Vitaminc C, any conclusion?

Do any of you supplement Vitamin C above RDA doses? I mean 500 mg higher daily.

There has been discussion in the past about Vitamin C reducing Nrf2-KEAP pathway activation by scrubbing specific radicals/oxidants that activate protein Nrf2?

I personal do not supplement Vit C but I wanted to hear what other people's opinion was.

From what I've read, large doses of oral Vitamin-C are poorly absorbed and the only way to maintain consistently elevated levels of C are to take low doses rather frequently throughout the day.

When taken with food, any amount of Vitamin-C greatly increases absorption of dietary iron from the food, which can cause iron accumulation in men and non-menstruating females which may be problematic over long periods of time.

I take 500mg of C two to three times per day, but always make sure I do so on an empty stomach. The risk/reward of C taken in this manner seems the smart thing to do.

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From what I've read, large doses of oral Vitamin-C are poorly absorbed and the only way to maintain consistently elevated levels of C are to take low doses rather frequently throughout the day.

Liposomal Vitamin C, which is taken orally, is comparable to, or even more potent, than the high dose IV vitamin C (users experiences; sense of "well being" is the most common report). One can also make it at home for dosing at IV levels for pennies per day. I have been using it for several months and the effects on some chronic inflammatory conditions were nothing short of miraculous.

Edited by nightlight, 25 December 2013 - 02:59 PM.

I wouldn't recommend large doses of vitamin C for generally healthy people. Plasma levels become fully saturated at intakes of ~400mg, divided in two or more doses. Doses above the RDA cause a short transient increase in plasma levels, until the kidneys have excreted the excess ascorbic acid (the larger the dose, the steeper the transient, but intestinal absorption decreases at the same time). There has to be a good, evolutionary reason for such a tight control of vitamin C. My hypothesis is that the loss of endogenous ascorbate synthesis, which originally may have occured for economic reasons, opened new possibilities for hormetic stress signaling. Ascorbic acid is a pretty "dumb" antioxidant, which quenches most radical species, regardless whether they are harmful or useful. Hence, we have evolved a tight regulation for exogenous ascorbate, keeping the plasma level at a maximum of ~100mcg/ml, much less than that of most ascorbate synthesizing species (a discrepancy which mislead Linus Pauling into his megadosing theory). Consequently, it has been shown that 1g/day of ascorbic acid may hamper beneficial effects of exercise in healthy young man. On the other hand, ascorbic acid is a very effective glycation inibitor and in one study a dose of 1g/day led to an almost 50% decrease of serum protein glycation in healthy, non-diabetic subjects.

Therefore, I think it is advisable to keep the plasma level saturated by insuring a total intake of at least 400mg (agreeing with the LPI's recommendations), which is easily achieved by taking a multivitamin, eating several servings of vitamin C-rich fruits and vegetables and e.g. a yogurt fortified with ascorbic acid - but to generally avoid mega-dosing, even more so of liposomal forms which bypass the intestinal regulation of vitamin C uptake, and not to take supplemental vitamin C immediately before exercising.

Edited by timar, 25 December 2013 - 04:42 PM.

Plasma levels become fully saturated at intakes of ~400mg, divided in two or more doses. ...Hence, we have evolved a tight regulation for exogenous ascorbate, keeping the plasma level at a maximum of ~100mcg/ml, much less than that of most ascorbate synthesizing species (a discrepancy which mislead Linus Pauling into his megadosing theory).

Timar, do you have reliable sources for this claim that plasma levels would already be saturated at ~100mcg/ml?

I found this one only, where it says:

Measurements: Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g.

On the other had this one study actually measured multiple times higher levels in Mega-dosers:

Self-reported daily intake varied from 0 to 20 g/day. The plasma AA levels ranged from 11.4 to 517 µmol/L and correlated well with the reported intake. Regression analysis of their GHb and plasma AA values showed a statistically significant inverse association (eg, each 30 µmol/L increase in plasma AA concentration resulted in a decrease of 0.1 in GHb).

My personal beneficial experiences with mega-dosing Vitamin C is related in this post already.

From what I've read, large doses of oral Vitamin-C are poorly absorbed and the only way to maintain consistently elevated levels of C are to take low doses rather frequently throughout the day.

When taken with food, any amount of Vitamin-C greatly increases absorption of dietary iron from the food, which can cause iron accumulation in men and non-menstruating females which may be problematic over long periods of time.

