Resveratrol

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi.

The effects of resveratrol are currently a topic of numerous animal and human studies. Its effects on the lifespan of many model organisms remain controversial, with uncertain effects in fruit flies, nematode worms, and short-lived fish. In mouse and rat experiments, anticancer, anti-inflammatory, blood sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. These results have yet to be replicated in humans.

In one positive human trial, extremely high doses (3–5 g) of resveratrol, in a proprietary formulation designed to enhance its bioavailability, significantly lowered blood sugar. This 28-day Phase 1b study was conducted privately in India by pharmaceutical company Sirtris, and was announced at an investors conference in 2008. However, although it has been alluded to in review articles, the study itself has never been published in a peer-reviewed scientific publication. Despite the mainstream press alleging resveratrol's anti-aging effects, there are no accepted data to form a scientific basis for the application of these claims to mammals (see life extension section below). At the present time, research on resveratrol is in its infancy and the long-term effects of supplementation in humans are not known.

Resveratrol is found in the skin of red grapes and in other fruits. However, red wine contains very little of it, in the order of one milligram per glass. Resveratrol has also been produced by chemical synthesis and by biotechnological synthesis (metabolic engineered microorganisms) and is sold as a nutritional supplement derived primarily from Japanese knotweed.

Discovery and name
Resveratrol was initially mentioned in a Japanese article in 1939 by M. Takaoka, who isolated it from the poisonous but medicinal Veratrum album, variety grandiflorum. The name presumably comes from the fact that it is a resorcinol derivative coming from a Veratrum species.

Life extension
The groups of Howitz and Sinclair reported in 2003 in the journal Nature that resveratrol significantly extends the lifespan of the yeast Saccharomyces cerevisiae. Later studies conducted by Sinclair showed that resveratrol also prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. In 2007, a different group of researchers were able to reproduce Sinclair's results with C. elegans, but a third group could not achieve consistent increases in lifespan of either D. melanogaster or C. elegans.

In 2006, Italian scientists obtained the first positive result of resveratrol supplementation in a vertebrate. Using a short-lived fish, Nothobranchius furzeri, with a median life span of nine weeks, they found a maximal dose of resveratrol increased the median lifespan by 56%. Compared with the control fish at nine weeks, that is by the end of control fish's life, the fish supplemented with resveratrol showed significantly higher general swimming activity and better learning to avoid an unpleasant stimulus. The authors noted a slight increase of mortality in young fish caused by resveratrol, and hypothesized its weak toxic action stimulated the defense mechanisms and resulted in the life span extension.

Later the same year, Sinclair reported resveratrol counteracted the detrimental effects of a high-fat diet in mice. The high-fat diet was compounded by adding hydrogenated coconut oil to the standard diet; it provided 60% of energy from fat, and the mice on it consumed about 30% more calories than the mice on standard diet and became obese and diabetic. Mice on the high-fat diet exhibited a high mortality rate compared to mice fed the standard diet; mice fed the high-fat diet plus 22 mg/kg resveratrol had a 30% lower risk of death than the mice on the high-fat diet alone, making their death rates similar to those on the standard diet. The supplement also partially corrected a subset of the abnormal gene expression profile and abnormal insulin and glucose metabolism. However, resveratrol supplements did not change the levels of free fatty acids and cholesterol, which were much higher than in the mice on standard diet.

A further study by a group of scientists, which included Sinclair, indicated resveratrol treatment had a range of beneficial effects in elderly mice, but did not increase the longevity of ad libitum–fed mice when started midlife. Later, the National Institute on Aging's Interventions Testing Program (ITP) also tested three different doses of resveratrol in mice on a normal diet beginning in young adulthood, and again found no effect on lifespan, even at doses roughly eight times higher than those that had normalized the lifespan of the high-fat-fed, obese mice in the earlier study.

However, a 2011 study published in Nature showed that the benefits demonstrated in previous studies stemmed from errors in controls.

Cancer prevention
In 1997, Jang reported that topical resveratrol applications prevented skin cancer development in mice treated with a carcinogen. There have since been many studies of the anti-cancer activity of resveratrol in animal models. No results of human clinical trials for cancer have been reported.

