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Resveratrol and Joints


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#1 geddarkstorm

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Posted 31 January 2009 - 04:17 AM


Warning: This is going to be a lot of speculation and conjecture.

There has been a low proportion of people around these boards who take resveratrol and subsequently comment about joint pain. Since the number of people has been small compared to the number who take resveratrol, and since we can factor out 50% mixtures of resveratrol as other grape OPCs can cause adverse effects at high doses, the issue has remained an odd curiosity. Add to the confusion the demonstrated in vivo effects of resveratrol to protect joints from damage, either in inflammatory arthritis or osteoarthritis models. In vitro studies have directly shown resveratrol's anti-inflammatory (inhibits NF-kB) and condrocyte protective abilities. It should be expected then, from all evidence, that resveratrol would fight arthritis, inflammation, and protect joints quite potently.

However, there are three potential ways resveratrol could lead, in some people at high enough doses and in response to certain conditions, to joint pain. This doesn't mean joint damage per ce, but pain.

The first two ideas come directly from Maxwatt, so all credit goes to him.

1. Suppression of angiogenesis.


Resveratrol is known to reduce angiogenesis. This is great for fighting tumors and cancer, but can slow tissue repair on the other hand. Areas of repeated stress may be in need of more repair than otherwise, such as the joints and surrounding tissue. As damage accrues, the nerves signal that there's unrepaired tissue, and pain my result (similar to how ripped muscles ache after intense exercise?).

On the other hand, angiogenesis is actually one of the pathological effectors of inflammatory arthritis. Indeed, blocking angiogenesis has been shown to alleviate arthritis in in vivo studies. The same is true for osteoarthritis, where angiogenesis is one of the factors that lead to this condition and joint pain.

If anything, this suggests that resveratrol's anti-angiogenesis properties is yet another way it protects joints from pain, inflammation (tendinitis included), and degradation. In the absence of direct tissue damage, such as a cut, angiogenesis within the body seems to lead to more trouble than good, and is generally avoided. More evidence is needed to correlate a lack of angiogenesis in healthy joints with pain, and so far we see the reverse with arthritis. This does not absolutely rule out a lack of basal angiogenesis as being responsible for minor joint pain in otherwise healthy, heavily used joints. In fact, a ripped tendon might need angiogenesis to heal, and a lack there of may rapidly cause inflammation and pain. Still, it seems less likely a cause than the following two possibilities, in my opinion.

Solving this issue would simply require taking breaks from resveratrol dosage, such as two days out of a week or every other week, or taking a pro-angiogenesis supplement at the end of the day if resveratrol is taken at the beginning. However, I advice against the latter, as again, too much angiogenesis is directly associated with joint inflammation and arthritis.

2. Insufficient niacinamide levels.

This is a very interesting idea of Maxwatt's I hadn't even begun to consider. If resveratrol is activating Nampt as its main mode of action, then the conversion of niacinamide to NAD+ could lead to a deficiency in niacinamide if the levels were already too low in a person's body to sustain the burst of Nampt protein expression and activity. In fact, this idea is supported by the observation that increasing niacinamide in the diet of human participants lowered osteoarthritis impact and joint damage. Pain levels did not go down, the study reported, but the individuals on niacinamide were able to reduce their anti-inflammation medications by 13%, which is a metric for reduced pain, just not all the way on its own. While this does not prove that loss of niacinamide will increase joint pain, it does suggest it. Another study also showed the ability of niacin to similarly reduce arthritis damage in rats.

We can hypothesize that systemic stimulation of Nampt by resveratrol could lead to a sudden, acute drop in niacinamide levels. If there is not enough niacinamide in the blood stream to make up the difference and feed the machine that has been started, transient deficiency might result. Of course, this will be reversed once Nampt returns to basal levels and NAD+ using systems kick in, or if more niacinamide is ingested. In short, resveratrol may simply make known in the joints a pre-existing deficiency in niacinamide levels. Again, this is only a hypothesis and remains to be tested, even anecdotally.

Solving this issue would simply require niacinamide supplements 3 hours after resveratrol, or taking a break from resveratrol similarly to the solution for problem 1.

