14 replies to this topic

[brasscupcakes]

Pardon me for starting a whole new topic to ask a question but I'm not sure which thread to address it to.

I recall reading a long time ago in this forum that with Reservatrol (and some other supplements) some studies indicate that if you go over (or under) a certain dosage, the effect is actually the opposite of what Reservatrol is thought to do. I'm not referring to known side effects like muscle soreness, but purported benefits, such as reducing inflammation.

Does this sound familiar to anyone, or am I confusing Reservatrol with something else? Because I'm a lifelong journalist and I've been thinking about writing a piece for a mainstream audience about how critical dosage is to any program.

As everyone here knows, it is often the case, particularly with Chinese and Indian herbs, that the dosages employed in various trials are far beyond what all but miniscule number of people in the West take. It seems common in these places for people to address chronic health problems by chugging an inch or two of nasty sludge from the bottom of a glass a couple of times a day, but my own attempts to do this on any kind of regular basis always fail, even when I'm getting good results.

Trials showing efficacy with very large doses are common, trials revealing a sweet spot -- a dosage one is best off not going above or below for the greatest benefit (and absence of harm).

Anyhow, whether or not reservatrol is on it, if anyone here can readily think of any supplements I might add to this list, I could really use the help.

Many thanks,
Amy

[maxwatt]

Everything in the world is on your list, in truth: If you were to drink a bit over a gallon of water before your kidneys could process it, you would die. It was a method of torture used by the CIA during Vietnam, a funnel and a tube stuffed down the throat, but all in all I preferred it to the Special Forces' technique of dangling someone by his feet from a helicopter until he talked, or fell and they grabbed the next guy. Usually the second guy talked before they pushed him out the door.

Resveratrol in doses over a gram or so is probably wasted for most people, but up to 5 grams have been taken for short periods in studies, and at least one contributor to this forum reports taking 3 grams daily for several years without ill effect (on the contrary, his capacity for exercise has increased phenomenally, due perhaps to resveratrol-induced mitochondrial biogenesis.) Perhaps the worst effect from high doses of resveratrol is diarrhea.

A Mr. S-a-r-d-i, who sells a (relatively) low dose resveratrol pill combined with ferulic acid and other magical things, has in the past claimed that high dose resveratrol would cause heart attacks. He based his supposition (it was little more than that) on the work of disgraced scientist Dipak Das, who was dismissed from the University of Hartford for falsifying data in some 30 papers that were subsequently withdrawn from publication, perhaps including the study that Mr. S. commissioned that showed such putative harmful effects in mouse hearts when removed from the mouse. (Really. The resveratrol-treated hearts "died" or stopped beating faster than the controls. This may evince common sense on the part of the hearts' rather than a desire to die; but I digress.) Even if the data in that study weren't falsified, it was obviously cherry picked.

There is no doubt a sweet spot for resveratrol dosage, but no one agrees what it is, and I suspect it varies considerably with the individual, and with a person's exercise and nutrient status, and past use of resveratrol as well.

[niner]

The sweet spot probably intends on the effects you're looking for. Very high doses are pro-apoptotic; that is, they encourage damaged cells to commit suicide. That's exactly what you want if you have cancer. It's not what you want if you have a heart attack or stroke. As I recall, low doses are anti-apoptotic, so if you are at risk of a vascular incident, maybe that would be a good idea. I'm not sure about the dose specificity of mitocondrial biogenesis, but it's probably in the mid range. The body is really good at gobbling up and excreting resveratrol, so the common wisdom used to be that you needed a lot in order to overwhelm those mechanisms. That may still be true for the mitochondrial or pro-apoptotic effects, but more recent work has shown value in surprisingly low doses. Resveratrol is a very complicated drug. It doesn't just act at a single receptor, like synthetic pharmaceuticals are designed to do (though they sometimes don't). Resveratrol acts at multiple molecular sites. It does, after all, look a little like estrogen, so you might expect a lot of effects from something hormone-like.