Clinical trials to investigate the effects on colon cancer and melanoma (skin cancer) are currently recruiting patients. However, the study of pharmacokinetics of resveratrol in humans concluded even high doses of resveratrol might be insufficient to achieve resveratrol concentrations required for the systemic prevention of cancer.

This is consistent with the results from the animal cancer models, which indicate the in vivo effectiveness of resveratrol is limited by its poor systemic bioavailability. The strongest evidence of anticancer action of resveratrol exists for tumors it can contact directly, such as skin and gastrointestinal tract tumors. For other cancers, the evidence is uncertain, even if massive doses of resveratrol are used.

Thus, resveratrol (1 mg/kg orally) reduced the number and size of the esophageal tumors in rats treated with a carcinogen.; and in several studies, small doses (0.02–8 mg/kg) of resveratrol, given prophylactically, reduced or prevented the development of intestinal and colon tumors in rats given different carcinogens. Similarly, topical application of resveratrol in mice, both before and after the UVB exposure, inhibited the skin damage and decreased skin cancer incidence. However, oral resveratrol was ineffective in treating mice inoculated with melanoma cells. Resveratrol given orally also had no effect on leukemia and lung cancer; however, injected intraperitoneally, 2.5 or 10 mg/kg of resveratrol slowed the growth of metastatic Lewis lung carcinomas in mice.

Resveratrol treatment appeared to prevent the development of mammary tumors in animal models; however, it had no effect on the growth of existing tumors. Paradoxically, treatment of prepubertal mice with high doses of resveratrol enhanced formation of tumors. Injected in high doses into mice, resveratrol slowed the growth of neuroblastomas.

All of the aforementioned in vivo studies have been in animal models in which the cancer has been artificially induced by some experimental means. Three other studies have investigated the effect of resveratrol on the risk of cancer in normal mice living out a normal lifespan; all of them have found resveratrol supplementation has no significant effect on the burden of tumors, nor on the rate of cancer death.

Other applications
Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal Cell in November, 2006. Mice fed resveratrol for fifteen weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of the Sirtuin 1 gene.

Nicholas Wade's interview-article with Dr. Auwerx stated the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (175 lb) person, the 400 mg/kg of body weight amount used in Auwerx's mouse study would total 30,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4000 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There are limited human safety data. Long-term safety has not been evaluated in humans.

In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn more energy, indicating the same pathway shown in the lab mice works in humans.

Neuroprotective effects: In November 2008, researchers at the Weill Medical College of Cornell University reported dietary supplementation with resveratrol significantly reduced plaque formation in animal brains, a component of Alzheimer's disease and other neurodegenerative diseases. In mice, oral resveratrol produced large reductions in brain plaque in the hypothalamus (-90%), striatum (-89%), and medial cortex (-48%) sections of the brain. In humans, oral doses of resveratrol thoretically may reduce beta amyloid plaque associated with aging changes in the brain. Researchers theorize that one mechanism for plaque eradication is the ability of resveratrol to chelate (bind) copper. The neuroprotective effects have been confirmed in several animal model studies.

Anti-inflammatory effects: The anti-inflammatory effects of resveratrol have been demonstrated in several animal model studies. In a rat model of carrageenan-induced paw edema, resveratrol inhibited both acute and chronic phases of the inflammatory process. Similarly, preincubation with resveratrol decreased arachidonic acid release and COX-2 induction in mouse peritoneal macrophages stimulated with tumor promoter PMA, ROI, or lipopolysaccharides (LPS). In an experimental rabbit inflammatory arthritis model, resveratrol showed promise as a potential therapy for arthritis. When administered to rabbits with induced inflammatory arthritis, resveratrol protected cartilage against the progression of inflammatory arthritis.

