, or CCND2) methylation. We previously reported that RASSF1a methylation increases with disease progression from precancer to cancer in breast intraductal and tissue samples (22). The decrease in RASSF-1a methylation and association of methylation decrease with a decrease in PGE2 are consistent with the known chemopreventive effects of resveratrol.
https://aacrjournals.org/cancerres/article/70/22/9003/561017/Repeat-Dose-Study-of-the-Cancer-Chemopreventive2.5Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 ..in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity. Cancer Res; 70(22); 9003–11. ©2010 AACR.The interest stems from the fact that these agents can engage a plethora of intriguing anticarcinogenic mechanisms in cellular studies in vitro, although hardly any of these processes have hitherto been explored as potential efficacy biomarkers in humans. The indication described here that resveratrol affects the IGF axis hints at the possibility that IGF-I and/or IGFBP-3 may serve as potential markers of chemopreventive efficacy when these dietary agents are eventually evaluated in definitive clinical chemoprevention studies
https://www.sciencedirect.com/science/article/pii/S0965229922000218#2.5Resveratrol supplementation improves glycemic control by showing a maximum decrease in HOMA-IR and insulin levels. Change in FPG and HbA1c was although significant but percentage reduction was very less. Resveratrol also shows a significant decline in inflammation and oxidative stress. microRNA expression was also significantly improved. There was no major or minor side effect observed during the studyResveratrol supplementation contributes in improvement of glycemic control by reducing insulin resistance. It has significant beneficial impact on chronic inflammation, oxidative stress and associated microRNA expression in diabetic patients. Thus, supplementation of resveratrol along with oral hypoglycemic agents may be useful in the reduction of diabetic associated complications.
https://pubmed.ncbi.nlm.nih.gov/30017172/2.5 Available evidence from RCTs suggests that resveratrol supplementation significantly reduced TNF-α and hs-CRP levels. Significant improvement in inflammatory markers support resveratrol as an adjunct to pharmacologic management of metabolic diseases. Resveratrol supplementation had no significant effect on the level of IL-6 (WMD, -0.16; 95% CI, -0.53 to 0.20; P = 0.38; Q statistic = 36.0; I2 = 72.3%; P = 0.001). Statistically significant heterogeneity was observed for the type of sample in IL-6 and study duration in inflammatory markers IL-6, TNF-α, and hs-CRP.
https://pubmed.ncbi.nlm.nih.gov/25885871/2.5 Meta-analysis of data from 10 RCTs (11 treatment arms) did not support a significant effect of resveratrol supplementation in altering plasma CRP concentrations ...data from 10 RCTs (11 treatment arms) did not support a significant effect of resveratrol supplementation in altering plasma CRP concentrations (WMD: -0.144 mg/L, 95% CI: -0.968-0.680, p = 0.731). Resveratrol supplementation was not found to alter plasma levels of total cholesterol his meta-analysis of available RCTs does not suggest any benefit of resveratrol supplementation on CV risk factors... It also slightly reduced high density lipoprotein cholesterol concentrations (WMD: -4.18 mg/dL, 95% CI: -6.54 to -1.82, p = 0.001). Likewise, no significant effect was observed on systolic (WMD: 0.82 mmHg, 95% CI: -8.86-10.50, p = 0.868) and diastolic blood pressure (WMD: 1.72 mm Hg, 95% CI: -6.29-9.73, p=0.674)
https://pubmed.ncbi.nlm.nih.gov/30013206/2The analysis indicated possible decreasing effect of resveratrol on CRP, but it might not be able to change IL-6 and TNF-α concentrations...The meta-analysis and systematic review considered 15 trials, involving 658 adults aged 18-75 years. Resveratrol significantly reduced serum CRP levels (WMD = -0.54; 95% CI: -0.78, -0.30; I2 = 77.7%; P < 0.0001), but it had no significant effect on serum IL-6 (WMD = -0.06; 95% CI: -0.27, 0.14; I2 = 62.0%; P = 0.005) and TNF-α levels
https://journals.physiology.org/doi/full/10.1152/ajpheart.00168.20142The overall conclusion of the present study is that, whereas exercise training effectively induces an angiogenic response and capillary growth in aged sedentary men, resveratrol at the given dose of 250 mg/day has no beneficial effect on angiogenesis and may even lower the training-induced angiogenic response.The dose of resveratrol (250 mg/day) used in the present study was based on previous literature in humans (49, 64) and recommendations by the producer of resveratrol and was selected to achieve effects while still being safe. We have previously published that resveratrol reduced overall muscle acetylation, indicating increased SIRT-1 activity . The total protein content of SIRT-1 was, on the other hand, not changed by resveratrol supplementation
https://pmc.ncbi.nlm.nih.gov/articles/PMC4537354/2These data suggest that 4000 mg of MPX is safe, and exploratory review of a lengthening in PSADT of a median of 5.3 months supports further exploration of MPX. Both low dose (500 mg) and high dose (4,000 mg) MPX [grape skin extract] are being further investigated in a randomized, multicenter, placebo-controlled, dose evaluating phase II trial.Seven patients with no evidence of radiographic progression remained on MPX for 21–30+ months due to perceived ongoing clinical benefit. The lack of dose limiting toxicities led to the selection of 4,000 mg/day as the recommended phase II dosing. A goal of the study was to characterize the plasma pharmacokinetics of MPX components in the conjugated and unconjugated forms at the maximum tested dose. At the 4000 mg dose level, ellagic acid, quercetin, and resveratrol were undetectable in the plasma

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