I take 500mg of C two to three times per day, but always make sure I do so on an empty stomach. The risk/reward of C taken in this manner seems the smart thing to do.

I wasn't aware of the iron issue, do you have a link? Is there anything that can be taken to chelate iron?

I usually put a couple grams of C in my fiber drink along with a bunch of other supplements periodically, so I suppose I might need to combat iron accumulation at some point or if I wish to continue using C as a sweetener.

When taken with food, any amount of Vitamin-C greatly increases absorption of dietary iron from the food, which can cause iron accumulation in men and non-menstruating females which may be problematic over long periods of time.

I suppose I might need to combat iron accumulation at some point or if I wish to continue using C as a sweetener.

C as sweetener? First test serum Iron, Ferritin, Transferrin and Transferrin Saturation to see if you're accumulating.

In my case about 20 g/d of Vitamin C for 5 years didn't raise them at all from lowish levels (male, 46).

When taken with food, any amount of Vitamin-C greatly increases absorption of dietary iron from the food, which can cause iron accumulation in men and non-menstruating females which may be problematic over long periods of time.

I suppose I might need to combat iron accumulation at some point or if I wish to continue using C as a sweetener.

C as sweetener? First test serum Iron, Ferritin, Transferrin and Transferrin Saturation to see if you're accumulating.

In my case about 20 g/d of Vitamin C for 5 years didn't raise them at all from lowish levels (male, 46).

Yeah I was curious as to why no one had used C as a sweetener until I read about the iron thing. It's a great citrus flavor. I buy metamucil b/c it's readily available at the stores around here as my base fiber source and it already has some sugar in it, but not enough to mask the flavor of some of the less tasty supplements that I like to put into it. So I added C and it not only masks the taste of the veggie extracts, it also makes the drink sweeter. If I start buying psylium fiber as a bulk supplement (probably will), I'll probably eschew sugars for C. Though I've read lots of good things like antibiotic properties of xylitol, so may experiment further with those.

Good to hear that you're taking so much without getting high iron levels, are your results common among people taking so much C?

BTW, I've tried liposomal/lipospheric C (I bought the equipment to produce it myself) and didn't feel like it was all that beneficial. I think the fiber may slow the absorption of the C and make it a kind of time release which seems to be effective. So far it hasn't stopped me from getting sick when I've been exposed to sick people on regular intervals, but it did seem to prevent me from getting full blown symptoms, though it may have just delayed the symptoms... I still wound up taking antibiotics.

Well here's a good paper on the effect Vitamin-C has on iron absorption, though it seems a bit confusing. It starts out by acknowledging the "pronounced enhancing effect on the absorption of dietary nonheme iron" from Vitamin-C, but goes on to state "This contrasts with the negligible effect on iron balance of long-term supplementation with vitamin C".

http://ajcn.nutritio...nt/73/1/93.full

Then in Table 1, the data seems to show a moderately substantial increase in iron absorption in the high C diet.

Don't know why, but my ferritin seems to jump sharply if I don't keep it in check with blood donation and IP6. I am rather carnivorous though, so perhaps this is the culprit.

IP6 (inositol hexaphosphate) really does chelate iron, and helps me keep ferritin down between blood donations when taken properly (on an empty stomach with a full glass of plain water).

I've never felt better in my life since going "low iron"... Insulin response is greatly improved and I can skip breakfast without getting shaky and week (fasting hypoglycemia). Energy is up and triglycerides are down. The cure for middle age metabolic syndrome!
http://www.scientifi...or-met-12-05-30

Plasma levels become fully saturated at intakes of ~400mg, divided in two or more doses. ...Hence, we have evolved a tight regulation for exogenous ascorbate, keeping the plasma level at a maximum of ~100mcg/ml, much less than that of most ascorbate synthesizing species (a discrepancy which mislead Linus Pauling into his megadosing theory).

Timar, do you have reliable sources for this claim that plasma levels would already be saturated at ~100mcg/ml?

The review I have linked to provides plenty of sources. Here is a relevant open-access study, measuring plasma concentrations during depletion and repletion phases in hospitalized, healthy woman:

I found this one only, where it says:

Measurements: Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g.

On the other had this one study actually measured multiple times higher levels in Mega-dosers:

Self-reported daily intake varied from 0 to 20 g/day. The plasma AA levels ranged from 11.4 to 517 µmol/L and correlated well with the reported intake. Regression analysis of their GHb and plasma AA values showed a statistically significant inverse association (eg, each 30 µmol/L increase in plasma AA concentration resulted in a decrease of 0.1 in GHb).