[Andey]

The sweet spot probably intends on the effects you're looking for. Very high doses are pro-apoptotic; that is, they encourage damaged cells to commit suicide. That's exactly what you want if you have cancer. It's not what you want if you have a heart attack or stroke. As I recall, low doses are anti-apoptotic, so if you are at risk of a vascular incident, maybe that would be a good idea. I'm not sure about the dose specificity of mitocondrial biogenesis, but it's probably in the mid range. The body is really good at gobbling up and excreting resveratrol, so the common wisdom used to be that you needed a lot in order to overwhelm those mechanisms. That may still be true for the mitochondrial or pro-apoptotic effects, but more recent work has shown value in surprisingly low doses. Resveratrol is a very complicated drug. It doesn't just act at a single receptor, like synthetic pharmaceuticals are designed to do (though they sometimes don't). Resveratrol acts at multiple molecular sites. It does, after all, look a little like estrogen, so you might expect a lot of effects from something hormone-like.

What dosage range you consider as a mid range ?
Any guess to what can be appropriete dosage for antiaging purpose of mid aged man ? )

[Dolph]

Niner's comment is unfortunately also based on discredited pieces of "work" published by the infamous Dipak Das. As far as I know nobody else was able to find that kind of dose effect.

[Kevnzworld]

Here is a study that looked at dosing in terms of bioavailability
Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers.
http://www.mendeley....thy-volunteers/

[Andey]

Here is a study that looked at dosing in terms of bioavailability
Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers.
http://www.mendeley....thy-volunteers/

Thanks for link. It seems that bioavailability grow faster and faster with increasing dosage. I consider now for starting resveratrol (even bought pilot bulk of 250mg and 500mg capsules) but surprisingly cant find here credible info of how to use this so advertised all around web supplement.

[niner]

Niner's comment is unfortunately also based on discredited pieces of "work" published by the infamous Dipak Das. As far as I know nobody else was able to find that kind of dose effect.

Das' report of cardioprotection from low dose resveratrol is not in question. It has been replicated. The thing that is in question is his claim as to the proteins and/or pathways involved in the effect.

I don't know if this means that the dose dependency of resveratrol's effect on apoptosis is in question, but resveratrol certainly appears to have both pro- and anti-apoptotic effects.

[niner]

Here is a study that looked at dosing in terms of bioavailability
Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers.
http://www.mendeley....thy-volunteers/

Thanks for link. It seems that bioavailability grow faster and faster with increasing dosage. I consider now for starting resveratrol (even bought pilot bulk of 250mg and 500mg capsules) but surprisingly cant find here credible info of how to use this so advertised all around web supplement.

This dose-dependent bioavailability has been seen in other dose-ranging pharmacokinetic studies of resveratrol, so it looks like a real effect. This could be caused by a metabolic pathway that gets swamped as doses increase, or maybe it's something else. In this particular PK experiment, they dosed six times a day, which would be out of the question for most of us, I suspect. If the experiment were run longer (it was only two days), you might see bioavailability suffer, since drug metabolic enzymes are usually upregulated by high levels of substrate.

As far as how to use it, I would recommend a high purity (98+%) resveratrol, first of all. Reasonable doses could be as low as 15mg or as high as a gram. People here have taken higher doses as well. I don't really know what's optimal. If I had cancer, I'd probably take a lot (multiple grams) and otherwise I'd probably be under half a gram.

[Andey]

Here is a study that looked at dosing in terms of bioavailability
Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers.
http://www.mendeley....thy-volunteers/

Thanks for link. It seems that bioavailability grow faster and faster with increasing dosage. I consider now for starting resveratrol (even bought pilot bulk of 250mg and 500mg capsules) but surprisingly cant find here credible info of how to use this so advertised all around web supplement.

This dose-dependent bioavailability has been seen in other dose-ranging pharmacokinetic studies of resveratrol, so it looks like a real effect. This could be caused by a metabolic pathway that gets swamped as doses increase, or maybe it's something else. In this particular PK experiment, they dosed six times a day, which would be out of the question for most of us, I suspect. If the experiment were run longer (it was only two days), you might see bioavailability suffer, since drug metabolic enzymes are usually upregulated by high levels of substrate.

As far as how to use it, I would recommend a high purity (98+%) resveratrol, first of all. Reasonable doses could be as low as 15mg or as high as a gram. People here have taken higher doses as well. I don't really know what's optimal. If I had cancer, I'd probably take a lot (multiple grams) and otherwise I'd probably be under half a gram.