3. Increases in extracellular Nampt levels lead to joint inflammation.

Out of all the possibilities, this one is quite interesting to me. This possibility will only be true, I think, if resveratrol's main target is Nampt, not Sirt1, and only Sirt1 by extension of Nampt function.

Nampt (PBEF) is a very curious enzyme. Not only does it reside intracellularly, but it is secreted through an unknown mechanism (it lacks a secretion tag!) and acts extracellularly as a signaling hormone, pro-inflammatory cytokine, and innate immune system modulator. Extracellular Nampt can effect macrophages and other immune system modulators completely independently of its niacinamide to NMN catalytic role. Additionally, extracellular Nampt has been shown to increase inflammation and damage in arthritis. Consequently, inhibition of Nampt leads to reduced severity of arthritis.

What this suggests, is that we know resveratrol increases Nampt expression by up to 3 fold intracellularly, and that this leads to Sirt1 and AMPK activation, and NF-kB inhibition - acting as an anti-inflammatory. However, if some signal was received, how that is regulated I do not know, to cause release of the resveratrol increased Nampt from the cell, one would expect pro-inflammation to result from eNampt signaling. It may be, for some people especially in the joints, that Nampt is being released from the cells instead of being retained, and causing inflammation and tendinitis.

Again, how this would happen, I do not know. Obviously, this is not the norm. The levels of resveratrol that are taken may directly correlate to the level of Nampt overexpression. As overexpression goes up, for some people, the probability of Nampt secretion may also go up. Therefore, a solution to the problem may simply be to reduce resveratrol intake to levels that do not cause joint pain or inflammation.

Alternatively, the same solution of not taking resveratrol for two days out of a week, or every other week, may also work.



Which of these is most likely? I do not know. The first possibility seems least likely of all, to me, while the third and second seem to both have a good chance depending on the biochemical background of the person involved. Without further research, it is impossible to say which of the remaining two are more likely: we have to see if a large enough niacinamide drop occurs from Nampt activation and if this causes transient pain or inflammation in joints, and we need to know what signals cause Nampt secretion and what factors may prevent that. In short, for some people it may be reason 2, and for others reason 3 (or reason 1, can't rule that out still). At least if it's reason 2, one just needs niacinamide and that should fix it - I await any anecdotal reports. Also, there could always be more pathways we do not know of or have not considered that are causing these joint problems for some.

None the less, all studies with resveratrol have shown it to protect joints rather potently. Even if increased pain or inflammation is occurring, the joints are likely still in good shape, and modulating resveratrol and/or niacinamide should be all that is needed to reverse the condition.

Edited by geddarkstorm, 31 January 2009 - 05:16 AM.


#2 nowayout

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Posted 31 January 2009 - 05:31 AM

None the less, all studies with resveratrol have shown it to protect joints rather potently. Even if increased pain or inflammation is occurring, the joints are likely still in good shape, and modulating resveratrol and/or niacinamide should be all that is needed to reverse the condition.


That does not seem likely if you consider that some of us are still suffering long after stopping resveratrol.

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#3 geddarkstorm

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Posted 31 January 2009 - 05:45 AM

That does not seem likely if you consider that some of us are still suffering long after stopping resveratrol.


Hm, I have not heard of this before. This evidence is hard to reconcile with any of the possibilities above, other than extreme versions of the first and third one really. I say that because extracellular Nampt can perpetuate itself to some degree if I am reading this paper's results right. Extreme loss of angiogenesis could prevent tissue from properly healing, I would reason, though I don't know of any proof off hand. And again, something completely unknown could be happening too.

I do not know what to tell you. It is very rare apparently for something like that to occur, and has not appeared in any studies, which is why it perplexes me. Could it be resveratrol interacted with some other supplement, causing an unexpected, aberrant result? How could it remain chronic and persistent, and avoid healing by the body? Do anti-inflammatory drugs help you at all? For me, my joints have apparently improved with resveratrol, otherwise I could attempt to diagnosis your problem better...

In any case, I'm really sorry to hear that has happened to you. If we knew exactly how it was happening, we might be able to counter it.. maybe a Nampt inhibitor, if those are marketed and not toxic (Nampt loss is embryonic lethal for instance, but might not do much harm if transiently inhibited, since this has been proposed for arthritis treatment).

