16 replies to this topic

[maxwatt]

In this post andre noted that pomegranate seemed to cause joint pain when combined with his resveratrol supplementation:

.... Also, I might mention that the tendinitis got worse a couple of weeks ago as I was experimenting with adding pomegranate extract (Jarrow brand, which I believe to be reputable) to my regimen. I stopped and it got better. Coincidence maybe?

Maybe not a coincidence. I have been experimenting with pomegranate juice (Knudson's Just Pomegranate) and had the same experience. 6 ounces of juice in the morning and in three days I've tendinitis in my right arm and fingers, and joint pain in my big toe. It is similar to my reaction to quercetin (250 mg with bromelain) and to luteolin at 50 mg. When I stop, the pain subsides over several days. If I stop resveratrol, I get arthritic pain in the big toe and my knuckles, but no tendinitis. I have not used pomegranate alone without resveratrol often or long enough to say if it causes tendinitis by itself, but the combination definitely brings it on.

The enzymes that process these phytochemicals show quite a bit of variability depending on one's genetic phenotype, and I do not know if andre's or my experiences are typical.

One theory was that quercetin, which is abundant in Pomegranate juice, and may be present in andre's extract, was blocking Sirt1. Geddarkstorm has discounted that theory with more recent studies showing Sirt1 activation by quercetin, the blocking action by it's metabolite being an artifact of the testing methods in Sinclair's 2006 paper. Perhaps quercetin and luteolin by binding to the sulfonation enzymes permit greater serum levels of resveratrol to be attained, which in turn somehow causes the symptoms? I doubt this, for low doses (<500 mg)of resveratrol with quercetin or pomegranate juice cause these symptoms, whereas high doses of resveratrol alone (>2 g) apparently do not. It is not unusual to get high doses of quercetin from dietary sources, and I wonder if the joint and tendon pain others have reported could be associated with dietary factors. Pomegranate is particularly rich in phytoestrogens, and has been found to actually contain a significant amount of estrone, as well as estradiol and estriol (PMID 15099854 - I would like to see this confirmed, though.) I think this would run counter to the theory that it is resveratrol's anti-aromatase action causing joint pain.

FWIW, I supplement with CoQ10, 400 mg in an oil base, and with D3. This does not seem to affect things one way or another. I've tried niacinamide in the morning, no effect. I posted in "Supplements" asking if anyone experienced joint pain or tendinitis with pomegranate, and apparently no one did. Does anyone here with joint pain on resveratrol have experiences with pomegranate or quercetin or dietary items to add to the data pool? Does anyone taking resveratrol want to drink some pomegranate juice daily to see if it causes tendinitis?

[nowayout]

In this post andre noted that pomegranate seemed to cause joint pain when combined with his resveratrol supplementation:

.... Also, I might mention that the tendinitis got worse a couple of weeks ago as I was experimenting with adding pomegranate extract (Jarrow brand, which I believe to be reputable) to my regimen. I stopped and it got better. Coincidence maybe?

Maybe not a coincidence. I have been experimenting with pomegranate juice (Knudson's Just Pomegranate) and had the same experience. 6 ounces of juice in the morning and in three days I've tendinitis in my right arm and fingers, and joint pain in my big toe. It is similar to my reaction to quercetin (250 mg with bromelain) and to luteolin at 50 mg. When I stop, the pain subsides over several days. If I stop resveratrol, I get arthritic pain in the big toe and my knuckles, but no tendinitis. I have not used pomegranate alone without resveratrol often or long enough to say if it causes tendinitis by itself, but the combination definitely brings it on.

Interesting observation. I have noticed that my tendinitis also seems to increase after taking AOR multi basics, which I believe contains quercetin - enough so to have stopped taking this multi lately. Also, the original liquid that contained the resveratrol and that I thought caused the problem to begin with also contained pomegranate.

Edited by andre, 22 February 2009 - 08:20 PM.

[nameless]

Interesting observation. I have noticed that my tendinitis also seems to increase after taking AOR multi basics, which I believe contains quercetin - enough so to have stopped taking this multi lately. Also, the original liquid that contained the resveratrol and that I thought caused the problem to begin with also contained pomegranate.

I'm not so sure the quercetin in multi-basics would cause tendinitis really. I mean, one cap, which I think you said you were taking, contains approx. 22mg quercetin.

