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Resveratrol

Resveratrol

For Patients & Caregivers

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In laboratory studies, resveratrol was found to reduce inflammation and to have antitumor properties, but human studies have not been conducted.

A naturally occurring compound in the skin of red grapes and other botanicals, resveratrol has been shown to reduce inflammation. It also has antioxidant properties and may help to protect against thickening of arterial walls and heart disease. Animal studies have shown that resveratrol has the ability to prevent certain cancer cells from dividing. Human studies on the anticancer effect of resveratrol supplements are lacking. Eating a diet rich in resveratrol does not lower the risk of dying from cancer or heart disease.

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  • Thickening of arterial walls
    Laboratory studies have shown that resveratrol helps in preventing atherosclerosis.
  • Coronary heart disease
    There is limited scientific evidence to support this use.
  • Cancer prevention
    Several laboratory studies have demonstrated the ability of resveratrol to prevent the growth of cancer cells. However, it is not clear if similar effects could occur in humans, and its hormone-like properties may stimulate some types of cancer cells.
  • Inflammation
    This use is supported by data from laboratory studies.
  • Anti-aging
    This effect has only been demonstrated in lab studies.
  • To treat metabolic disorders
    In a study of obese healthy men, resveratrol did not affect blood pressure, fat content, or inflammatory and metabolic biomarkers.
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  • You have a hormone-sensitive cancer: Resveratrol has hormone-like properties that may stimulate some types of cancer cells.
  • You are taking antiplatelet drugs: Resveratrol may increase the risk of bleeding.
  • You are taking cytochrome P450 substrate drugs: Resveratrol may increase the risk of side effects of some drugs and make others less effective.
  • You are taking carbamazepine: An herbal supplement rich in resveratrol was found to increase blood levels of this antiepileptic drug. 
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Mild to moderate gastrointestinal symptoms and diarrhea at high doses

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For Healthcare Professionals

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3,5,4'-trihydroxystilbene
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Resveratrol is a polyphenolic compound found in many botanical products. Red wine is a natural source of resveratrol as it is rich in grape skin and seeds. However, resveratrol is usually consumed as a dietary supplement for its purported antioxidant and anti-inflammatory properties. It is also marketed as an anti-aging supplement based on findings that it prolongs the life span of yeast cells (1) (2). This effect has not yet been demonstrated in humans.

A long-term randomized double-blind trial indicates that resveratrol and its major metabolites penetrate the blood-brain barrier to have effects on some biomarkers associated with Alzheimer’s disease (45), but a meta analysis did not find any significant effect on memory or cognitive performance (47). Resveratrol is also thought to have cardioprotective effects. Earlier studies found that it reduces the oxidation of low density lipoproteins (LDL), inhibits platelet aggregation, and may protect against atherogenesis (3) (4). Consumption of wine or a resveratrol-rich grape supplement is associated with reduction in risk of cardiovascular disease (5) (6) and may help promote circulatory system health (7) (8) (9). However, it does not decrease the risk of all-cause mortality in older adults (42). Data on effectiveness of resveratrol against non-alcoholic fatty liver disease are conflicting (44) (48).

Resveratrol has also been shown to increase insulin sensitivity in diabetic patients (10) (11) (43), but supplementation did not improve their metabolic patterns nor reduce C-reactive protein concentrations (46). Interestingly, conclusions of a meta analysis suggest that high doses of resveratrol are effective in promoting cardiovascular health (49); and supplementation improved arterial stiffness and reduced oxidative stress (50). But data on the effects of resveratrol in controlling metabolic syndromes in obese subjects are inconclusive (12) (13)

In vitro and animal studies show that resveratrol inhibits proliferation of cancer cells via different mechanisms (14) (15) (16) (17) (18) (19). It may also protect against chemotherapy-induced cardiotoxicity (19) (20). Further clinical studies are needed to confirm these effects in humans.

External application of a resveratrol-containing gel reduced acne symptoms  (21). Whereas resveratrol is generally safe, high doses can cause gastrointestinal side effects, such as diarrhea. Resveratrol inhibits cytochrome P450 enzymes (22) (23) and may increase the risk of adverse effects of certain drugs. It also exhibits estrogen-like properties and activates transcription by both estrogen and androgen receptors that can lead to the stimulation of cancer cell proliferation (18).

