Resveratrol: Don't Buy the Hype
Stephen Barrett, M.D.
Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of red grapes, is a component of Ko-jo-kon, an oriental medicine used to treat diseases of the blood vessels, heart [1,2], and liver . It came to scientific attention during the mid-1990s as a possible explanation for the "French Paradox"—the low incidence of heart disease among the French people, who eat a relatively high-fat diet . Since then, it has been touted by manufacturers and examined by scientific researchers as an antioxidant , an anti-cancer agent, and a phytoestrogen . It has also been advertised on the Internet as "The French Paradox in a bottle." One company even markets a red-wine extract antioxidant product called "French Parad'ox."
While present in other plants, such as eucalyptus, spruce, and lily, and in other foods such as mulberries and peanuts, resveratrol's most abundant natural sources are Vitis vinifera, labrusca, and muscadine grapes, which are used to make wines. It occurs in the vines, roots, seeds, and stalks, but its highest concentration is in the skin , which contains 50-100 micrograms (µg) per gram . Resveratrol is a phytoalexin, a class of antibiotic compounds produced as a part of a plant's defense system against disease . For example, in response to an invading fungus, resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA . Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration .
The resveratrol content of wine is related to the length of time the grape skins are present during the fermentation process. Thus the concentration is significantly higher in red wine than in white wine, because the skins are removed earlier during white-wine production, lessening the amount that is extracted . Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. Since wine is the most notable dietary source, it has been the object of much speculation and research. But a recent review noted that (a) the presence of resveratrol in the human diet is almost negligible, and a role for resveratrol in explaining the "French paradox," has likely been overestimated, and if resveratrol or similar compounds are proven useful against cardiovascular disease, a supplement (or drug) rather diet is likely to be the source .
Resveratrol is also available from supplement pills and liquids, in which it is sometimes combined with vitamins and/or other ingredients. It is also an ingredient in topical skin creams. The supplements are generally labeled as containing from 20 to 500 mg per tablet or capsule. However, the purity of these products is unknown. And, because dietary supplements are loosely regulated, it should not be assumed that the labeled dosage is accurate.
Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Several studies have demonstrated that resveratrol has antioxidant properties [7-10]. It is claimed that because it contains highly hydrophilic and lipophilic properties, it may provide more effective protection than other well-known antioxidants, such as vitamins C and E . On the other hand, it is less effective than the antioxidants quercetin and epicatechin found in red wine . Reduced platelet aggregation has also been demonstrated in studies on resveratrol, which could contribute to prevention of atherosclerosis [2,9]. Prior to 2010, however, most of the research on resveratrol's antioxidant and anti-platelet properties was done using test-tube or tissue-culture preparations. Since that time, some human trials have been conducted, but the evidence is not yet sufficient to draw practical conclusions [6,11].
Many studies have found that resveratrol can affect the initiation, promotion, and progression of cancer, which has raised hopes that it has potential for both prevention and treatment . A recent review concluded that it is not a good drug candidate because it lacks potency, high efficacy, and target specificity. But researchers hope that similarly-structured derivatives can be found that will be useful .
Studies in laboratory mice have found increased survival and lower incidence of several diseases and conditions associated with aging, but the results are contradictory. Protective effects have been found in mice fed a high-fat or a low-calorie diet, but one study found that mice fed a standard diet beginning at age 12 months did not live longer [14-16]. In 2009, after reviewing the animal studies, the highly respected Medical Letter concluded: "Resveratrol appears to produce some of the same effects as calorie-restricted diets that have reduced the incidence of age-related diseases in animals. Whether it has any benefit in humans remains to be established." 
One of the mouse studies was reported in a New York Times article which described how a researcher was taking resveratrol himself and had founded Sirtris Pharmaceuticals to develop chemicals that mimic the role of resveratrol but at much lower doses . GlaxoSmithKline acquired Sirtris for $720 million in 2008 and hopes to develop drugs that target the sirtuins, a group of enzymes associated with the aging process . However, a spokesperson said recently that the company is focused on compounds other than resveratrol that can activate sirtuins .
In 2012, the University of Connecticut announced that it had concluded that Dipak K. Das, Ph.D., a professor in its Department of Surgery and director of the Cardiovascular Research Center, was guilty of 145 counts of fabrication and falsification of data and that the university had notified eleven journals about this problem . In recent years, Das had gained attention for his reports on allegedly beneficial properties of resveratrol. As of March 2014, journals had retracted 20 of his papers, many of which were repeatedly cited by others . Das died in 2013.
Caution Is Advisable
Although laboratory tests have demonstrated that resveratrol might help prevent cardiovascular disease and cancer, there are several reasons why a population-wide increase would be premature.
- The research on resveratrol has focused on its short-term effects and has been dominated by in vitro (laboratory) studies on non-human models.
