Resveratrol pill health benefit and side effects, review of anti-aging claims, will this supplement help you live longer? by Ray Sahelian, M.D.
March 2 2014

Resveratrol was first isolated in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum), but has since been found in various plants, including grapes, berries, cacao, and peanuts. What made it popular was a 2006 study that reported mice lived longer when given a resveratrol supplement.
   Research studies continue to find more interesting benefits from this red wine compound, including potential anti-cancer and anti-aging activity. It is not surprising that extensive research from all over the globe indicates that it has a wide range of beneficial properties, including vision enhancement. If you would like to improve your vision and have better color perception, see Eyesight.

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Trans-3,5,4'-trihydroxystilbene is a protective compound produced by grapes and other plants in response to environmental stresses. Studies have demonstrated that it has potent antioxidant activity and also has the ability to inhibit platelet aggregation. These actions may help prevent free radical damage throughout the body and provide protective support to the cardiovascular system. Red wine has about 1.5 to 3 milligrams per liter (a liter is almost 34 ounces).

Resveratrol 10 mg
- extract from Hy Zhang Root Extract (Polygonum cuspidatum)
Suggested Use:  One capsule with breakfast a few times a week.


My comments about this dose of 10 mg: Some people think the more they take the better. This is not necessarily true. Sometimes smaller amounts are better overall to the body than larger dosages. When participants in a high intensity exercise trial were given 250 mg, this high dosage counteracted the positive effects of exercise on blood pressure, levels of fat in the blood and the capacity of the body to transport and use oxygen.  July 22, 2013, Journal of Physiology


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Where is it found?
As red wine is a rich source, many sources will reference it as "red wine polyphenols," "red-wine extract," etc. Unfortunately, there is a great deal of misinformation, so you need to keep the following in mind when reviewing articles and marketing information about related products. As it is found in the skins of grapes, red wine will provide several times more resveratrol than white wine. Grape skins are not used in the production of white wine. Since it is produced within the grape skin in response to attack by specific molds, grapes and wine produced in moist, northern climates (where these fungi are more prevalent) yield more resveratrol. As it is vulnerable to fairly rapid destruction by light and oxygen, the fact that wine is stored in air-tight, cool conditions away from sun light protects the resveratrol content. Only immediately after a bottle of wine is opened is the maximum resveratrol potency available. Since making wine also involves the potential damage from alcohol and preservatives, many people prefer a dietary supplement source.
   Much of the resveratrol sold in supplement form is from the herb
Polygonum cuspidatum which is available in various extract potencies, ranging from 5 percent to 50 percent.

Resveratrol side effects, safety, caution, danger, toxicity, risks
Since human studies are minimal, we do not know the full range of resveratrol side effects, risks or benefits at this time. No significant resveratrol side effects have been mentioned in the medical literature as of March 2014. Perhaps if a person takes several pills a day they may have headache, nausea, restlessness and perhaps shallow sleep but this is just early feedback from some users and I am not certain yet that it is accurate.

Testimonial regarding adverse reaction
I did a search "can Resveratol make you nauseous?" and your web article came up mentioning in higher amounts of multiple doses it may cause various troubles among them nausea. I can confirm that in myself. One night I ate dinner a couple hours earlier, but popped one of the 500 mg Resveratols with half a banana. Within about 15 minutes I was feeling nauseous. 30 minutes later its a little better, but I reflect back on hours of nausea after some meals. Sometimes I could manage not to throw up, but others I was miserable for hours till I finally threw up. For myself, tonight, there is a definite connection. Not sure if I have some food allergies and sensitivities but none of those make me sick in the gut, but rather sinus/ cold like symptoms. I may try to use smaller amounts. Thought my experience may be of interest to you.
   Dr. S answers: I am not sure if it is the resveratrol itself causing the nausea, the herb which it is derived from which is in the product, or the combination.

Potential benefits
Over the next few years we are likely to discover that resveratrol has potential in the therapy of many conditions. It is a potent chemical and studies show it has anti-inflammatory, antioxidant, anti-infective properties, and it activates the longevity gene in fruit flies and worms.
Other supplements that are excellent antioxidants include acai berry pills, carnosine, acetyl l-carnitine, alpha lipoic acid, vitamin C, vitamin E, and mangosteen pills.