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  • Grape skins and seeds
  • Peanuts
  • Mulberries
  • Polygonum cuspidatum or Japanese knotweed
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  • Atherosclerosis
  • Cancer prevention
  • Coronary heart disease
  • Inflammation
  • Anti-aging
  • Metabolic disorders
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Resveratrol acts as an antioxidant and inhibits oxidation of low density lipoproteins (LDL) (21), platelet aggregation, and eicosanoid synthesis (4); induces nitric oxide (NO) production (24) (25) and increases arterial blood flow (8). These actions may contribute to its purported cardiovascular health benefits. Resveratrol also acts as an anti-inflammatory agent by inhibiting cyclooxygenase (COX) activity (26). It has been shown to decrease C-reactive protein and tumor necrosis factor, and to increase anti-inflammatory interleukin-10 and intercellular adhesion molecule-1 in humans (5). Other effects include decreasing oxidative stress and improving insulin sensitivity by increasing protein kinase activities (10). Resveratrol was also shown to decrease circulating insulin-like growth factor-1 (IGF-I) and IGF-binding protein-3 (IGFBP-3) levels (27) which may account for its anti-diabetic effects in humans. Preliminary data suggest that it increases the life span of yeast cells by activating sirtuins (1) (2), inhibiting human Sirt3 along with stimulating Sirt5 and Sirt1 (28)The neuroprotective effects of resveratrol were shown to be via regulating autophagy and apoptosis mediated by the Akt/mTOR pathway (51).

Resveratrol has also been investigated for its anticancer potential. It was found to inhibit proliferation of cancer cells via apoptosis and by exerting anti-estrogenic effects (14) (15) (16) (17).  Trans-resveratrol appears to decrease methylation of the tumor suppressor gene RASSF-1alpha in women at increased breast cancer risk (29). In addition, reductions in breast cancer cell migration and invasion were observed after supplementation (30) (31). Resveratrol growth factor heregulin-beta1 (HRG-beta1) mediated matrix metallopeptidase 9 (MMP-9) expressions in human breast cancer cells (30). But contradictory data show that resveratrol mimics phytoestrogens and could activate genes that are normally regulated by estrogens  (18) or androgens  (19). In other studies resveratrol helped reduce prostate tumorigenesis through a reduction in prostatic levels of mTOR complex 1 (mTORC1) activity and increased expression of SIRT1  (32); and  modulated steroid hormone-dependent pathways to inhibit prostate cancer cell growth. However, it also increases angiogenesis and inhibits apoptosis in vivo (19). Further research is needed.

Additional findings show that resveratrol downregulates p21 and upregulates cyclin E leading to S-phase accumulation and apoptosis in neuroblastoma cells (14). It also inhibits CYP1A1, CYP1A2, and CYP1B1 enzymes in tumor cells, perhaps exerting antitumor effects as some of these enzymes are known to be involved in the activation of procarcinogens and toxins (22) (23). Protective effects of resveratrol against doxorubicin-induced cardiotoxicity are due to upregulation of SIRT1-mediated p53 deacetylation. (20). Also, it protects against cisplatin-induced cardiotoxicity by suppressing oxidative stress (19).

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Patients with hormone-sensitive cancers should use caution, as resveratrol exhibits estrogen-like properties and activates transcription by both estrogen and androgen receptors that lead to the stimulation of cancer cell proliferation  (18).

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Mild to moderate gastrointestinal symptoms and diarrhea at high doses (2.5 and 5 g daily) (27) (33).

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  • Antiplatelet drugs: Because resveratrol inhibits platelet aggregation, concurrent use of other antiplatelet drugs may increase bleeding risk.
  • Cytochrome P450 substrates: Resveratrol inhibits CYP3A4, CYP2D6, CYP2C9, and induces CYP1A2, thereby affecting the levels of drugs that are metabolized by these enzymes (39).
  • Carbamazepine: Polygonum cuspidatum, an herbal supplement rich in resveratrol, can increase carbamazepine blood levels due to CYP3A inhibition and multidrug resistance-associated protein 2 (MRP 2) (40).
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  1. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. Sep 11 2003;425(6954):191-196.

  2. Wong RH, Howe PR, Buckley JD, et al. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis. Nov 2011;21(11):851-856.

  3. Magyar K, Halmosi R, Palfi A, et al. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012;50(3):179-187.

  4. Crandall JP, Oram V, Trandafirescu G, et al. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci. Dec 2012;67(12):1307-1312.