Obviously, I wasn't talking about IV dosing. But I said that there is a transient increase in plasma levels after oral doses above the RDA. If you mega-dose 20 g of ascorbic acid and measure the plasma level one hour later. it may well be above 500 µmol/L (Note that I confused the units above. I wrote µg/ml but meant µmol/L. 100 µmol/L is 17.6 µg/ml), while the kidneys are busy filtering out all that excess vitamin C. However, eventually, after two or three hours, the level will fall below 100 µmol/L.

Edited by timar, 26 December 2013 - 09:09 AM.

Plasma levels become fully saturated at intakes of ~400mg, divided in two or more doses. ...Hence, we have evolved a tight regulation for exogenous ascorbate, keeping the plasma level at a maximum of ~100mcg/ml, much less than that of most ascorbate synthesizing species (a discrepancy which mislead Linus Pauling into his megadosing theory).

Timar, do you have reliable sources for this claim that plasma levels would already be saturated at ~100mcg/ml?

The review I have linked to provides plenty of sources. Here is a relevant open-access study, measuring plasma concentrations during depletion and repletion phases in hospitalized, healthy woman:

Interesting paper. However, I wouldn't need plenty of sources in the 1-2 gram intake range, but only one which actually measured plasma concentrations at different intervals with mega-doses, about 10 to 20 grams.

If you mega-dose 20 g of ascorbic acid and measure the plasma level one hour later. it may well be above 500 µmol/L (Note that I confused the units above. I wrote µg/ml but meant µmol/L. 100 µmol/L is 17.6 µg/ml), while the kidneys are busy filtering out all that excess vitamin C. However, eventually, after two or three hours, the level will fall below 100 µmol/L.

That's a very plausible extrapolation from the low-dose studies, but very far from conclusive.

I think case studies with mega-doses are still much more relevant and show that even after 7-8 hours with low doses like 5 gram plasma levels are still far from below 100 µmol/L.

As for example in this one, though a bid strange since they compared 5 gram of regular oral ascorbic acid to 20g or 36g liposomal: in that resulting plasma levels of equal oral doses (5g) showed almost identical!

Pharmacokinetics of oral vitamin C

STEPHEN HICKEY, HILARY J. ROBERTS, & NICHOLAS J. MILLER

"Figure 1 shows the response of the female subject to single 5 g doses of liposomal and
standard formulation vitamin C; both produced similar response curves. These results are
comparable in form and magnitude to those expected for oral vitamin C in previously
depleted subjects. However, peak values exceeded 220 mM L which has been reported as
the maximum value attainable with repeated oral doses of 3 g six times daily [8]. The
subjects were experienced users of high-dose vitamin C and neither suffered any
gastrointestinal effects at this dose level.5 "

 oral vrs liposomal.png   45.25KB   19 downloads

Increasing the dose of liposomal vitamin C to 20g gave a broader response, with
a delayed maximum, as shown in Figure 2. In this graph, the 20g liposomal dose is
compared with a 5g standard dose (male subject). With a 20g intake, the peak plasma
level was delayed and the response was broader, indicating a greater absorption of
vitamin C. The 5g data set shows a marked outlier (peak): this is attributed to the fact
that one of the (5g) blood samples was difficult to extract, with inflammation at the
puncture site, providing only a small sample. The subject experienced no bowel
tolerance effects at either of these intakes.

 liposomal20.png   14.33KB   19 downloads

Figure 3 shows plasma levels following a 36g dose of liposomal vitamin C, for
both subjects. This resulted in peak plasma levels, in the region of 400 µM/L. A 95%
interfractile range (34-114), which contains 95% of the distribution with a mean of 74
corresponds to a calculated standard deviation of 17.4. We note that, under these
conditions, an outlier measurement of 400 µM/L would correspond to a deviation of
10.3 σ with a theoretical p value of 1.6x10 -13 (i.e. P<0.0000000000001). With this high
dose, both subjects exceeded their bowel tolerance, leading to diarrhoea. This
intolerance presumably arose from the high intake of phospholipid, without food
buffering, in fasting individuals. However, our observations using hourly doses suggest
that daily intakes of this magnitude are tolerable without bowel effects, as long as the
dose is spread throughout the day.

 liposomal36.png   14.8KB   11 downloads

However that may be - as transient as some would like to interpret - the effects of mega-doses in comparison aren't that transient:

Self-reported daily intake varied from 0 to 20 g/day. The plasma AA levels ranged from 11.4 to 517 µmol/L and correlated well with the reported intake. Regression analysis of their GHb and plasma AA values showed a statistically significant inverse association (eg, each 30 µmol/L increase in plasma AA concentration resulted in a decrease of 0.1 in GHb).