Cardioprotective effects: Moderate drinking of red wine has long been known to reduce the risk of heart disease. This is best known as “the French paradox”. Studies suggest resveratrol in red wine may play an important role in this phenomenon. It achieves the effects by the following functions: (1) Inhibition of vascular cell adhesion molecule expression; (2) Inhibition of vascular smooth muscle cell proliferation;   (3) Stimulation of endolethelial nitric oxide synthase (eNOS) Activity;   (4) Inhibition of platelet aggregation;   (5) Inhibition of LDL peroxidation;  The cardioprotective effects of resveratrol are also theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy. A 2011 study concludes, “Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via the SAFE pathway.”

Antidiabetic effects: Studies have shown resveratrol possesses hypoglycemic and hypolipidemic effects in both streptozotocin (STZ)-induced diabetes rats and STZ-nicotinamide-induced diabetes rats. Resveratrol ameliorates common diabetes symptoms, such as polyphagia, polydipsia, and body weight loss. Other diabetic animal model studies by different researchers have also demonstrated the antidiabetic effects of resveratrol. In human clinical trials, resveratrol has lowered blood sugar levels in both Phase Ib and Phase IIa, conducted by Sirtris Pharmaceuticals, Inc.

Antiviral effects: Studies show resveratrol inhibits herpes simplex virus (HSV) types 1 and 2 replication by inhibition of an early step in the virus replication cycle. In vivo studies in mice found resveratrol inhibits or reduces HSV replication in the vagina and limits extravaginal disease. The skin of resveratrol-treated animals showed no apparent dermal toxicity, such as erythema, scaling, crusting, lichenification, or excoriation. Studies also show resveratrol inhibits varicella-zoster virus, certain influenza viruses, respiratory viruses, and human cytomegalovirus. Furthermore, resveratrol synergistically enhances the anti-HIV-1 activity of several anti-HIV drugs.

Pharmacokinetics
One way of administering resveratrol in humans may be buccal delivery, that is without swallowing, by direct absorption through the inside of the mouth. When one milligram of resveratrol in 50 mL 50% alcohol/ water solution was retained in the mouth for one minute before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form. However, the viability of a buccal delivery method is called into question due to the low aqueous solubility of the molecule. For a drug to be absorbed via the transmucosal membrane, the drug must be in free-form/dissolved. Resveratrol fits the criteria for oral transmucosal dosing, except for this caveat. The low aqueous solubility greatly limits the amount that can be absorbed through the buccal mucosal, and is why the method has not been seriously explored further. All resveratrol that is attempted to be taken buccaly will fail to pass through the mucous membrane of the mouth and be absorbed as an oral dose. However, a need to explore buccal delivery in future pharmasutical formulations has been expressed.

About 70% of the resveratrol dose given orally as a pill is absorbed; nevertheless, oral bioavailability of resveratrol is low because it is rapidly metabolized in intestines and liver into conjugated forms: glucuronate and sulfonate. Only trace amounts (below 5 ng/mL) of unchanged resveratrol could be detected in the blood after 25 mg oral dose. Even when a very large dose (2.5 and 5 g) was given as an uncoated pill, the concentration of resveratrol in blood failed to reach the level claimed to be necessary for the systemic cancer prevention. A formulation of resveratrol in a chewing gum form is now in production, and this would be expected to achieve much higher blood levels than oral formulations. Resveratrol given in a proprietary formulation SRT-501 (3 or 5 g), developed by Sirtris Pharmaceuticals, reached five to eight times higher blood levels. These levels did approach the concentration necessary to exert the effects shown in animal models and in vitro experiments. However, on May 5, 2010, GlaxoSmithKline (GSK) said it had suspended a small clinical trial of SRT501, a proprietary form of resveratrol, due to safety concerns, and terminated the study on December 2, 2010 [ClinicalTrials.gov Identifier: NCT00920556]. Sirtris Pharmaceuticals, which U.K.-based GlaxoSmithKline bought for $720 million in 2008, was developing the drug. GlaxoSmithKline is now focusing its efforts on more potent and selective SIRT1 activators—SRT2104 and SRT2379—both of which are involved in several exploratory clinical trials.