That's less quercetin than an apple has (I think). And probably a lot less than you consume normally from other food sources (green tea, berries, etc).

Although I suppose the effect could be cumulative. And if quercetin increases the bioavailability of resveratrol, it could cause joint pain.

Edited by nameless, 22 February 2009 - 08:49 PM.

[suspire]

I've taken a number of rev products with quercetin over the last couples of years. Never had a problem. Current choice: One of RevG's Tween (250 mg) and 800 mg of quercetin. No problem. Then again, I am usually a poor study for these things; nothing seems to phase me positively or negative that I ever notice. Except caffeine pills--those I notice (but cups of coffee don't do much).

[maxwatt]

Interesting observation. I have noticed that my tendinitis also seems to increase after taking AOR multi basics, which I believe contains quercetin - enough so to have stopped taking this multi lately. Also, the original liquid that contained the resveratrol and that I thought caused the problem to begin with also contained pomegranate.

I'm not so sure the quercetin in multi-basics would cause tendinitis really. I mean, one cap, which I think you said you were taking, contains approx. 22mg quercetin.

That's less quercetin than an apple has (I think). And probably a lot less than you consume normally from other food sources (green tea, berries, etc).

Although I suppose the effect could be cumulative. And if quercetin increases the bioavailability of resveratrol, it could cause joint pain.

More like 65 mg of quercetin dihydrate yielding 55 mg of quercetin in AOR multi basics. There are also 100 mg of citrus bioflavonoids. That might bring it up to a level that has an effect if andre is particularly sensitive.

I doubt that the increase in resveratol bioavailability with quercetin is a cause; I found even low doses of resveratrol in combination with quercetin had the effect, and high doses of resveratrol, which should have resulted in a serum level of resveratrol higher than obtained from a low dose plus quercetin, did not.

[nameless]

I believe Andre said he took 1/3 dose of Multi-Basics (in his regimen post), which would be one capsule. The 65mg is for a full dose, 3 capsules. The actual quercetin yield for what he was taking would actually be lower than I stated, approx. 18mg.

I think a medium-sized apple has around 40mg quercetin. So... I don't really think the amount in Multi-Basics would really do a whole lot. I'm not going to dismiss the possibility, or some odd interaction there, but unless he was getting tendinitis from dietary sources too, I don't see how Multi-Basics really overloaded him with quercetin or caused the problem.

[unglued]

I take resveratrol and I frequently drink fresh juice blends containing pomegranate. I haven't had tendinitis. I occasionally get a little soreness in my left knee that has never been diagnosed, and I can't really say the resveratrol makes it any worse. I definitely have not noticed any correlation with pomegranate juice. I also recently started taking 500mg/day quercetin and haven't had a recurrence of knee soreness in that time. I've also been drinking almost 10 cups/day of green tea for years.

[davidd]

FWIW, I supplement with CoQ10, 400 mg in an oil base, and with D3. This does not seem to affect things one way or another. I've tried niacinamide in the morning, no effect. I posted in "Supplements" asking if anyone experienced joint pain or tendinitis with pomegranate, and apparently no one did. Does anyone here with joint pain on resveratrol have experiences with pomegranate or quercetin or dietary items to add to the data pool? Does anyone taking resveratrol want to drink some pomegranate juice daily to see if it causes tendinitis?

I've had a little tendonitis in my left wrist a couple weeks ago. I chalked it up to a bad seating arrangement at work and doing a lot of typing (carpal tunnel-like). However, it got really painful, really fast. I could have sworn I had one other tendon incident in the past few months, but now I can't remember what that would have been. I remember thinking the same thing -- that it got really bad, really fast. I wonder if resveratrol isn't necessarily the cause of the problems, but maybe it causes things to get worse than they otherwise would have?

Incidentally, I didn't have any problems when I was taking resveratrol with a large amount of quercetin/bromelain in summer of 2008. For me, that combo resulted in a superb ability to reduce pain that would normally come from exertion as well as very quick recovery time (stiffness was short-lived).

Is the tedonitis that others are experiencing coming on after some sort of repetitive activity? (something that is repeated multiple days out of the week) I don't have much of that type of activity, other than typing.

How much quercetin is in pomegranate juice?

