Resveratrol bioavailability and toxicity in humans.

Resveratrol bioavailability and toxicity in humans.
Cottart CH, Nivet-Antoine V, Laguillier-Morizot C, Beaudeux JL.

APHP, Hôpital Universitaire Charles Foix, Service de Biochimie, Ivry sur Seine, France.

Numerous data are now available on the beneficial properties of the polyphenolic compound resveratrol including its anti-inflammatory and antitumor effects. However, few studies have been performed with resveratrol in humans, and the results of these studies appear fragmentary and sometimes contradictory due to variations in conditions of administration, protocols and methods of assessment. This review article presents the results of recent studies investigating the pharmacokinetics, bioavailability, and toxicity of resveratrol in humans. Resveratrol is well absorbed, rapidly metabolized, mainly into sulfo and glucuronides conjugates which are eliminated in urine. Resveratrol seems to be well tolerated and no marked toxicity was reported. These data are important in the context of human efficacy studies, and they provide further support for the use of resveratrol as a pharmacological drug in human medicine.

Full study attached.

Thanks drmz, very good stuff:

Nice list of possible mild adverse effects for the total of 104 patients:

The adverse effects in humans have been investigated in several studies after high-dose resveratrol intake [27–29], representing a total of 104 patients (including placebo). The highest doses were 5 g/70 kg for a single intake and 0.9 g/day for iterative administration, corresponding, respectively, to approximately 1/40 and 1/200 of the dose reported to cause nephrotoxicity and 1/4 and 1/20 of the highest dose reported to be safe in rats [35]. No serious adverse event was detected in any of these studies. Adverse events were mild and only lasted a few days. After a single administration of 400mg of resveratrol, Vaz-da-Silva et al. [28] reported three events (blood electro- lyte changes, nasopharyngitis and erythematous rash) in 3/24 patients, possibly related to treatment. In the other single-dose administration pharmacokinetic study [27], 2/40 patients receiving 1g resveratrol exhibited one or more minor biological adverse event, consisting of a small increase in blood bilirubin or alanine amino trans- ferase level. In the multiple-dose study, 40 volunteers received one dose of resveratrol (25, 50 100, 150mg, or placebo) every 4 h for 48 h. The most frequent adverse event was frontal headache (three cases). The other adverse events appeared only once: headache, myalgia of the lower extremities, somnolence (25 mg group), epididymitis (100mg group), and dizziness and occipital headache (150 mg group), without any clear relation to the adminis- tered dose [29].

The effects really look pretty mild, dont they?
I think this is what many people wanted to know.

The conlcusions are interesting as ell:

In conclusion, the pharmacological properties of resveratrol in the field of antitumor therapy or in relation to its anti- inflammatory/antioxidant effects support the use of this agent as a complementary nutritional/pharmacological biomolecule. Numerous data are now available on its bioavailability and toxicity in humans. However, these data are still patchy and many areas warrant further investigation and clarification. In particular, the exact nature of the endogenous metabolites, including their biological properties, and the precise distribution of the molecule within tissues and cells remain to be determined precisely.

I believe this last one is important, and help understand resveratrol's beneficial limits in humans.

I will keep looking through it.
A

Edited by Anthony_Loera, 19 December 2009 - 01:45 PM.

The adverse effects in humans have been investigated in several studies after high-dose resveratrol intake [27–29], representing a total of 104 patients (including placebo). The highest doses were 5 g/70 kg for a single intake and 0.9 g/day for iterative administration, corresponding, respectively, to approximately 1/40 and 1/200 of the dose reported to cause nephrotoxicity and 1/4 and 1/20 of the highest dose reported to be safe in rats [35]. No serious adverse event was detected in any of these studies. Adverse events were mild and only lasted a few days. After a single administration of 400mg of resveratrol, Vaz-da-Silva et al. [28] reported three events (blood electro- lyte changes, nasopharyngitis and erythematous rash) in 3/24 patients, possibly related to treatment. In the other single-dose administration pharmacokinetic study [27], 2/40 patients receiving 1g resveratrol exhibited one or more minor biological adverse event, consisting of a small increase in blood bilirubin or alanine amino trans- ferase level. In the multiple-dose study, 40 volunteers received one dose of resveratrol (25, 50 100, 150mg, or placebo) every 4 h for 48 h. The most frequent adverse event was frontal headache (three cases). The other adverse events appeared only once: headache, myalgia of the lower extremities, somnolence (25 mg group), epididymitis (100mg group), and dizziness and occipital headache (150 mg group), without any clear relation to the adminis- tered dose [29].