Full formal pharmacokinetics of oral resveratrol 2000 mg twice daily in humans, studying interaction with concurrent ethanol, quercetin and fat meal has been published. Mean peak serum resveratrol concentration was 1274 ng/mL at steady-state, which was reduced 46% by a fat meal at dosing. There was no effect of concurrent oral quercetin or ethanol. Healthy volunteers had frequently reported minor diarrhea, and laboratory measures identified slight changes in liver function tests, and serum potassium. No adverse effect on renal function was identified, although only eight healthy adults were observed in the two-week study.

In humans and rats,  less than 5% of the oral dose is being observed as free resveratrol in blood plasma. The most abundant resveratrol metabolites in humans, rats, and mice are trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Walle suggests sulfate conjugates are the primary source of activity, Wang et al. suggests the glucuronides, and Boocock et al. also emphasized the need for further study of the effects of the metabolites, including the possibility of deconjugation to free resveratrol inside cells. Goldberd, who studied the pharmacokinetics of resveratrol, catechin and quercetin in humans, concluded "it seems that the potential health benefits of these compounds based upon the in vitro activities of the unconjugated compounds are unrealistic and have been greatly exaggerated. Indeed, the profusion of papers describing such activities can legitimately be described as irrelevant and misleading. Henceforth, investigations of this nature should focus upon the potential health benefits of their glucuronide and sulfate conjugates."

The hypothesis that resveratrol from wine could have higher bioavailability than resveratrol from a pill has been refuted by experimental data. For example, after five men took 600 mL of red wine with the resveratrol content of 3.2 mg/L (total dose about 2 mg) before breakfast, unchanged resveratrol was detected in the blood of only two of them, and only in trace amounts (below 2.5 ng/mL). Resveratrol levels appeared to be slightly higher if red wine (600 mL of red wine containing 0.6 mg/mL resveratrol; total dose about 0.5 mg) was taken with meal: trace amounts (1–6 ng/mL) were found in four out of ten subjects. In another study, the pharmacokinetics of resveratrol (25 mg) did not change whether it was taken with vegetable juice, white wine or white grape juice. The highest level of unchanged resveratrol in the serum (7–9 ng/mL) was achieved after 30 minutes, and it completely disappeared from blood after four hours. The authors of both studies concluded the trace amounts of resveratrol reached in the blood are insufficient to explain the French paradox. The beneficial effects of wine apparently could be explained by the effects of alcohol or the whole complex of substances wine contains; for example, the cardiovascular benefits of wine appear to correlate with the content of procyanidins.

Adverse effects and unknowns
Long-term effects of using resveratrol are as of yet unknown. One study has theorized it may stimulate the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen. However, other studies have found resveratrol intake is inversely associated with breast cancer risk, and acts to slow the progression of breast cancer that has been transplanted into mice. Some studies suggest resveratrol slows the development of blood vessels, which suppresses tumors, but also slows healing. Citing the evidence that resveratrol is estrogen antagonistic, some retailers of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product, while others advise that resveratrol should not be taken by children or young adults under 18, as no studies have shown how it affects their natural development. A small study found a single dose of up to 5 g of trans-resveratrol caused no serious adverse effects in healthy volunteers.

Possible carcinogenicity
Resveratrol in common with other polyphenols, was found to be a strong topoisomerase inhibitor, sharing similarities to chemotherapeutic anticancer drugs, such as etoposide and doxorubicin. This may simultaneously contribute to both the potential anticarcinogenic and carcinogenic properties of the substance in given circumstances. Harmful properties of resveratrol may be pronounced in the human fetus, as it has diminished detoxification systems. Therefore, resveratrol as commonly sold combined with other "bioflavonoids", should be not used by pregnant women.

Mechanisms of action
See Calorie restriction for the details of the debate on resveratrol, calorie restriction and life extension.

The mechanisms of resveratrol's apparent effects on life extension are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction. Some studies indicates resveratrol activates Sirtuin 1 (SIRT1) and PGC-1α and improves the functioning of the mitochondria. Other research calls into question the theory connecting resveratrol, SIRT1, and calorie restriction. In addition resveratrol's ability to directly activate sirtuin 1 has been called into question.