David

[maxwatt]

FWIW, I supplement with CoQ10, 400 mg in an oil base, and with D3. This does not seem to affect things one way or another. I've tried niacinamide in the morning, no effect. I posted in "Supplements" asking if anyone experienced joint pain or tendinitis with pomegranate, and apparently no one did. Does anyone here with joint pain on resveratrol have experiences with pomegranate or quercetin or dietary items to add to the data pool? Does anyone taking resveratrol want to drink some pomegranate juice daily to see if it causes tendinitis?

I've had a little tendonitis in my left wrist a couple weeks ago. I chalked it up to a bad seating arrangement at work and doing a lot of typing (carpal tunnel-like). However, it got really painful, really fast. I could have sworn I had one other tendon incident in the past few months, but now I can't remember what that would have been. I remember thinking the same thing -- that it got really bad, really fast. I wonder if resveratrol isn't necessarily the cause of the problems, but maybe it causes things to get worse than they otherwise would have?

Incidentally, I didn't have any problems when I was taking resveratrol with a large amount of quercetin/bromelain in summer of 2008. For me, that combo resulted in a superb ability to reduce pain that would normally come from exertion as well as very quick recovery time (stiffness was short-lived).

Is the tedonitis that others are experiencing coming on after some sort of repetitive activity? (something that is repeated multiple days out of the week) I don't have much of that type of activity, other than typing.

How much quercetin is in pomegranate juice?

David

Not much more than many other juices like apple, grapefruit or concord grape, I imagine. However a study I cited in the first post claims pomegranate actually contains a significant amount of estradiol and other estrogens. I am dubious, but it is possible there are other estrogens or estrogen like substances that are particularly potent. If they block estrogen receptors without activating them the effect could be similar to that of an anti-aromatase.

I was not doing any particular activity that would have caused tendinitis. I added and withdrew pomegranate juice from my regiment and noted the result. It is possible there is phenotype some people share that makes for an interaction between some phytochemicals and resveratrol that is not seen in other people. I'm looking for input if anyone has noted a possible interaction between resveratrol and anything else, like quercetin or pomegranate such as Andre and I seem to have experienced.

I want to point out that tendinitis was not a reported side effect in the Sirtiris studies, which had both a large sample and a very high dose.

[nowayout]

I believe Andre said he took 1/3 dose of Multi-Basics (in his regimen post), which would be one capsule. The 65mg is for a full dose, 3 capsules. The actual quercetin yield for what he was taking would actually be lower than I stated, approx. 18mg.

I think a medium-sized apple has around 40mg quercetin. So... I don't really think the amount in Multi-Basics would really do a whole lot. I'm not going to dismiss the possibility, or some odd interaction there, but unless he was getting tendinitis from dietary sources too, I don't see how Multi-Basics really overloaded him with quercetin or caused the problem.

Just to clarify - the 1/3 AOR was my daily average, but I was really achieving it by doing 2/3 each other day. Even so, you are probably correct that it is not significant, unless there is some synergy with other ingredients, or unless the stuff gets absorbed in a shorter burst than it does with food-based sources. Bit this is all very subjective and possibly coincidental, so I would not suggest taking the AOR implication very seriously at this point.

In any case, I am stopping most supplements for a washout period. I might add stuff in then and see if the problem recurs.

[maxwatt]

I think niner has found the mechanism of for this kind of pain in this post. Inhibition of CYP450 3A4 and 2C9 enzymes by pomegranate can lead to various myopathies as documented with various drug interactions.

This may also explain some of the joint-pain problems people have reported with resveratrol.

[geddarkstorm]

I think niner has found the mechanism of for this kind of pain in this post. Inhibition of CYP450 3A4 and 2C9 enzymes by pomegranate can lead to various myopathies as documented with various drug interactions.

This may also explain some of the joint-pain problems people have reported with resveratrol.

And with quercetin. Quercetin is a lot more potent than resveratrol at inhibiting CPY3A4.

If that is the cause, a really easy test would be to take grapefruit juice alone and no other supplement. Since grapefruit juice is extraordinarily powerful at disaibling CPYs for days even, especially 3A4, then if that is the cause of this pain in some people, the juice would rapidly lead to it. If it requires a mixture of things, then adding in one supplement at a time (quercetin, resveratrol) would eventually pinpoint the interaction.