  5. ElAttar TM, Virji AS. Modulating effect of resveratrol and quercetin on oral cancer cell growth and proliferation. Anticancer Drugs. Feb 1999;10(2):187-193.

  6. Gehm BD, McAndrews JM, Chien PY, et al. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A. Dec 9 1997;94(25):14138-14143.

  7. Wang TT, Hudson TS, Wang TC, et al. Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. Oct 2008;29(10):2001-2010.

  8. Zhang C, Feng Y, Qu S, et al. Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovascular research. Jun 1 2011;90(3):538-545.

  9. Fabbrocini G, Staibano S, De Rosa G, et al. Resveratrol-containing gel for the treatment of acne vulgaris: A single-blind, vehicle-controlled, pilot study. Am J Clin Dermatol. Apr 1 2011;12(2):133-141.

  10. Liu J, Wang Q, Wu DC, et al. Differential regulation of CYP1A1 and CYP1B1 expression in resveratrol-treated human medulloblastoma cells. Neurosci Lett. Jun 17 2004;363(3):257-261.

  11. Gresele P, Pignatelli P, Guglielmini G, et al. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr. Sep 2008;138(9):1602-1608.

  12. Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. Jan 10 1997;275(5297):218-220.

  13. Gertz M, Nguyen GT, Fischer F, et al. A molecular mechanism for direct sirtuin activation by resveratrol. PloS One. 2012;7(11):e49761.

  14. Zhu W, Qin W, Zhang K, et al. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr Cancer. Apr 2012;64(3):393-400.

  15. Tang FY, Su YC, Chen NC, et al. Resveratrol inhibits migration and invasion of human breast-cancer cells. Mol Nutr Food Res. Jun 2008;52(6):683-691.

  16. Vaz-da-Silva M, Loureiro AI, Falcao A, et al. Effect of food on the pharmacokinetic profile of trans-resveratrol. Int J Clin Pharmacol Ther. Nov 2008;46(11):564-570.

  17. Rotches-Ribalta M, Andres-Lacueva C, Estruch R, et al. Pharmacokinetics of resveratrol metabolic profile in healthy humans after moderate consumption of red wine and grape extract tablets. Pharmacol Res. Nov 2012;66(5):375-382.

  18. Boocock DJ, Faust GE, Patel KR, et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev. Jun 2007;16(6):1246-1252.

  19. Chow HH, Garland LL, Hsu CH, et al. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev Res. Sep 2010;3(9):1168-1175.

  20. Chi YC, Lin SP, Hou YC. A new herb-drug interaction of Polygonum cuspidatum, a resveratrol-rich nutraceutical, with carbamazepine in rats. Toxicol Appl Pharmacol. Sep 15 2012;263(3):315-322.

  21. Patel KR, Brown VA, Jones DJ, et al. Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res. Oct 1 2010;70(19):7392-7399.

  22. Semba R, Ferrucci L, Bartali B, et al. Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med. 2014 Jul;174(7):1077-84. 

  23. Turner RS, Thomas RG, Craft S, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. Oct 20 2015;85(16):1383-1391.

  24. Farzaei MH, Rahimi R, Nikfar S, Abdollahi M. Effect of resveratrol on cognitive and memory performance and mood: A meta-analysis of 225 patients. Pharmacol Res. 2018 Feb;128:338-344.

  25. Elgebaly A, Radwan IA, AboElnas MM, et al. Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis. J Gastrointestin Liver Dis. 2017 Mar;26(1):59-67.

  26. Fogacci F, Tocci G, Presta V, Fratter A, Borghi C, Cicero AFG. Effect of resveratrol on blood pressure: A systematic review and meta-analysis of randomized, controlled, clinical trials. Crit Rev Food Sci Nutr. 2018 Jan 23:1-14.

  27. Imamura H, Yamaguchi T, Nagayama D, Saiki A, Shirai K, Tatsuno I. Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus. Int Heart J. 2017 Aug 3;58(4):577-583.

  28. Guo D, Xie J, Zhao J, Huang T, Guo X, Song J. Resveratrol protects early brain injury after subarachnoid hemorrhage by activating autophagy and inhibiting apoptosis mediated by the Akt/mTOR pathway. Neuroreport. 2018 Jan 22. doi:10.1097/WNR.0000000000000975. [Epub ahead of print]

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