A paper by Robb et al. discusses resveratrol action in cells. It reports a fourteen-fold increase in the action of MnSOD (SOD2). MnSOD reduces superoxide to hydrogen peroxide (H2O2), but H2O2 is not increased due to other cellular activity. Superoxide O2- is a byproduct of respiration in complexes 1 and 3 of the electron transport chain. It is "not highly toxic, [but] can extract an electron from biological membrane and other cell components, causing free radical chain reactions. Therefore it is essential for the cell to keep superoxide anions in check." MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction, permeability transition, and apoptotic death in various diseases. It has been implicated in lifespan extension, inhibits cancer, (e.g. pancreatic cancer ) and provides resistance to reperfusion injury and irradiation damage. These effects have also been observed with resveratrol. Robb et al. propose MnSOD is increased by the pathway RESV → SIRT1 / NAD+ → FOXO3a → MnSOD. Resveratrol has been shown to cause SIRT1 to cause migration of FOXO transcription factors to the nucleus which stimulates FOXO3a transcriptional activity and it has been shown to enhance the sirtuin-catalyzed deacetylation (activity) of FOXO3a. MnSOD is known to be a target of FOXO3a, and MnSOD expression is strongly induced in cells overexpressing FOXO3a.

Resveratrol interferes with all three stages of carcinogenesis—initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor NF-κB, inhibition of the cytochrome P450 isoenzyme CYP1A1 (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene ), alterations in androgenic actions and expression and activity of cyclooxygenase (COX) enzymes. In vitro, resveratrol "inhibited the proliferation of human pancreatic cancer cell lines." In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells. Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2. Resveratrol also possesses antioxidant and anti-angiogenic properties.

Resveratrol was reported to be effective against neuronal cell dysfunction and cell death, and, in theory, could be effective against diseases such as Huntington's disease and Alzheimer's disease. Again, this has not yet been tested in humans for any disease.

Research at the Northeastern Ohio Universities College of Medicine and Ohio State University indicated resveratrol has direct inhibitory action on cardiac fibroblasts, and may inhibit the progression of cardiac fibrosis.

Resveratrol also significantly increases natural testosterone production from being both a selective estrogen receptor modulator and an aromatase inhibitor.

In December 2007, work from Irfan Rahman's laboratory at the University of Rochester demonstrated resveratrol increased intracellular glutathione levels via Nrf2-dependent upregulation of gamma-glutamylcysteine ligase in lung epithelial cells, which protected them against cigarette smoke extract-induced oxidative stress.

Another potentially important mechanism common to both resveratrol supplementation and caloric restriction is the modulation of autophagy SIRT1 is a hypothesized target of both resveratrol and caloric restriction, and has been shown to facilitate autophagy through the inhibition of mTOR, which itself negatively regulates autophagy.

Chemical and physical properties
Resveratrol (3,5,4'-trihydroxystilbene) is a stilbenoid, a derivate of stilbene.

It exists as two geometric isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. The trans- and cis-resveratrol can be either free or bound to glucose. The trans- form can undergo isomerisation to the cis- form when exposed to ultraviolet irradiation. Trans-resveratrol in the powder form was found to be stable under "accelerated stability" conditions of 75% humidity and 40°C in the presence of air. Resveratrol content also was stable in the skins of grapes and pomace taken after fermentation and stored for a long period. lH- and 13C-NMR data for the four most common forms of resveratrols are reported in literature.

Plants and foods
Resveratrol is produced in plants with the help of the enzyme resveratrol synthase.

Resveratrol was originally isolated by Takaoka from the roots of hellebore in 1940, and later, in 1963, from the roots of Japanese knotweed. However, it attracted wider attention only in 1992, when its presence in wine was suggested as the explanation for cardioprotective effects of wine.

In grape, trans-resveratrol is a phytoalexin produced against the growth of fungal pathogens such as Botrytis cinerea. Its presence in Vitis vinifera grapes can also be constitutive, with accumulation in ripe berries of different levels of bound and free resveratrols, according to the genotype. In grapes, resveratrol is found primarily in the skin, and, in muscadine grapes, also in the seeds. The amount found in grape skins also varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content.