These are incredibly curious observations, and imply we might be seeing an indirect effect going on - it might even be a food interaction. What strikes me most curiously, is that a low resveratrol dose with quercetin leads to pain in you, Maxwatt, while a high resveratrol dose with quercetin does not (if I read what you were saying correctly?). That implies we are observing a ratiometric event, something that is occurring only once a certain ratio of factors is reached (or ratio of inhibitions/activations of different enzymes in the body). We are still very much so in the dark, but at least making progress.

Edited by geddarkstorm, 25 February 2009 - 05:54 PM.

[maxwatt]

I think niner has found the mechanism of for this kind of pain in this post. Inhibition of CYP450 3A4 and 2C9 enzymes by pomegranate can lead to various myopathies as documented with various drug interactions.

This may also explain some of the joint-pain problems people have reported with resveratrol.

And with quercetin. Quercetin is a lot more potent than resveratrol at inhibiting CPY3A4.

If that is the cause, a really easy test would be to take grapefruit juice alone and no other supplement. Since grapefruit juice is extraordinarily powerful at disaibling CPYs for days even, including 3A4, then if that is the cause of this pain in some people, the juice would rapidly lead to it. If it requires a mixture of things, then adding in one supplement at a time (quercetin, resveratrol) would eventually pinpoint the interaction.

These are incredibly curious observations, and imply we might be seeing an indirect effect going on - it might even be a food interaction. What strikes me most curiously, is that a low resveratrol dose with quercetin leads to pain in you, Maxwatt, while a high resveratrol does with quercetin does not (if I read what you were saying correctly?). That implies we are observing a ratiometric event, something that is occurring only once a certain ratio of factors is reached (or ratio of inhibitions/activations of different enzymes in the body). We are still very much so in the dark, but at least making progress.

No, no... high dose of quercetin was worse than low dose. Pomegranate juice was almost as bad as high dose quercetin. I also have prescriptions for hydrocodone and sometimes Provigil, which complicates things.

[geddarkstorm]

No, no... high dose of quercetin was worse than low dose. Pomegranate juice was almost as bad as high dose quercetin. I also have prescriptions for hydrocodone and sometimes Provigil, which complicates things.

What about this quote of yours just above?

"I found even low doses of resveratrol in combination with quercetin had the effect, and high doses of resveratrol, which should have resulted in a serum level of resveratrol higher than obtained from a low dose plus quercetin, did not." -Post #5

Edit: I see what you are saying now. I originally read it as you were saying that still taking quercetin with a high blast of resveratrol didn't cause pain, unlike quercetin plus low resveratrol. But you really meant that a high level of resveratrol which should have equaled resveratrol serum levels the same as "low resv + quer" did not cause pain.

If CYP3A4 inhibition is behind this, then that is not surprising, considering how much lower resveratrol inhibition of the enzyme is verses quercetin. And the two together would be expected to synergize.

Edited by geddarkstorm, 25 February 2009 - 06:12 PM.

[malbecman]

Not to burst any bubbles but I've been taking pomegranate supplements all along w/ my Resveratrol for the whole time now and not had any joint/tendonitis issues. And, I've recently increased my running and not had any problems with that either.
I know, just a lucky young whippersnapper at 41 yrs of age but there you are.

[maxwatt]

Not to burst any bubbles but I've been taking pomegranate supplements all along w/ my Resveratrol for the whole time now and not had any joint/tendonitis issues. And, I've recently increased my running and not had any problems with that either.
I know, just a lucky young whippersnapper at 41 yrs of age but there you are.

There is a lot of individual variation in the CYP enzymes; some people will be much more prone to such problems than others. Also, the prescription drugs I take complicate things.

[geddarkstorm]

It's still a very good and interesting lead, but we have some problems none the less that remain. Tenocytes are not myocytes; but are extremely different in morphology and activity. Even the myopathy linked by Niner was still associated with the loss of the metabolism of a drug (rosuvastatin. And it is a known problem with statins that they can cause myopathy and tendinitis) that lead to its accumulation, and thus the statin drug itself caused the myopathy, not the inhibition of CYPs directly. We have a correlation, where increasing CYP inhibition seems to link with increasing tendon pain, but this does not in any way mean causation other than through an increase of CYP metabolized drugs in the serum, and then those drugs going on to cause the problems.