Thanks )

[Mike C]

So the consensus here seems to be that low doses may be all that is needed for cardio-protection. Anyone care to take a stab at the possibilities for those of us already practicing good habits like 5 oz red wine daily, EVOO, high berry/vegetable consumption, not smoking, maintaining 20 BMI, exercising aerobic etc. I know Michael Rae made the comment here that a glass of red wine would be better than resveratrol on another thread about David Sinclair's interview. That gives me pause in shelling out money for the stuff because Michael ain't no dummy.

That said the cardio thing fascinates me because of family history and a damaged heart valve from early rheumatic fever so I don't expect miracles but if resveratrol would help a heart beyond all the good habits then i'd be on board.
SO any opinion on that point-because my guess is that most people here already practice good habits and must be guessing resveratrol does something beyond that.

Thanks-Mike C.

Mike C

[Kevnzworld]

So the consensus here seems to be that low doses may be all that is needed for cardio-protection. Anyone care to take a stab at the possibilities for those of us already practicing good habits like 5 oz red wine daily, EVOO, high berry/vegetable consumption, not smoking, maintaining 20 BMI, exercising aerobic etc. I know Michael Rae made the comment here that a glass of red wine would be better than resveratrol on another thread about David Sinclair's interview. That gives me pause in shelling out money for the stuff because Michael ain't no dummy.

That said the cardio thing fascinates me because of family history and a damaged heart valve from early rheumatic fever so I don't expect miracles but if resveratrol would help a heart beyond all the good habits then i'd be on board.
SO any opinion on that point-because my guess is that most people here already practice good habits and must be guessing resveratrol does something beyond that.

Thanks-Mike C.

Mike C

Though this study was done with rats with high cholesterol , it still demonstrated some considerable cardiovascular protection with 20mg/,kg resveratrol.
Quote: " The present study demonstrates, for the first time, that high cholesterol diet-induced myocardial complications such as increased infarct size, extent of apoptosis, impaired angiogenesis could be controlled aggressively with dietary resveratrol supplementation."
http://www.ncbi.nlm....les/PMC1857339/
This study showed cardioprotective efficacy with rats fed a high fructose diet at 10mg/kg
Quote:" In concert with other effects, the increase in eNOS activity may contribute to the protective properties attributed to RV and, thus, to its beneficial effects on the cardiovascular system. These results suggest that an adequate supplementation of RV might help to prevent or delay the occurrence of atherogenic cardiovascular diseases associated to insulin-resistant states."
http://www.sciencedi...895706105000130
Here is a human trial with patients already with MI. The dosage here was just 10mg.
Quote: " Our results show that resveratrol improved left ventricle diastolic function, endothelial function, lowered LDL-cholesterol level and protected against unfavourable hemorheological changes measured in patients with coronary artery disease (CAD)."
http://iospress.meta...g3115637734386/
This recent double blind crossover human study was conducted on smokers using 500 mg.
Quote:" Resveratrol significantly reduced C-reactive protein (CRP) and triglyceride concentrations, and increased Total Antioxidant Status (TAS) values. Conclusions: Because resveratrol has anti-inflammatory, anti-oxidant, and hypotriglyceridemic effects, its supplementation may beneficially affect the increased cardiovascular risk of healthy smokers."
http://www.ncbi.nlm....pubmed/23298135
This is another in vivo human trial, triple blind, randomized, and placebo controlled trial using 350mg.
"Consumption of a grape extract supplement containing resveratrol decreases oxidized LDL and ApoB in patients undergoing primary prevention of cardiovascular disease: a triple-blind, 6-month follow-up, placebo-controlled, randomized trial."
" This GE-RES reduced atherogenic markers and might exert additional cardioprotection beyond the gold-standard medication in patients from PCP. The presence of resveratrol in the GE was necessary to achieve these effects."
http://www.ncbi.nlm....pubmed/22648627

MR can say that resveratrol supplementation produces no positive effect, and one would be better off consuming a glass of red wine, but the evidence above would contradict that.
I take 100mg twice a day.