Edited by pamojja, 26 December 2013 - 04:54 PM.

If you mega-dose 20 g of ascorbic acid and measure the plasma level one hour later. it may well be above 500 µmol/L (Note that I confused the units above. I wrote µg/ml but meant µmol/L. 100 µmol/L is 17.6 µg/ml), while the kidneys are busy filtering out all that excess vitamin C. However, eventually, after two or three hours, the level will fall below 100 µmol/L.

That's a very plausible extrapolation from the low-dose studies, but very far from conclusive.

With up to 2.5 g this is neither a "low-dose" study, nor does this or several other studies showing a similar plasma-dose curve allow for any other extrapolation. Have a look at graph C and read again what the authors of the study concluded:

The data in this paper describe, to our knowledge for the first time, the relationship between vitamin C doses and steady-state concentrations in healthy young women, by using a dose range of 30–2,500 mg. In plasma, there was a steep sigmoidal relationship between vitamin C doses and resulting concentrations for doses of 30–100 mg daily, with an approximate 5-fold increase in plasma concentration over this dose range. At doses of 200 mg daily and higher, there was little change in plasma concentrations, with saturation between 200 and 400 mg daily. Circulating neutrophils, monocytes, and lymphocytes contained 0.5–4.0 mM concentrations of vitamin C and also saturated between 200 and 400 mg daily. At doses of 400 mg daily and higher, vitamin C plasma concentrations did not increase, in part because of increasing vitamin C excretion in urine. In contrast to in vitro observations, in vivo F₂-isoprostanes in plasma and urine and a urine F₂-isoprostanes metabolite were unchanged at all vitamin C doses.

If you really think that those studies are not conclusive, you obviously have an irrational affection with vitamin C.

The mega-dosing study you mentioned is as uncontrolled as it can possibly get and pretty much worthless. It didn't even report the time point at which the subjects took their self reported mega doses, so it doesn't allow for any meaningful conclusion regarding steady state plasma levels whatsoever. It's unfathomable how such a complete mess made it through the peer review process (even in the "New Zealand Medical Journal").

That said, of course it would be possible to continuously overload the kidneys with periodic mega-dosing. That would be an option for severe illnesses where supraphysiological plasma levels have shown promise (e.g. cancer) and IV dosing is impractical. However, as I said before, I think that healthy people want to avoid such plasma levels. We have to assume that there is a good evolutionary reason for this regulatory mechanism.

Edited by timar, 26 December 2013 - 06:13 PM.

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With up to 2.5 g this is neither a "low-dose" study, nor does this or several other studies showing a similar plasma-dose curve allow for any other extrapolation.

...If you really think that those studies are not conclusive, you obviously have an irrational affection with vitamin C.

1.25 g single Vitamin C doses 2 times a day are low compared to the up to 9 g single doses 3 times a day regularly taken by me.
Those couple of higher dose case studies by Hickey or Copplestone, where plasma levels were repeatedly meassured above the usually maximum possible 220 µmol/L - even if not published in a pharma-sponsored journal - should raise the concern that further investigations would have to be done before taking assumptions, in the face of however feeble opposing evidence, as conclusive.

My personal beneficial experiences with mega-dosing Vitamin C is related in this post already:

• Vitamin C (after a PAD diagnosis almost 5 years ago, together with lysine and all other nutrients recommended by Linus Pauling) - pain-free walking distance improved from mere 3-400 meters up to 2 hours. But only once I exceeded the in his view minimal therapeutic dose of 6g/d. Side-benefits: a since 2 years persistent skin-rush cleared up, hay-fewer symptoms recurring every spring since 12 years got alleviated (though this year it took 30 g/d; in avg. about 20 g/d for 5 years). HbA1c stayed unproportionally low, compared to rising blood glucose. Truly addictive stuff for someone with my health-issues. Only negative side-effect: flatulence.
• ...