Edit: Heck, there's even evidence that suggests resveratrol leads to joint healing in osteoarthritis. This is quite a challenge to reconcile all together with our current knowledge.

Edited by geddarkstorm, 31 January 2009 - 05:56 AM.


#4 maxwatt

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Posted 31 January 2009 - 06:04 AM

None the less, all studies with resveratrol have shown it to protect joints rather potently. Even if increased pain or inflammation is occurring, the joints are likely still in good shape, and modulating resveratrol and/or niacinamide should be all that is needed to reverse the condition.


That does not seem likely if you consider that some of us are still suffering long after stopping resveratrol.


There is at least one instance I know of where resveratrol contaminated by excessive amounts of mercury made it into a 50% supplement. The joint/tendon pain symptoms, and some descriptions of mental confusion or fog are consistent with mercury poisoning. This could persist for a long time if heavy-metal chelation is not done. I do not know if any of the individuals complaining of such symptoms had their mercury levels checked. With treatment, mercury poisoning is usually completely reversible.

Andre, kindly remind us of what kind (percentage) and dose of resveratrol you were taking, for how long, and how long since you stopped that the pain persisted, with or without any alleviation? Thank you.

So, geddarkstorm: we have a fourth possibility here.

#5 geddarkstorm

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Posted 31 January 2009 - 06:11 AM

There is at least one instance I know of where resveratrol contaminated by excessive amounts of mercury made it into a 50% supplement. The joint/tendon pain symptoms, and some descriptions of mental confusion or fog are consistent with mercury poisoning. This could persist for a long time if heavy-metal chelation is not done. I do not know if any of the individuals complaining of such symptoms had their mercury levels checked. With treatment, mercury poisoning is usually completely reversible.

Andre, kindly remind us of what kind (percentage) and dose of resveratrol you were taking, for how long, and how long since you stopped that the pain persisted, with or without any alleviation? Thank you.

So, geddarkstorm: we have a fourth possibility here.


Yes, contamination is definitely always a possibility and issue for ill effects with resveratrol or any kind of supplements. It's one reason that anecdotal evidence is so difficult to process. Andre apparently does a ton of exercise, so at least he can't be suffering too badly.

#6 Brainbox

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Posted 31 January 2009 - 11:30 AM

For what it's worth, I know of one good anecdotal reference that someone who does have a manageable form of RA (only NSAID treatment) did get a severe increase of RA symptoms when taking resveratrol, up to a point were the RA became almost disabling normal daily activities. In this case, stopping resveratrol and taking niacinamide complete reversed the increase of symptoms and even induced a spectacular decrease of RA symptoms on the longer term. Niacinamide dose 2 to 2,5 grams a day.

#7 caston

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Posted 31 January 2009 - 12:29 PM

What this suggests, is that we know resveratrol increases Nampt expression by up to 3 fold intracellularly, and that this leads to Sirt1 and AMPK activation, and NF-kB inhibition - acting as an anti-inflammatory. However, if some signal was received, how that is regulated I do not know, to cause release of the resveratrol increased Nampt from the cell, one would expect pro-inflammation to result from eNampt signaling. It may be, for some people especially in the joints, that Nampt is being released from the cells instead of being retained, and causing inflammation and tendinitis.



Would it be possible to activate Sirt1 and AMPK and inhibit NF-kB without increasing Nampt expression?

#8 maxwatt

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Posted 31 January 2009 - 01:54 PM

What this suggests, is that we know resveratrol increases Nampt expression by up to 3 fold intracellularly, and that this leads to Sirt1 and AMPK activation, and NF-kB inhibition - acting as an anti-inflammatory. However, if some signal was received, how that is regulated I do not know, to cause release of the resveratrol increased Nampt from the cell, one would expect pro-inflammation to result from eNampt signaling. It may be, for some people especially in the joints, that Nampt is being released from the cells instead of being retained, and causing inflammation and tendinitis.



Would it be possible to activate Sirt1 and AMPK and inhibit NF-kB without increasing Nampt expression?