The highest dose for iterative administration was 0.9g/d, which is a quite normal dose around here. Many of these adverse event reports were generated from PK studies of very small amounts for very short duration, so this is not a very well-powered analysis. Here at ImmInst, we've had probably a dozen different reports of joint/tendon issues, most of which resolved with cessation of use. As I recall there was at least one "resveratrol ruined my life" type of post. The difference between these two "datasets" is that ImmInst reports are self-selected. If you took resveratrol and had no adverse effects, as I have, you are unlikely to report that. On the other hand, if you had a really bad experience, you might seek out all possible resveratrol communities on the net in order to spread your news. As a result, we know how many adverse event reports we've had, but we don't know how many subjects there were, so we have no idea of the frequency. It is entirely possible that resveratrol is "worse than ciprofloxacin". Getting "floxed" is a low-frequency severe side effect that is highly reported on the net, but millions of people have had quinolones. Likewise, I suspect that really bad resveratrol outcomes are also that way. I further suspect that joint/tendon pains that resolve on cessation or dose reduction are somewhat common, but we have no way to evaluate the frequency. So far, the largest trials of resveratrol in controlled situations, those run by Sirtris and other clinical trials underway, are not included in this review. This review performs a valuable service by pulling the literature together, but I think all we can really take home from it is "no blatant acute toxicities".

Thanks for posting that. The bottom line is; if you are taking the best Resveratrol product available and you are getting side effects that you can actually attribute to Resveratrol use and no other cause, you probably should stop, then resume. If the sides continue then drop it from your regimen. IMO the benefits far outweigh any transient or tolerable side effects.

Thanks for posting that. The bottom line is; if you are taking the best Resveratrol product available and you are getting side effects that you can actually attribute to Resveratrol use and no other cause, you probably should stop, then resume. If the sides continue then drop it from your regimen. IMO the benefits far outweigh any transient or tolerable side effects.

Bottom line for me is somewhat different. My bottom line is that there are more questions open then answered, that results for mouse studies are not 1 on 1 transposable to humans and that the exact workings and long term implications of resveratrol are not studied yet. Further it's problematic to say anything about dosage in humans because it could well be a known or unknow metabolite of resveratrol doing the "good things", so stuffing yourself with high doses of resveratrol to get res plasma levels up could well be very damaging in the long run. So the "benefits"in human are just not known or studied. There is no way you can say that the benefits outweigh any transient or tolerable side effects as ling as there benefits are not founded on human studies. Besides that it's not said that a substance is safe if you don't notice any immediate side effects. I can eat lots of beta-carotene or selenium or the wrong vitamin E day in day out for years without a problem without knowing i'm increasing my risk to cancer. I could even say i feel much better taking it, but in the long it could be very bad for my health. I think the same goes for resveratrol. I can't understand people are not more cautious about this. I really don't. Probably because of the "agressive marketing"mentioned in the article/study.

So for me the bottom line is that i have to 1. be very cautious 2. I need to wait for the clinical trials to finish 3. Watch my food intake and spent $40 a month to the gym which enables me to workout 3-4 times a week to give me well studied proven benefits instead of spending $40 a month (for a lifetime when i would buy it for anti-aging purposes) for something that , and this is highly doubtful, could maybe decrease cancer risk. There are probably 100 or more other, more cheaper and well known methods or activities that accomplish the same results. Maybe resveratrol increases cancer risk in the long run, who knows. Good nutrition and regular exercising surely doesn't.

Anyways, i'm glad there are pioneers or guinea pigs out there, i have the time so i rather wait Still some years to go. Still it seems counterintuitive to me that people who want to live longer and healthier are into gambling with their body.


In Western populations, where obesity is difficult to control, resveratrol is
commercially available as a dietary supplement with aggressive
marketing and represents a potential life-long medicine.
Today, numerous data are available on the beneficial
properties of resveratrol. However, confusion exists due to
several pieces of contradictory information, essentially
because in vitro and animal experimental approaches are
often presented as directly transposable to humans."


First, resveratrol seems to be well tolerated. However, no
information is available on long-term administration. For
use in chronic diseases such as diabetes, colorectal cancer or
Alzheimer’s disease, or for prevention of cardiovascular
disease and anti-aging antioxidative care, resveratrol
administration would occur over several months/years at
doses which are not yet known.

Edited by drmz, 20 December 2009 - 09:49 AM.

Okay, whatever you say. Can you get the best Resveratrol available where you live?

Okay, whatever you say. Can you get the best Resveratrol available where you live?

Best resveratrol quality has nothing to do with herr drmz's objections. Even the best might have side effects that will not be manifest for years. Like Vioxx, or now Celebrex known to increase risk for heart attack.

Millions are drinking water with unsafe but legal levels of trichloroacetic acid. Every day twenty new chemical are registered, whose effects on people are unknown. They are used world-wide until there is a proven problem, and then withdrawn only after court fights by the manufacturers to keep making money.

