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THE SCIENTIFIC BASIS OF THE VITAMIN C DOSAGE OF NUTRITION INVESTIGATOR

Update Jan, 2012
A reader asked how much vitamin C to take, and I replied that if you read the scientific literature, summarized below, the answer is likely to be 500 mg twice a day, about every 12 hours, once in the morning and again in the evening. He referred me to Psychology Today 2003 [not a peer-reviewed journal], and was surprised I had never heard of a connection between vitamin C and stress. The article, Vitamin C: Stress buster -reports that people getting 1g of vitamin C daily (given as a single dose and thus less effective the 500mg BID] had significantly lower levels of cortisol and blood pressure than controls.

Update summer, 2010: http://www.ncbi.nlm.nih.gov:80/pmc/articles/PMC2682928/
Vitamin C supplementation lowers serum low-density lipoprotein cholesterol and triglycerides: a meta-analysis of 13 randomized controlled trials by Marc P. McRae
This meta-analysis of 13 randomized controlled trials indicates that supplementation with at least 500 mg/d of vitamin C, for a minimum of 4 weeks, can result in a significant decrease in serum LDL cholesterol [-8 mg/dl] and triglyceride [-20 mg/dl] concentrations.

On the downside, a study in 2010 published in AJCN indicates that Swedes, taking supplements of 1,000 mg at a time, may accelerate the development of cataracts.

Original essay: The free radical theory of aging proposed by Dr. Denham Harman has been well established as a basis for the onset of age-associated diseases. The physiological mechanisms of antioxidant vitamins, particularly vitamins C and E (including alpha- and gamma-tocopherol), in reducing free radical damage has been well established in vitro and in vivo in humans. Until 1994, there were only two recommendations for vitamin C dosage, the 60 mg RDA to prevent scurvy and "up to 10,000 mg daily" from Dr. Linus Pauling to prevent colds, cancer, and other diseases.

It was widely agreed that megadoses (more than 10x the RDA) of vitamin C were excreted rapidly in the urine. In 1994, I conducted a study (1) to determine how much vitamin C a person must take in order to have a continuously elevated level of vitamin C in the urine, and how often that dosage must be taken to provide a continuously elevated level. Five hundred mg of vitamin C taken twice a day is the lowest dosage that produces a continuously elevated level of vitamin C in the urine of healthy young individuals.

Dr. Mark Levine subsequently began a study (2) published in 1996 of 7 healthy, young men at the National Institutes of Health, with a similar design to my study, but was also able to measure blood plasma levels of vitamin C and excretion of byproducts of vitamin C. While the results were similar to mine, the conclusion was strikingly different - 200 mg of vitamin C daily was recommended for the RDA. Three important reasons were stated for this dosage: 1) this is the highest level one can obtain in the diet without supplementation, 2) at 500 mg twice a day, excretion of oxalic acid rises, which might lead to kidney stones, and 3) at 200 mg the plasma level of vitamin C is elevated close to plateau levels.

In 1997, a third study by Blanchard (3) developed a pharmacokinetic model of vitamin C absorption and excretion, based on existing published studies like those of Ordman and of Levine, and concluded that even 200 mg per day was too much. This model was used to justify that a dosage as low as 138 mg per day could potentially saturate the body pool of a healthy young man.

Numerous clinical trials and physiological studies have demonstrated that high intake of vitamin C in the diet or supplement form may reduce the risk of age-associated diseases. If one accepts the validity of those studies, how much vitamin C can a person take safely and usefully, based on available scientific evidence? The plasma levels of vitamin C reported by Levine show that 200 mg per day is barely adequate to elevate blood levels in young, healthy males in a controlled environment, and does not consider specific body pools which are particularly challenged by other factors such as illness (7), smoking, and age. Smoking a pack of cigarettes per day increases vitamin C demand by approximately 140 mg.

The 1,000 mg dosage is the lowest to show significantly elevated levels of oxalic acid in the urine, which Levine states might increase the risk of kidney stones. However, the slight acidification of the urine could also have benefits, and the study of Stampfer (4) has shown that those taking elevated doses of vitamin C in fact have a 22% lower incidence of kidney stones.