- Not enough is known about the absorption and clearance of resveratrol, the identities of its metabolic products, or its effects on the liver.
- Resveratrol's role as a potentiator of breast carcinomas may significantly limit its use.
- Its main dietary source is red wine. Not only is its concentration in wine extremely variable, but recommending increased consumption of red wine to boost resveratrol intake could certainly do more harm than good. In spite of any beneficial aspects, red wine and other alcoholic beverages pose health risks that include liver damage and physical addiction. While taking resveratrol pills is certainly safer than heavy wine consumption, supplementing with unproven substances is generally unwise. At this point, occasional use of red wine seems far more prudent.
In 2011, a systematic review with 21 co-authors noted that people were consuming resveratrol concluded that, "the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources."  Curiously, Das was one of the co-authors.
The Bottom Line
Epidemiologic studies can find associations between the consumption of foods or dietary supplements and various health outcomes. Animal experiments can demonstrate what can happen in the species tested. However, only human clinical trials can determine whether supplementation is useful for humans. Most clinical trials of other antioxidants have failed to demonstrate the benefits suggested by preliminary studies. Some substances—most notably beta-carotene—have even produced adverse effects. Prior to 2010, resveratrol had not been tested in clinical trials. Since that time there have been some, most of which were small, short-term (a year of less), and designed to evaluate possible therapeutic effects rather than disease-preventive effects. A trial to evaluate preventive effects would need to be large and lengthy and would therefore be extremely expensive .
My advice is to ignore the hype surrounding resveratrol and eat a balanced diet that contains adequate amounts of fruits and vegetables.
For Additional Information
- 2nd International Scientific Conference on Resveratrol and Health (2012): Summary and Conclusions
- 3rd International Scientific Conference on Resveratrol and Health (2014): (Reports will be posted)
- Celotti E and others. Resveratrol content of some wines obtained from dried Valpolicella grapes: Recioto and Amarone. Journal of Chromatography A 730(1-2): 47-52, 1996.
- Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: A molecule whose time has come? And gone? Clinical Biochemistry 30:91-113, 1997.
- Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? European Journal of Endocrinology 138:619-620, 1998.
- Jang M and others. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218-220, 1997.
- Gehm H and others. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proceedings of the National Academy of Sciences U.S.A. 94:557-562, 1997.
- Tomé-Carneiro J. and others. Resveratrol in primary and secondary prevention of cardiovascular disease: a dietary and clinical perspective. Annals of the New York Academy of Sciences 1290:37-51, 201 .
- Chanvitayapongs S, Draczynska-Lusiak B, Sun AY. Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells. Neuroreport 8:1499-1502, 1997.
- Belguendouz L, Fremont L, Gozzelino MT. Interaction of transresveratrol with plasma lipoproteins. Biochemical Pharmacology 55:811-816, 1998.
- Rotondo S and others. Effect of trans-resveratrol, a natural polyphenolic compound, on human polymorphonuclear leukocyte function. British Journal of Pharmacology 123:1691-1699, 1998.
- Frankel EN, Waterhouse AL, Kinsella JE. Inhibition of human LDL oxidation by resveratrol. Lancet 341:1103-1104, 1993.
- Wong RHX and others. Evidence for circulatory benefits of resveratrol in humans. Annals of the New York Academy of Sciences 1290:52-58, 2013.
- Bishayee A. Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prevention Research 2:409-418, 2009.
- Ogas T and others. Resveratrol analogs: promising chemopreventive agents. Annals of the New York Academy of Sciences 1290:21-29, 2013
- Baur JA and others. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337-342, 2006.
- Pearson KJ and others. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metabolism 8:157-168, 2008.
- Barger JL and others. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3:e2264, 2008.
- Resveratrol. The Medical Letter on Drugs and Therapeutics, 51:74-75, 2009.
- Wade N. Substance in red wine extends life of mice. New York Times, Nov 1, 2006.
- Edes A. GlaxoSmithKline to close Sirtris unit in Cambridge. Boston Globe, March 13, 2013.
- Scientific journals notified following research misconduct investigation. UConn Today, Jan 12, 2012.
- Oransky I. Late resveratrol researcher Dipak Das up to 20 retractions. Retraction Watch Web site, April 3, 2014.
- Vang O and others. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PloS One 6(6): e19881. doi:10.1371/journal.pone.0019881, 2011.
- Vang O. and others. What is new for resveratrol? Is a new set of recommendations necessary? Annals of the New York Academy of Sciences 1290:1-11, 2013.
The first version of this article was written in 1999 by Melissa Q.B. McElderry, MS, RD., a dietitian who co-owned and operated several restaurants and theater-pubs.This article was revised on December 11, 2014.