The levels of resveratrol found in food varies greatly. Red wine contains between 0.2 and 5.8 mg/L, depending on the grape variety, while white wine has much less, because red wine is fermented with the skins, allowing the wine to extract the resveratrol, whereas white wine is fermented after the skin has been removed. The composition of wine is different from that of grape since the extraction of resveratrols from grape depends on the duration of the skin contact, and the resveratrol 3-glucosides are in part hydrolised, yielding both trans- and cis-resveratrol. A number of reports have indicated muscadine grapes may contain high concentrations of resveratrol, and that wines produced from these grapes, both red and white, may contain more than 40 mg/L. However, subsequent studies have found little or no resveratrol in different varieties of muscadine grapes.

The fruit of the mulberry (esp. the skin) is a source, and sold as a nutritional supplement.

Cocoa powder, baking chocolate and dark chocolate also have low levels of resveratrol in normal consumption quantities (0.35 to 1.85 mg/kg).

Content in wines and grape juice
The trans-resveratrol concentration in 40 Tuscan wines ranged from 0.3 to 2.1 mg/L in the 32 red wines tested and had a maximum of 0.1 mg/L in the 8 white wines in the test. Both the cis- and trans-isomers of resveratrol were detected in all tested samples. cis-Resveratrol levels were comparable to those of the trans-isomer. They ranged from 0.5 mg/L to 1.9 mg/L in red wines and had a maximum of 0.2 mg/L in white wines.

In a review of published resveratrol concentrations, the average in red wines is 1.9 ± 1.7 mg trans-resveratrol/L (8.2 ± 7.5 μM), ranging from nondetectable levels to 14.3 mg/L (62.7 μM) trans-resveratrol. Levels of cis-resveratrol follow the same trend as trans-resveratrol.

Reports suggest some aspect of the wine making process converts piceid to resveratrol in wine, as wine seems to have twice the average resveratrol concentration of the equivalent commercial juices.

In general, wines made from grapes of the Pinot Noir and St. Laurent varieties showed the highest level of trans-resveratrol, though no wine or region can yet be said to produce wines with significantly higher concentrations than any other wine or region.

Content in selected foods
Ounce for ounce, peanuts have about half as much resveratrol as red wine. The average amount in peanuts in the marketplace is 79.4 µg/ounce.

In comparison, some red wines contain approximately 160 µg/fluid ounce. Resveratrol was detected in grape, cranberry, and wine samples. Concentrations ranged from 1.56 to 1042 nmol/g in Concord grape products, and from 8.63 to 24.84 µmol/L in Italian red wine. The concentrations of resveratrol were similar in cranberry and grape juice at 1.07 and 1.56 nmol/g, respectively.

Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than 10% of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half.

Supplementation
As a result of extensive news coverage, sales of supplements greatly increased in 2006. This was despite the existence of studies cautioning that benefits to humans are unproven.

Supplements vary in purity, and can contain anywhere from 50 percent to 99 percent resveratrol. Many brands consist of an unpurified extract of Japanese knotweed; these contain about 50 percent resveratrol by weight, as well as emodin, which, while considered safe in moderate quantities, can have a laxative effect in high amounts.

Harvard University scientist Professor David Sinclair is often quoted in online ads. Sinclair, who has studied resveratrol extensively, has gone on record in Bloomberg Businessweek to say he never uttered many of the statements attributed to him on these sites.

Testosterone
A Korean study showed that trans-resveratrol supplementation increased testosterone levels in men in vivo, which has led to its marketing as a bodybuilding supplement. A Spanish study has also shown the antioxidant to increase sperm production in rats.

Related compounds

 * Epsilon-viniferin, a resveratrol dimer
 * Hopeaphenol, a resveratrol tetramer
 * Pallidol, a resveratrol dimer
 * Piceatannol, an active metabolite of resveratrol found in red wine
 * Piceid, a resveratrol glucoside
 * Trans-diptoindonesin B, a resveratrol trimer