The possible unknown side effects of resveratrol do seem to me a better bet than the known risks for NSAIDS, COX2 inhibitors and other meds used to treat arthritis. I find resveratrol is more effective at controlling the symptoms for me than any of the officially prescribed medications I have used, and in my estimation is a lot less risky, at least in the intermediate term. There are a lot more potential benefits, including vis-a-vis breast and colorectal cancer, and improved glucose metabolism.

"You pays your money and you takes your choice." - Anon.

Edited by maxwatt, 20 December 2009 - 03:27 PM.

Okay, whatever you say. Can you get the best Resveratrol available where you live?

Yeah we're all living in the global village. My objections are indeed (like maxwatt said) different and are not solved by quality resveratrol. I can order at Revgenetics whenever i want. My objections will probably be solved over time, i'm not in a hurry It's just my personal stance, maybe it will change over time, maybe not.

Edited by drmz, 20 December 2009 - 03:04 PM.

Agreed, thinking in a crtical manner is vital to intelligence. Just because I think Resveratrol is worth taking doesnt mean you should or will.There is a difference in product and its effects though, as I have experienced. I think its interesting that you dont use Resveratrol, but still have an interest and post here. Maxwatt, why is your avatar not showing up? I loved that mask, its a sigil of healthy Id. Ah, there it is!

Edited by 2tender, 20 December 2009 - 11:59 PM.

Okay, whatever you say. Can you get the best Resveratrol available where you live?

I have taken the "the best Resveratrol" available in moderate doses for a very short amount of time and still suffer from joint pain in the hands which was not present before over a year later. I'm young, don't take other supplements, blame Resveratrol, and am not alone in this stance.

Yet, there are not studies which reflect this effect in mice or men.

Okay, whatever you say. Can you get the best Resveratrol available where you live?

I have taken the "the best Resveratrol" available in moderate doses for a very short amount of time and still suffer from joint pain in the hands which was not present before over a year later. I'm young, don't take other supplements, blame Resveratrol, and am not alone in this stance.

Yet, there are not studies which reflect this effect in mice or men.

Yes, but those of us using this forum prolly do represent one of the larger groups of people chronically using (or abusing, depending on your point of view) resveratrol.
Joint/tendon pain may only occur in a very small % of this group but we have a large enough group and enough chronic useage to "show" this effect.

FYI, my basic philisophy re: resveratrol useage is basically in agreement w/ what Maxwatt stated earlier. Far too much potential upside/benefits and limited downside not to take it.....
YMMV.

Thanks for posting. I looked at the forum for quite some time before deciding to actually try the current versions of Resveratrol available. I had sides from an earlier version probably related to high emodin content. I ordered 2 types from different companies, one of them was worth continueing. I think that there are many people that use Res. but dont post here. Every now and then some members that have used it for years pop in and post. How long have you used Resveratrol, Malbecman? What type and dose?

Okay, whatever you say. Can you get the best Resveratrol available where you live?

I have taken the "the best Resveratrol" available in moderate doses for a very short amount of time and still suffer from joint pain in the hands which was not present before over a year later. I'm young, don't take other supplements, blame Resveratrol, and am not alone in this stance.

Yet, there are not studies which reflect this effect in mice or men.

This is exactly the sort of adverse effect that I was talking about in post #3 of this thread. ("Resveratrol ruined my life", though I hope that Shay doesn't consider his life to be ruined.) I wish that we had a better sense of the frequency of this problem. Shay, can you say anything about others who have seen this sort of effect?

Okay, whatever you say. Can you get the best Resveratrol available where you live?

I have taken the "the best Resveratrol" available in moderate doses for a very short amount of time and still suffer from joint pain in the hands which was not present before over a year later. I'm young, don't take other supplements, blame Resveratrol, and am not alone in this stance.

Yet, there are not studies which reflect this effect in mice or men.

This is exactly the sort of adverse effect that I was talking about in post #3 of this thread. ("Resveratrol ruined my life", though I hope that Shay doesn't consider his life to be ruined.) I wish that we had a better sense of the frequency of this problem. Shay, can you say anything about others who have seen this sort of effect?

I can only speak for myself, and it doesn't appear to be life ruining. The joint pains slowly receded from full body down to just the hands (maybe aggravated by much typing on my part), and the hand pain seems to come and go on a weekly basis.

My gut feeling is that there have been 20-30 people complaining of pain, and 5 or less with seriously negative effects. I can't quote threads, but there has been a very lively (and apparently easily dismissed by naysayers) debate about the joint pains on Imminst. If you dig, you'll find that there are people on these boards who have considered resv life ruining.