Curr Med Chem. 2013. Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. We evaluated whether resveratrol has beneficial effects on markers of inflammation and oxidative stress in smokers. A randomized, double- blind, cross-over trial was performed in 50 healthy adult smokers: 25 were randomly allocated to "resveratrol-first" (30-days: 500 mg resveratrol / day, 30-days wash-out, 30-days placebo) and 25 to "placebo-first" (30-days placebo, 30-days wash-out, 30-days 500mg resveratrol / day). Resveratrol significantly reduced C-reactive protein (CRP) and triglyceride concentrations, and increased Total Antioxidant Status (TAS) values. Uric acid, glucose, insulin, cholesterol, liver enzyme concentrations, and weight, waist circumference, and blood pressure values did not significantly change after supplementation. Because it has anti-inflammatory, anti-oxidant, and the ability to lower triglyceride effects, its supplementation may beneficially affect the increased cardiovascular risk of healthy smokers.

Alzheimer's disease
Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity. Gerontology. 2003.

Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C.
Br J Pharmacol. 2004.
Protein kinase C is involved in the neuroprotective action of resveratrol against Abeta-induced toxicity.

Anti-aging and longevity
As to its anti-aging potential, resveratrol activates a cell's survival defense enzyme, which prolongs the time cells have to repair their broken DNA. It acts on fruit flies and worms in the same way as a method known to extend the life of animals including monkeys -- sharply restricting how much they eat. Resveratrol has been found to help mice live longer. Thus far, the research has focused in animals, worms and fruit flies, and we have no idea what would happen if humans ingested this supplement for prolonged periods, and how it interacts with other supplements or medications. Most of the resveratrol supplements on the market are an extract, usually 5 to 40 percent, of an herb called Polygonum cuspidatum which has a very high content of the substance. Therefore, when you take a resveratrol pill, you are also ingesting many other substances found within this herb. It is likely these substances are also beneficial, but we don't know for sure. The resveratrol product sold on the Physician Formulas website has 10 mg of this antioxidant derived from 40 mg of Polygonum Cuspidatum root. Hence it is a 25 % extract.
   Even if this substance has anti-aging benefits in humans, we have no idea what the proper amount would be. Is it 5 mg a day, 10 mg, 50 mg, or more? There are a number of unanswered questions. For practical purposes, if you do wish to take this pill, I think a safe approach is to take one capsule of the 10 mg product 2 or 3 times a week. There are countless beneficial antioxidant substances in the form of supplements available to the consumer and I think taking small amounts of different ones is a reasonable approach until we have a clearer idea of the proper dosages.

Resveratrol improves health and survival of mice on a high-calorie diet.
Nature. 2006.
Mice were fed a large dose of resveratrol, 24 milligrams per kilogram of body weight. Red wine has about 1.5 to 3 milligrams of resveratrol per liter, so a 150-lb person would need to drink 1,000 bottles of red wine a day to get such a dose. Dr. Richard Hodes, director of the National Institute on Aging, which helped support the study, said that people should wait for the results of safety testing. Substances that are safe and beneficial in small doses, like vitamins, sometimes prove to be harmful when taken in high doses. Sirtris Pharmaceuticals, a therapeutics company co-founded by David Sinclair, M.D., has started a trial of a proprietary formulation of resveratrol in patients with type 2 diabetes.

I came across an article that stated most of it taken orally gets converted by the digestive process to other compounds, and thus it's effect on the "longevity" genes is effectively nullified. The article recommended much higher oral dosages to increase the amount that gets absorbed before the digestive juices alter it. So, a formulation of 10 mg seems very paltry in the face of vitamin companies that are hawking 500 and 1000 mg preparations.
   Many people, including some scientists, make the mistake of assuming the same benefits in animals will also occur in humans. When animals are given a substance, they are not taking anything else with it. In contrast, most humans who take a resveratrol pill are also ingesting other supplements, antioxidants, medications, caffeine, alcohol, and additional substances that may interact and give an outcome that is different than that obtained in rodents. Even if supplementation has a benefit in humans, the ideal dosage is not clear and anyone who claims they are certain of the right dosage is not being scientifically honest. Furthermore, some antioxidants or beneficial substances may show early benefits the first few weeks or months and then end up causing toxicity or harm. How do we know that some of the metabolites, when ingested in 500 or 1000 mg dosages, are not harmful? Another point to keep in mind is that it is not easy to find 99 percent or 100 % pure resveratrol on the market as it often used in research studies. The ones sold on the market are 10 to 50% extracts of herbs and some companies mislead the consumer by mentioning the total amount of the herb rather than the amount of resveratrol in it. When taking a resveratrol supplement, people are likely ingesting other substances found within the herb, for instance
Polygonum cuspidatum, that is present in the capsule, and we don't know the long term benefits and risks of taking this herb or others from which it is extracted. I have personally tried 10 mg resveratrol capsules and started having headaches when I reached 4 capsules. Mice are not likely to report headaches or other minor symptoms.