I am not sure you would want to if you could:

Nampt/PBEF/Visfatin: A regulator of mammalian health and longevity?
Experimental Gerontology
Volume 41, Issue 8, August 2006, Pages 718-726
Hongying Yang, Siva Lavu1 a and David A. Sinclair

Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA, USA

Received 23 April 2006; revised 31 May 2006; accepted 1 June 2006. Available online 13 July 2006.
Abstract

Eukaryotes have evolved elaborate mechanisms to survive periods of adversity. By manipulating genes that control these mechanisms, researchers have found they can generate more stress resistant, longer-lived organisms. One of these is the PNC1 gene of Saccharomyces cerevisiae, a master “longevity regulatory gene” that translates a variety of environmental stresses into lifespan extension by activating the sirtuin family of longevity deacetylases. Master longevity genes such as PNC1 are highly adaptive because they allow organisms to respond in a concerted way to adversity and to rapidly evolve life strategies to compensate for a changing environment. Hence, they should be well conserved. We propose that there is a functional equivalent of PNC1 in mammals called Nampt (a.k.a. PBEF/Visfatin), a stress-responsive gene that would coordinately regulate metabolism, cell defenses, and resistance to diseases of aging.



#9 maxwatt

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Posted 31 January 2009 - 01:56 PM

For what it's worth, I know of one good anecdotal reference that someone who does have a manageable form of RA (only NSAID treatment) did get a severe increase of RA symptoms when taking resveratrol, up to a point were the RA became almost disabling normal daily activities. In this case, stopping resveratrol and taking niacinamide complete reversed the increase of symptoms and even induced a spectacular decrease of RA symptoms on the longer term. Niacinamide dose 2 to 2,5 grams a day.


It has been proposed that any autoimmune disease could be aggravated by resveratrol, and helped by niacinamide/niacin.

Edited by maxwatt, 31 January 2009 - 04:54 PM.


#10 caston

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Posted 31 January 2009 - 03:14 PM

It has been proposed that any autoimmune disease could be aggravated by resveratrol, and helped my niacinamide/niacin.


What actually is niacinamide? is found in plants, made by animals or synthetic?

#11 nowayout

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Posted 31 January 2009 - 03:55 PM

None the less, all studies with resveratrol have shown it to protect joints rather potently. Even if increased pain or inflammation is occurring, the joints are likely still in good shape, and modulating resveratrol and/or niacinamide should be all that is needed to reverse the condition.


That does not seem likely if you consider that some of us are still suffering long after stopping resveratrol.


There is at least one instance I know of where resveratrol contaminated by excessive amounts of mercury made it into a 50% supplement. The joint/tendon pain symptoms, and some descriptions of mental confusion or fog are consistent with mercury poisoning. This could persist for a long time if heavy-metal chelation is not done. I do not know if any of the individuals complaining of such symptoms had their mercury levels checked. With treatment, mercury poisoning is usually completely reversible.


Let me caution first that I guess we will never know whether all this was definitely due to resveratrol. I made the association later because of the very strong and sudden appearance of agonizing pain in the rhomboid-scapular attachment area the days on and after starting res, and then the chronic tendinitis, causing me to do some research that brought me to the large number of similar complaints in these forums.

No brain fog or mental confusion in my case. Just the chronic tendinitis and possibly some bursitis. Only soft tissues are affected, and tests, X-rays and MRIs have shown that I have absolutely no RA or any other problems with cartilage or bone, as confirmed by a rheumatologist.

The impaired healing hypothesis seems plausible to me. Anyone who walks, climbs steps, gets in an out of a car, carries groceries, or even rolls over in bed, not to mention those who exercise regularly, will challenge a tendon or muscle now and then. I am talking about such minor injuries that you don't even feel a couple of minutes later, never mind the next day. But I remember very well that on the first weekend I took resveratrol, a minor rhomboid sprain suddenly magnified into agony. To this day it has not healed, and soon I realized that I was even getting injured during these everyday normal use challenges that were not healing, not to mention during exercise, and as a result of this things snowballed until all my major joints were affected. I only took resveratrol for about a month, but these symptoms continued worsening for about four or five months after stopping resveratrol.