For my part, I'm waiting for more large scale studies to bring this issue to light. Then I'll wait for more studies to figure out how bad it really is. It certainly is frustrating watching myself age in the mean time.

Can anybody get the full Vaz-da-Silva paper and report what serum electrolyte disturbances there were in that one subject?

Anyways, i'm glad there are pioneers or guinea pigs out there, i have the time so i rather wait Still some years to go. Still it seems counterintuitive to me that people who want to live longer and healthier are into gambling with their body.

It sounds like you overvalue your life. Likely it would be of more value to the world for you to act as a guinea pig than whatever else you happen to be doing. Give of yourself drmz!

Anyways, i'm glad there are pioneers or guinea pigs out there, i have the time so i rather wait Still some years to go. Still it seems counterintuitive to me that people who want to live longer and healthier are into gambling with their body.

It sounds like you overvalue your life. Likely it would be of more value to the world for you to act as a guinea pig than whatever else you happen to be doing. Give of yourself drmz!

\

You have a strange interpretation of my sentence....Maybe it's my english, which isn't that good, not a native english speaker. (maybe the word "glad" is misplaced, not put there conciously)

Edited by drmz, 22 December 2009 - 06:52 PM.

Anyways, i'm glad there are pioneers or guinea pigs out there, i have the time so i rather wait Still some years to go. Still it seems counterintuitive to me that people who want to live longer and healthier are into gambling with their body.

It sounds like you overvalue your life. Likely it would be of more value to the world for you to act as a guinea pig than whatever else you happen to be doing. Give of yourself drmz!

\

You have a strange interpretation of my sentence....Maybe it's my english, which isn't that good, not a native english speaker. (maybe the word "glad" is misplaced, not put there conciously)

I'm just saying, some humans are going to need to test this stuff. Why not you? Rather than being a mere skeptic, you could be a bit of a hero, helping blaze a path toward a brighter tomorrow...

Sorry I dont agree here, the language difference explains some of the incongruities of his posts. While Resveratrol is powerfully beneficial for most people there are some who cant tolerate it in any form and should not take it. I had bad reactions to something as ordinary as a vitamin e softgel, which I had taken for years, it simply didnt agree with my system anymore.I dropped it from my regimen and the problem went with it. In a sense all supplement takers are "guinea pigs" of some sort. Its similar to the fact that some people cant eat certain foods. I highly doubt that Resveratrol could produce life long arthritic pain or "ruin" someones life without there being legitimate medical documentation, if this did indeed happen, I think it would be extremely rare or a case where someone was erroneously taking medications along with it. Medications and most supplements should not be taken at the same time, particularly antibiotics, a Doctor should always be apprised of what their patient is taking in the form of supplements and it is now common practice for them to ask. Albeit there are some people who just think,"hey these are just vitamins and are supposed to be good for me" DUH ! Its just my opinion from experience and I hope it helps.

Edited by 2tender, 23 December 2009 - 12:08 AM.

Okay, whatever you say. Can you get the best Resveratrol available where you live?

I have taken the "the best Resveratrol" available in moderate doses for a very short amount of time and still suffer from joint pain in the hands which was not present before over a year later. I'm young, don't take other supplements, blame Resveratrol, and am not alone in this stance.

Yet, there are not studies which reflect this effect in mice or men.

This is exactly the sort of adverse effect that I was talking about in post #3 of this thread. ("Resveratrol ruined my life", though I hope that Shay doesn't consider his life to be ruined.) I wish that we had a better sense of the frequency of this problem. Shay, can you say anything about others who have seen this sort of effect?

I can only speak for myself, and it doesn't appear to be life ruining. The joint pains slowly receded from full body down to just the hands (maybe aggravated by much typing on my part), and the hand pain seems to come and go on a weekly basis.

My gut feeling is that there have been 20-30 people complaining of pain, and 5 or less with seriously negative effects. I can't quote threads, but there has been a very lively (and apparently easily dismissed by naysayers) debate about the joint pains on Imminst. If you dig, you'll find that there are people on these boards who have considered resv life ruining.

For my part, I'm waiting for more large scale studies to bring this issue to light. Then I'll wait for more studies to figure out how bad it really is. It certainly is frustrating watching myself age in the mean time.

We have to consider that some of these posters are a little "off" think of Quasimodo and the bells, (trolls) or people that want to slam a product just for fun or that they actually work for a rival company, This has happened here in the past. I had some joint pain initially when I started taking 2 types of Resveratrol a year ago, I stopped taking one of the supplements and took a break from exercise, it has not returned, albeit slightly and I can definatively attribute it to lifting heavy weights with poor form and decades old prior injuries from MA. It may be that Resveratrol can rev the system to autoimmune symptoms in some people, while others with active autoimmune problems may benefit from it. Just my thoughts and opinions, I hope it helps.