I'm struggling between whether to go on a 100% natural diet with natural sources of resveratrol, or to use a high potency supplement. On one hand nobody can go wrong essentially with a natural diet. On the other hand, if anti-aging studies are true, perhaps high doses of this substance could help tremendously with aging. But would such high levels such as 100mg -- or 100x that found in peanuts and red grapes -- have negative consequences?
    There is a great deal we don't know about the benefits and side effects taken in pill form and there is not easy answer at this time. Some people take this antioxidant a couple of times a week as opposed to daily.

Blood flow to brain
Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation
American Journal of Clinical Nutrition, 2010.
The many putative beneficial effects of the polyphenol resveratrol include an ability to bolster endogenous antioxidant defenses, modulate nitric oxide synthesis, and promote vasodilation, which thereby improves blood flow. In this study, 22 healthy adults received placebo and 2 doses (250 and 500 mg) of trans-resveratrol in counterbalanced order on separate days. After a 45-min resting absorption period, the participants performed a selection of cognitive tasks that activate the frontal cortex. Administration resulted in dose-dependent increases in cerebral blood flow during task performance. Cognitive function was not affected.


Cancer prevention and perhaps treatment
Recent laboratory studies indicate that resveratrol has promising therapeutic activity in various cancers, including breast, prostate, and neuroblastoma. Human studies are lacking at this time.

Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies.
Anticancer Res. 2004.  
Resveratrol exhibits anticancer properties as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth-inhibitory effects are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases.

Breast cancer
Identification of a p53-dependent pathway in the induction of apoptosis of human breast cancer cells by the natural product, resveratrol.
J Altern Complement Med. 2004.

Glioma
Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats.
Clin Cancer Res. 2004.

Lung cancer
Consumption of red wine is associated with a slight but statistically significant reduction in the development of lung cancer, as reported in the journal Thorax.

Neuroblastoma
NB is an aggressive childhood cancer of the peripheral nervous system arising from neural crest sympathoadrenal progenitor cells.

Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma.
Anticancer Res. 2004.

Prostate cancer
Coral Lamartiniere, at the University of Alabama at Birmingham's Department of Pharmacology and Toxicology, gave male mice resveratrol, the equivalent of that found in a bottle of red wine in humans, and discovered that the mice were significantly less likely to develop prostate cancer.

Erectile dysfunction and impotence
This substance may dilate blood vessels and hence be of some help in those with ED.

Resveratrol has a potent relaxant effect on rat corpus cavernosum via endothelium-dependent and -independent mechanisms. Endothelium-dependent relaxation of corpus cavernosum is thought to be mediated primarily through NO/cGMP signaling pathway, and possibly an additional mechanism, endothelium-dependent hyperpolarization factor.

Exercise and heavy physical exertion
Perhaps small amounts may help, but supplementing with too high a dosage, such as 250 mg a day, is not advised. July 22, 2013, Journal of Physiology. This particular study by University of Copenhagen researchers involved 27 healthy but inactive men, all nonsmokers around 65 years old. The men were asked to engage in high-intensity exercise, which included full-body circuit training, for a total of eight weeks. During this time, half of the participants were given 250 mg of resveratrol daily and the others were given a placebo pill that contained no active ingredients. The results showed that supplements counteracted the positive effects of exercise on blood pressure, levels of fat in the blood and the capacity of the body to transport and use oxygen. The men who took the placebo pills had lower blood pressure and concentrations of LDL or "bad" cholesterol and triglycerides in their blood following the eight weeks of exercise. Resveratrol supplementation combined with physical activity, however, eliminated the reduction in blood pressure and blood fats, and led to a significantly lower increase in the amount of oxygen delivered to muscles during exercise.

Eye health
Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition.
Chem Biol Interact. 2005.

Influenza
Resveratrol treatment had the greatest effect when administered 3 hours after exposure to influenza. Smaller but significant effects were seen when treatment began 6 hours after infection, but at 9 hours after infection treatment had no effect. Pre-treatment also did not change susceptibility to infection. Studies in a mouse model of influenza showed that injections after inoculation of influenza increased survival by 40% compared with placebo injections. The amount of virus present in the lung 6 days after infection was 98% lower in the resveratrol -treated mice. The Journal of Infectious Diseases, 2005.

Metabolism
Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011.
We treated 11 healthy, obese men with placebo and 150 mg/day resveratrol in a randomized double-blind crossover study for 30 days. Treatment reduced sleeping and resting metabolic rate. In muscle and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.

Thyroid gland
Q. There is a website that which shows that resveratrol causes the thyroid to enlarge. If you google resveratrol and goitrogenic, it will bring up medical and non medical blogs where they mention it to be one of the worst goitrogenic food.
   A. A search on Medline in 2013 does not show any published studies in humans regarding this compound causing an enlarged thyroid. One unpublished study in rodents by Ibrahim Abduh Khardali B. Sc. Pharm for his masters at King Saud University concludes, "So the present study can give hints to potential goitrogenic effect of resveratrol. At this time it is too early to come to any conclusions regarding its hypothyroid or hyperthyroid inducing effects. But, as with most supplements, if breaks are taken occasionally side effects become minimal.