Over the past month I have seen some improvement, but I am taking a pain modifier, so it is hard to know if the improvement is real. As for doing plenty of exercise, no, I do what I can but I am down to about 10% to 20% of the (moderate) weights I was lifting 7 months ago. There are middle-aged women who use heavier weights. As for cardio, at the worst I could jog for four minutes every third day about four months after stopping resveratrol until the pain told me I was injuring myself more. Now I have recovered to the extent that I can run 15 minutes every second day.

So yes, in my case there has definitely been impaired healing.

Andre, kindly remind us of what kind (percentage) and dose of resveratrol you were taking, for how long, and how long since you stopped that the pain persisted, with or without any alleviation? Thank you.


It was LifeTime Resveratrol liquid bought from Whole Foods. It contains 300mg resveratrol per serving, but also some other things like pomegranate, blueberry, etc. I took an amount containing between 300 and 600 mg of resveratrol daily for about a month. Stopped about six months ago. Pain in rhomboid-scapular region appeared almost immediately and is still chronic and limiting, though not continuously agonizing any more (but it has its moments). Tendinitis started that first month but continued snowballing for at least four months after stopping. Some alleviation this past month on a pain modifier.

Edited by andre, 31 January 2009 - 04:08 PM.


#12 100YearsToGo

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Posted 31 January 2009 - 03:57 PM

There has been a low proportion of people around these boards who take resveratrol and subsequently comment about joint pain. [...]
However, there are three potential ways resveratrol could lead [...] to joint pain. [...]

1. Suppression of angiogenesis.

2. Insufficient niacinamide levels.
3. Increases in extracellular Nampt levels lead to joint inflammation.



Note that if there is insufficient niacinamide, the body will use thrytophan. This reaction is wasteful, requiring 60mg tryptophan to synthesize 1mg niacinamide. Deficiency of thrytophan can cause mood disorders, immunodeficiency, auto-immune disease, fatigue AND inflammation.

100YTG

Edited by Michael, 24 July 2009 - 05:23 PM.
Trim quote


#13 maxwatt

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Posted 31 January 2009 - 05:20 PM

.....

Andre, kindly remind us of what kind (percentage) and dose of resveratrol you were taking, for how long, and how long since you stopped that the pain persisted, with or without any alleviation? Thank you.


It was LifeTime Resveratrol liquid bought from Whole Foods. It contains 300mg resveratrol per serving, but also some other things like pomegranate, blueberry, etc. I took an amount containing between 300 and 600 mg of resveratrol daily for about a month. Stopped about six months ago. Pain in rhomboid-scapular region appeared almost immediately and is still chronic and limiting, though not continuously agonizing any more (but it has its moments). Tendinitis started that first month but continued snowballing for at least four months after stopping. Some alleviation this past month on a pain modifier.


I googled the product; it contains 300 mg of "resveratrol extract" per one ounce serving. Source and percentage not specified, but if it were 98% or 99% resveratrol they would have said so. It is a liquid, resveratrol is not water soluble, you need alcohol which this has not. Stability of resveratrol in this medium would be questionable. They say to shake well, so any resveratrol is in the sediment at the bottom of the bottle. We do not know if they used Polygonum, or a grape seed extract, or what. Some of the compounds in low purity extracts have undesirable effects, and most but not all joint, tenon and muscle complaints have come from people using 50% extracts from P. cuspidatum or even OPC grape seed extracts containing a negligible amount of actual resveratrol.

IMO, your problems can not be blamed on resveratrol, though possibly something else in this drink may have caused them.

Have you tried supplementing niacinamide? (Caution, it can be toxic to the liver at doses over 2 gram per day, I would stay well under that, say 250 mg., once a day if I were in your position.)

#14 nowayout

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Posted 31 January 2009 - 06:23 PM

.....
It was LifeTime Resveratrol liquid bought from Whole Foods.


I googled the product; it contains 300 mg of "resveratrol extract" per one ounce serving. Source and percentage not specified, but if it were 98% or 99% resveratrol they would have said so.


Yes, I certainly learned my lesson on using quality supplements.

Have you tried supplementing niacinamide? (Caution, it can be toxic to the liver at doses over 2 gram per day, I would stay well under that, say 250 mg., once a day if I were in your position.)


Thanks, I'll look into this.