[Mike C]

Thank you Kevnzworld.

.

[ianlib]

In his latest press conferences Sinclair is still pushing 500 to 1000mg of pharmacetical grade Resveratrol as a reasonable dosage for a synthetic version and in the past I know he has for the pharmaceutical grade also. In. "Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases"
Sung-Jun Park, Faiyaz Ahmad, Andrew Philp, Keith Baar, Tishan Williams, Haibin Luo, Hengming Ke, Holger Rehmann, Ronald Taussig, Alexandra L. Brown, Myung K. Kim, Michael A. Beaven, Alex B. Burgin, Vincent Manganiello, Jay H. Chung
Cell, Volume 148, Issue 3, 421-433, 3 February 2012 "

Jay H Chung has stated that Lead author Jay H. Chung, M.D., Ph.D., said:

"Resveratrol has potential as a therapy for diverse diseases such as type 2 diabetes, Alzheimer's disease, and heart disease. However, before researchers can transform resveratrol into a safe and effective medicine, they need to know exactly what it targets in cells." An analysis of the paper states " Resveratrol does not exist in wine or grapes in a high-enough amount to provide any significant health benefits or problems, the authors explained. Human trials with any relevant findings have used resveratrol doses equivalent to 667 bottles of red wine (1gm of resveratrol)."

A recent study on dementia got results with a gram that was presented at the Resveratrol Conference this year. Half a gram to 1 gram sounds reasonable.

[cudBwrong]

The phenomenon of different effects, especially, helpful versus harmful effects, seen at different dosages, is also known as hormesis. A review of the evidence for hormesis in resveratrol was published here:

http://www.ncbi.nlm....pubmed/21115559

However, some differences attributed to differences in dosage may in fact be due to differences in experimental design or execution.

This is a fundamental problem in science, identifying which correlations or associations are accidental coincidences, and which are examples of a fundamental, cause-and-effect relationship. It's a crucial question, especially for someone trying to decide whether to take resveratrol, and at what dose.

A classic discussion of the issue is the paper by Herbert Simon, “Spurious correlation: A Causal Interpretation,” Journal of the American Statistical Association, Volume 49, Number 264, 1954, pp. 467-479.

One example may be the question of apopotosis, or programmed cell death. Does resveratrol increase or decrease apoptosis? There is evidence for both, and we might be tempted to conclude that the difference is due to dose, an example of hormesis. However, I think there is another explanation, and the story is illustrated nicely in the context of a single paper:

http://www.ncbi.nlm....pubmed/21541654

"Pro-apoptotic versus anti-apoptotic properties of dietary resveratrol on tumoral and normal cardiac cells."

Looking at numerous studies that report an effect of resveratrol on the rate of apoptosis, I see a common theme. If the cells in question are in some way defective, if they are tumor cells, or cells which have been intentionally damaged by the experiment, for example, by the introduction of oxidative stress, then the rate of apopotosis increases. The bad cells die. However, if the cells in question are normal healthy cells, the rate of apoptosis decreases. The good cells live.

This was the finding in the cardiac cell study referenced above. Resveratrol increased apoptosis for the tumor cells and decreased it for the normal cells.

I call this a "theme" rather than a "fact" because there are exceptions, and we have to look at the total design of the experiment to try to understand and perhaps explain them. For example, resveratrol seemed to promote, rather than retard the growth of breast cancer cells, but only when they were transplanted to a severely immune deficient mouse. Other researchers, working with other kinds of mice showed an opposite effect.

One reason why the dose of resveratrol may be especially important is its low bioavailability. Resveratrol is broken down quickly by the liver, so very little may get a chance to circulate through the bloodstream for an extended period. At higher doses, bioavailability improves in a nonlinear fashion. It is as if the liver gets too busy to process everything at once, so a fraction of the dose is able to circulate for a longer period.

The effects of higher doses might be achieved at lower dose levels through the use of other substances that enhance bioavailability. Piperine has increased the bioavailability of resveratrol in an experimental animal:

https://www.ncbi.nlm...pubmed/23620848
https://www.ncbi.nlm...pubmed/21714124

Edited by cudBwrong, 21 May 2013 - 01:51 PM.