Triglyceride and lipid level reduction
Arterioscler Thromb Vasc Biol. December 2013. High-dose resveratrol treatment for 2 weeks inhibits intestinal and hepatic lipoprotein production in overweight/obese men.

Weight loss?
Results of a small study show that obese men who take a 150 mg daily dose appear to improve their metabolism as much as if they were on a strict low-calorie diet. Patrick Schrauwen, Ph.D., Maastricht University, the Netherlands; David L. Katz, M.D., M.P.H., director, Prevention Research Center, Yale University School of Medicine, New Haven, Conn.; Nov. 2, 2011, Cell Metabolism.

       
Summary and review
This molecule will certainly continue to get a lot of media attention. You may consider drinking an ounce or two of red wine a few times a week or you could take a resveratrol supplement a few times a week. Until we learn more about it, I prefer not to take it every single day since most people take medicines or other supplements and we don't know how it will interact with them in the long run. We also have no idea on what the right resveratrol dosage is when used for prolonged periods.

Cocoa, chocolate, cacao
In addition to being found in red wine and grape juice, ii is also found in dark chocolate and cocoa. Researchers at the Hershey's Center for Health and Nutrition tested cocoa powder, baking chocolate, dark chocolate, semi-sweet baking chips, milk chocolate and chocolate syrup for the level of resveratrol and a related compound, piceid. The levels found in cocoa and chocolate products were second only to red wine among known sources. Gram for gram, cocoa powder had the highest average amount of resveratrol and piceid, followed by baking chocolates, dark chocolates, semi-sweet chips, milk chocolate and chocolate syrup. Cocoa powder, baking chocolate and dark chocolate contain on average 14 micrograms to 18 micrograms per serving while the level found in the average California red wine is 800 micrograms per glass.

Research studies
Resveratrol in raw and baked blueberries and bilberries.
J Agric Food Chem. 2003.
Although blueberries and bilberries were found to contain it, the level of this chemoprotective compound in these fruits was <10% that reported for grapes. Furthermore, cooking or heat processing of these berries will contribute to its degradation.

Questions
I have heard of cis and trans resveratrol, can you explain?
   Resveratrol is a natural phenolic compound that exists as cis and trans isomers. t-resveratrol is a natural component of Vitis vinifera, abundant in the skin of grapes (but not in the flesh), and present in wines, especially red wines. It exhibits a number of biological activities, including anti-inflammatory and anticarcinogenic. It also exists in wines as a cis isomer, which, unlike trans isomer is not currently available commercially; as a result, little is known about this isomer's pharmacological activity.

I recently read that resveratrol, when taken as a supplement, is best absorbed buccally. Is buccal absortion necessary or preferable?
   Buccal mucosa is mucous membrane of the inside of the cheek. Do you mean absorption anywhere in the mouth or sublingual? The best way to absorb a substance in the mouth is sublingually, meaning under the tongue. I have not seen any evidence yet that under the tongue absorption of a resveratrol supplement is superior to swallowing a pill. Human research with is quite limited. I see no obvious problems allowing a resveratrol supplement to be absorbed under the tongue but I am not sure this is necessary.

My brother emailed you about resveratrol and buccal / mouth absorption awhile back, and your response suggested you didn't know of buccal or sublingual aborption being a superior way. My brother was referring to a scientific article. Buried deep within the article, it says: "When t-RES was orally administered to humans (four different people in our laboratory, 2644 years old), and retained in the mouth for 1.0 min before swallowing, 37 μg of RES/l were measured in plasma just 2.0 min after administration." Apparently, the amount of absorbed buccally, 1 mg, produced the same blood levels as 250 mg taken orally.
   Most of the resveratrol supplements on the market are not pure but an extract from
Polygonum cuspidatum. Therefore, there are many other compounds present. I will await to see human trials to determine whether buccal or sublingual administration is preferable to oral pills.

I have found a Chinese company, apparently a wholesaler, selling the basic product made from grape skins. They seem to have a compelling case for the use of the grape skins as opposed to another common plant that I believe is Japanese knotwood. This Chinese company says that people who use that one often suffer from diarrhea, but not with their product made from the red grapes.
    In addition to resveratrol, one has to see what other substances are present in the product promoted by the Chinese company.  We have not had any feedback from consumers using Japanese knotwood source that they have had diarrhea or gastrointestinal symptoms.