#15 2tender

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Posted 01 February 2009 - 12:33 AM

Joint pain and GI disturbances are the 2 main "sides" reported with Res. use, lowering your dose or discontinuing use is the best bet. I dont think it could be attributed to joint pain much later (after discontinuation) I would not use niacin in any form to counteract anything, except a niacin deficit.

#16 maxwatt

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Posted 01 February 2009 - 01:10 PM

Joint pain and GI disturbances are the 2 main "sides" reported with Res. use, lowering your dose or discontinuing use is the best bet. I dont think it could be attributed to joint pain much later (after discontinuation) I would not use niacin in any form to counteract anything, except a niacin deficit.


If you read this topic from the start, it was discussed how resveratrol might induce a niacin/niacinamide deficit.

So far we've seen no reports of muscle/joint/tendon pain attributed to resveratrol use, where the complainer subsequently reported niacinamide use, and whether it relieved symptoms or not. It would be nice to have some such data point. One poster developed an eczema-like dermatitis with resveratrol use; her holistic practitioner had her take niacinamide and the condition cleared up.

#17 2tender

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Posted 01 February 2009 - 01:48 PM

Thanks for posting that, its good to know that it worked that way for someone. My experience with niacinamide was one of red, burning skin. Resveratrol, on the other hand, helped releive an eczema type condition.

#18 Shay

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Posted 02 February 2009 - 05:09 PM

So far we've seen no reports of muscle/joint/tendon pain attributed to resveratrol use, where the complainer subsequently reported niacinamide use, and whether it relieved symptoms or not. It would be nice to have some such data point. One poster developed an eczema-like dermatitis with resveratrol use; her holistic practitioner had her take niacinamide and the condition cleared up.


I'm took 600-1000mg 98% daily with no other supplementation (very mild/sporadic exercise) and suffered joint pains in the feet, hands, and shoulders. It's been several months without any resv use and the issue has essentially receded. One of the last symptoms to go was pain in the index finger and thumb of both hands after playing basketball (perhaps my heavy keyboard/mouse use plays a role here?). An evening's round of basketball would leave those finger joints swollen and achy for a couple days. As for niacinamide, a google search mentions eggs, fish, fruits and vegetables as natural food sources – all of which I eat a great deal of on a normal basis. I'm not sure how much niacinamide that imparts compared to 250mg pill supplementation.

I'm planning to start on 99% resv soon, and will slowly ramp the dosage while watching for pain symptoms. If they appear again, I'll try niacinamde and see where things go.

#19 stevei

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Posted 02 February 2009 - 05:24 PM

According to this study:
http://www.ncbi.nlm....pubmed/16611627
resveratrol can act as an aromatase inhibitor. Has anyone had any before and after blood tests carried out to see if resveratrol reduces circulating estrogen levels? If it does reduce estrogen levels, would this not be expected to cause joint pain in some people?

#20 geo12the

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Posted 02 February 2009 - 07:57 PM

I am not sure if it's at all related but I was just reading this blurb on a study of the side effects of Statins:

http://www.sciencedaily.com/releases/2009/01/090127090735.htm

Apparently the muscle and joint effects of statins are related to Coenzyme Q10 depletion. I will read up on this in more detail when I have some free time but I thought I would throw it out there and see what people think.

FWIW my joint and muscle issues (including weird loud popping sounds from my back when I sat in my computer chair) went away when I decreased my dosage of resveratrol from 1 gram to 500mg a day.

#21 DavidB

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Posted 03 February 2009 - 01:48 AM

I've learned a lot from reading all of your posts. The least I can do is contribute an anecdotal report of my experience.

For the last 4 months I have been experiencing joint pain in my fingers. I started taking resveratrol about 8 months agos, originally starting with a 500mg/day capsule dosage and then, a couple of months ago, switching to 300mg/day of micro res. All product was purchased through Anthony's company so, based on what I've read, the quality of it was fine. I started taking a break from my daily dose last week and the pain is subsiding.

On the positive side, it has seemed easier to keep my weight down.

#22 geddarkstorm

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Posted 03 February 2009 - 03:52 AM

Wow, seems this started a very nice discussion. A big thank you to everyone providing anecdotal accounts. I would thoroughly recommend ramping up niacinamide dosage to those who experience pain and see if that changes anything, as it may for some people, according to what we see in this thread.