I wouldn't recommend large doses of vitamin C for generally healthy people.
... Hence, we have evolved a tight regulation for exogenous ascorbate, keeping the plasma level at a maximum of ~100mcg/ml, much less than that of most ascorbate synthesizing species (a discrepancy which mislead Linus Pauling into his megadosing theory).

That said, of course it would be possible to continuously overload the kidneys with periodic mega-dosing. That would be an option for severe illnesses where supraphysiological plasma levels have shown promise (e.g. cancer) and IV dosing is impractical. However, as I said before, I think that healthy people want to avoid such plasma levels. We have to assume that there is a good evolutionary reason for this regulatory mechanism.

That's where, I think, our different approaches come from. Where I can't but have to consider the beneficial effects I experienced from mega-dosing with severe illness (where the extrapolated ~100mcg/ml saturation levels just wouldn't make any sense) - healthy people wouldn't experience that many benefits, at least in the short term.

So according to your last post Pauling wasn't that mislead about mega-dosing with severe illness? How you reconcile that with the discrepancy of low-dose saturation you're still maintaining?

Therefore, I think it is advisable to keep the plasma level saturated by insuring a total intake of at least 400mg (agreeing with the LPI's recommendations), ..

The Difference Between Dr. Linus Pauling's Recommendations and the Linus Pauling Institute's Recommendation for Vitamin CIntake

In this context, it is important to note that data from the National Institutes of Health (NIH) have indicated that vitamin C levels in plasma and circulating cells become fully saturated at intakes of about 400 mg/day in young, healthy nonsmokers. These observations are consistent with other data that intakes of about 400 mg/day are associated with reduced risk of heart disease. While these NIH studies are the best we currently have regarding the pharmacokinetics of vitamin C in the human body, they have numerous limitations, including the fact that they are based on a small number of young, healthy men and women. We currently do not know how much vitamin C is required to achieve saturation of cells and tissues in children, older adults, and diseased or stressed individuals. A recent meta-analysis of 36 studies on the relationship between vitamin C intake and plasma concentrations found that the elderly require a substantially higher daily intake of vitamin C to attain plasma concentrations that younger adults achieve at a lower intake. Additionally, work by Linus Pauling Institute investigators has shown that cellular uptake of vitamin C declines with age, supporting the notion that vitamin C requirements are increased in the elderly.

About the safety of Vitamin C mega-dosing:

Safety, Toxicity

A number of possible problems with very large doses of vitamin C have been suggested, mainly based on in vitro experiments or isolated case reports, including genetic mutations, birth defects, cancer, atherosclerosis, kidney stones, "rebound scurvy," increased oxidative stress, excess iron absorption, vitamin B12 deficiency, and erosion of dental enamel. However, none of these alleged adverse health effects have been confirmed in subsequent studies, and there is no reliable scientific evidence that large amounts of vitamin C (up to 10 grams/day in adults) are toxic or detrimental to health.

And further their response about a Vitamin C UL:

With respect to the UL, we agree with the Panel that there is no scientific evidence that even very large amounts of vitamin C are toxic or exert adverse health effects. Specifically, in healthy individuals vitamin C does not cause mutations, cancer, birth defects, hardening of the arteries (atherosclerosis), kidney stones, pro-oxidant effects, "rebound scurvy," excess iron absorption, vitamin B12 deficiency, allergic response, or erosion of dental enamel. The Panel used osmotic diarrhea and gastrointestinal disturbances as criteria to determine the UL for vitamin C and arrived at a level of 2 grams/day. We disagree with this conclusion because it is based primarily on data from uncontrolled case reports. Some studies have reported no gastrointestinal disturbances or diarrhea at up to 6 grams/day of vitamin C, and gastrointestinal disturbances have been observed at widely differing threshold levels (from 3 grams/day up to 10 grams/day). More importantly, we believe that diarrhea and gastrointestinal disturbances are not toxic or severe enough effects to justify a UL based on these criteria. Thus, the side effects of vitamin C are generally not serious, and individuals experiencing these effects may easily eliminate them by reducing vitamin C intakes.
Based on our review of the literature, we conclude that the RDA for vitamin C should be 120 mg/day for optimum risk reduction of heart disease, stroke, and cancer in healthy individuals. Special populations, such as older adults and individuals with disease, may require substantially larger amounts of vitamin C to achieve optimum body levels and derive therapeutic benefits. Furthermore, we conclude that there is currently no consistent and compelling data for serious adverse effects of vitamin C in humans, and a UL can therefore not be established.