We do now have a 4th possibility (aside from bad supplements).

4. Resveratrol lowers estrogen levels.

Indeed, inhibition of estrogen production has been associated with joint pain in all forms of estrogen production inhibitors, including those for treating breast cancer. Furthermore, it has been shown in mice that resveratrol will lower plasma estrogen levels over long term use. It is interesting that resveratrol itself has some estrogen mimicry properties, especially beneficial ones. This supports all the more resveratrol's usefulness, especially in fighting cancers and breast cancer.

But, going back to that first paper I linked above, we see that the unexplained joint pain associated with lowered estrogen synthesis is completely abolished by increasing exposure to light. That is, it apparently is linked to the circadian rhythm and melatonin specifically. This is incredibly curious, and so much more research needs to be done to explain this currently bizarre phenominon. None the less, for some individuals this may occur with resveratrol supplementation, especially at high doses. If it does occur by this way then all that is needed to fix the problem is to increase one's exposure to sunlight, and/or decrease the dosage and/or days taking resveratrol.

-------------------------------------------------------------------------------------------------------

Personally, I think decreasing dosage won't be as potent as simply taking resveratrol less days out of a week - as the latter gives the body clear time to return to basal levels, while simply decreasing dosage may not. This is especially supported by the observations that resveratrol becomes more potent with time and use, not less - which ties in very well to Nampt. However, whatever works is what works, and I don't have evidence to say, which method is best, and when in doubt one can experiment, and/or do both.

In any event, each person may have a different reason for why they experienced the joint pain. That is very important for everyone to keep in mind. I cannot stress this enough: the joint pain could be through any one of these four reasons, though reason 1 seems very unlikely, despite and actually because of Andre's testimony, as it is unlikely he was getting much if any resveratrol depending on how well he shook up his mixture. That, and stopping resveratrol should immediately have allowed the body to heal, and the fact his symptoms got worst with time, after stopping resveratrol, is very clear indication it was not tied to resv, but something else. Personally, it sounds like some sort of poisoning, though I doubt heavy metal or mercury.

I really hope you get better Andre. The fact pain medication doesn't help too much shows it isn't inflammation. I don't know what exactly the source could be, especially since you reported your joints were fine. The most likely candidate is your bursa are swollen, which can last for a really, really long time, and is not helped by anti-inflammatory drugs unless they are extremely potent (personal past experience there).

Anyways, keep giving me your thoughts and experiences everyone. This is marvelous data we are collecting, and the more we can get, the better we can make this picture and nail down the true source(s) of the issue. So remember, if you experience joint pain and wish to do a little experiment, either up your dosage of niacinamide 3 hours after resv (taking most niacinamide supplements will give you more than you get in diet), or get a lot more sunlight. You need direct stimulation of the retina by sunlight to heal any pain caused by estrogen decrease (that does not mean looking at the sun, but being out in sunlight). Given our modern lives of being in doors all day, this issue exposes how our "unnatural" habits can interplay with circadian systems that usually wouldn't be affected to cause weird, unexplained effects. Also, this implies supplementing with melatonin when on resveratrol will lead to joint pain. So, if anyone has taken melatonin and resveratrol together, please tell us if you have experienced pain or not.

For most people, standard intake of resveratrol at 500mg does not cause any joint pain, so we have that minimum. But, according to all this data, specific individuals, already predisposed to certain states (low estrogen, low niacinamide) may experience joint pain when on high doses of resveratrol, or even 500mg if they are particularly sensitive.

Once again, thank you everyone who's so far contributed with opinions, thoughts, comments, and experience.

P.S. @ 2tender: Niacin and niacinamide are completely different, although structurally barely so, and have very different effects on the body during their processing into NAD+.

Edited by geddarkstorm, 03 February 2009 - 04:01 AM.


#23 maxwatt

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Posted 03 February 2009 - 04:06 AM

We do now have a 4th possibility (aside from bad supplements).

4. Resveratrol lowers estrogen levels.

Indeed, inhibition of estrogen production has been associated with joint pain in all forms of estrogen production inhibitors [...]

But, going back to that first paper I linked above, we see that the unexplained joint pain associated with lowered estrogen synthesis is completely abolished by increasing exposure to light.


Vitamin D. D3 or exposure to sun alleviate joint pain in women treated with aromatase inhibitors for breast cancer.

Edited by Michael, 24 July 2009 - 05:54 PM.
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#24 geddarkstorm

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Posted 03 February 2009 - 04:17 AM

Vitamin D. D3 or exposure to sun alleviate joint pain in women treated with aromatase inhibitors for breast cancer.


All this being accurate, then supplementing more vitamin D (which most of us should do, again because of our "unnatural" existance of working in doors all day long under artificial lighting) would attenuate the pain, if it is indeed caused by diminished estrogen levels.

So, we have three possible remedies (reasons 1 and 3 can only be solved with the first remedy so far as we know, if they are correct):

-Take a break a few days per week/lower dose.

-Take more niacinamide.

-Get more sunlight/take vitamin D3.

Edit: Oh, and to be fair to Maxwatt's great observations and detective work:

-Get a better, purer, supplement.

Edited by geddarkstorm, 03 February 2009 - 04:22 AM.


#25 2tender

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Posted 03 February 2009 - 06:03 AM

Geddarkstorm, thanks for great posting here. This board is filled with articulate intelligence!

#26 kenj

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Posted 03 February 2009 - 07:19 AM

We do now have a 4th possibility (aside from bad supplements).

4. Resveratrol lowers estrogen levels.

Geddarkstorm, I think you connect the dots quite well so far. I was indeed puzzled by my strange, brief incident of tendonitis after high dosing resveratrol. I was pretty affected for several days and then it just went away when I stopped resv. However prior to the incident I actually was having a week off work and wasn't getting my usual hours of daylight, - I supplemented melatonin and IIRC was not yet taking high dose vit D consistently. When I returned to my usual daily activities including being more outdoors again, the pain went away................... (I take a gram of resv for over a year now with no joint issues)

Edited by Michael, 24 July 2009 - 05:55 PM.
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#27 DavidB

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Posted 04 February 2009 - 01:58 AM

The "sunlight factor" is an interesting hypothesis. The pain for me started in October. I'm a suburban commuter in Toronto working long hours - so in the Winter months my drive starts and ends in the dark. Thanks for the suggestions. I'll experiment a little and report back if I find anything interesting.

#28 fatboy

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Posted 06 February 2009 - 10:57 PM

We do now have a 4th possibility (aside from bad supplements).

4. Resveratrol lowers estrogen levels.


Vitamin D. D3 or exposure to sun alleviate joint pain in women treated with aromatase inhibitors for breast cancer.


There are also men on TRT taking aromatase inhibitors to control estradiol. Been on 1g of resveratrol for three months now and am experiencing pain/soreness in the tendons of my elbows. Not going to stop taking it, but labs are next week and I may need to adjust some other meds in response. Been taking 2000 IU's of D3 daily for over a year now, so that ain't it.

Edited by fatboy, 06 February 2009 - 11:33 PM.


#29 maxwatt

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Posted 07 February 2009 - 12:27 AM

We do now have a 4th possibility (aside from bad supplements).

4. Resveratrol lowers estrogen levels.


Vitamin D. D3 or exposure to sun alleviate joint pain in women treated with aromatase inhibitors for breast cancer.


There are also men on TRT taking aromatase inhibitors to control estradiol. Been on 1g of resveratrol for three months now and am experiencing pain/soreness in the tendons of my elbows. Not going to stop taking it, but labs are next week and I may need to adjust some other meds in response. Been taking 2000 IU's of D3 daily for over a year now, so that ain't it.


Have you tried niacinamide to increase substrate for NAD+? Depletion by resveratrol is one hypothetical reason for joint pain.

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#30 fatboy

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Posted 07 February 2009 - 03:06 PM

Have you tried niacinamide to increase substrate for NAD+? Depletion by resveratrol is one hypothetical reason for joint pain.


Thanks, but I'm insulin resistant so I'm a little hesitant to try that. Aching joints is a common symptom among men who have driven their estradiol levels too low from Arimidex or some other aromatase inhibitor. Since resveratrol supposedly possesses some SERM-like properties that seems to me the most likely explanation in my case. I will get lab work to verify.




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