If 500 mg twice a day provide higher plasma levels of vitamin C, a continuously elevated level of vitamin C in the urine, a lower risk of kidney stones, and potential reduction of risk for age- associated diseases, why does Levine argue for a 200 mg per day RDA? The 200 mg level is the highest level that can be obtained in the diet, by selecting 5 servings of fruits and vegetables which are especially rich in vitamin C. Any higher dosage would require supplementation, and a variety of economic and political factors make it unlikely that the Food and Nutrition Board would ever endorse an RDA requiring supplementation. Thus, Dr. Levine has recommended the highest possible dosage which he believes might be acceptable to the Food and Nutrition Board. The Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000)from the Institute of Medicine set an Upper Limit of 2,000 mg per day.

The Blanchard study develops a model based on previously published data which can be used to justify a level close to the present RDA. However, by the authors' own admission, it is not valid for higher doses of vitamin C. For instance, in Table 1 the model predicts only 23% of a 1,000 mg dose will be absorbed, while published reports show 75% is absorbed.

Even the value of vitamin C for prevention of the common cold has been reexamined (5) in 1996, with the conclusion that vitamin C may indeed be useful, and that previous critical reviews were flawed. With progressing understanding of the interactions of vitamins C and E, and the importance of vitamin E in maintaining and restoring the immune response, it is well established that antioxidants enhance immunity. The "dogma" that supplements are of no value has begun to be questioned even in the Journal of the American Medical Association (8).

The existing evidence is consistent with the conclusion that 500 mg of vitamin C twice a day provides a continuously elevated level of vitamin C in the urine and blood plasma, is safe, and may reduce the risk of age-associated diseases. Dosages above 500 mg twice a day will increase urinary excretion without significantly increasing blood plasma levels, and dosages below 500 mg twice a day will not provide continuously elevated levels in the urine, will not provide saturating plasma levels in those who are ill or exposed to smoke, and are unlikely to produce saturating levels in older individuals or those exposed to other causes which generate free radicals.

Finally, in what form should vitamin C be taken? Despite advertising claims, careful research (6) indicates that there is no benefit associated with more expensive forms of vitamin C such as Ester- C. For this reason, taking 500 mg of generic vitamin C twice daily is convenient and inexpensive.

Antioxidants and physical performance in elderly persons: the Invecchiare in Chianti (InCHIANTI) study Matteo Cesari et al Am. J. Clinical Nutrition,  Feb 2004;  79:  289 - 294. Background: Muscle strength and physical performance in old age might be related to the oxidative damage caused by free radicals. Design:…986 Italians aged 65 y Conclusions: Plasma antioxidant concentrations correlate positively with physical performance and strength. Higher dietary intakes of most antioxidants, especially vitamin C, appear to be associated with higher skeletal muscular strength in elderly persons.

Vitamin C dose reduces heart disease! Here's just another study confirming 500mg twice a day works, but less may not! Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts Paul Knekt et al Am. J. Clinical Nutrition,  Dec 2004;  80:  1508 - 1520. Design:A cohort study pooling 9 prospective studies that included information on intakes of vitamin E, carotenoids, and vitamin C and that met specific criteria was carried out. During a 10-y follow-up, 4647 major incident CHD events occurred in 293 172 subjects who were free of CHD at baseline. Results:… Compared with subjects who did not take supplemental vitamin C, those who took >700 mg supplemental vitamin C/d had a relative risk of CHD incidence of 0.75…Supplemental vitamin E intake was not significantly related to reduced CHD risk. Conclusions:The results suggest a reduced incidence of major CHD events at high supplemental vitamin C intakes. ..

CAUTION (See Nov, 2004 litnotes link): However, for post-menopausal women with diabetes, there is a downside. Although based on a single study looking at heart disease and stroke, such women ought to realize there are circumstances when vitamin C may act as a pro-oxidant.

TO VITAMIN E DOSAGE ESSAY

1. King, G., Beins, M., Larkin, J., Summers, B., and Ordman, A.B., "Rate of Excretion of Vitamin C in Human Urine", AGE 17:87-92 (1994)

"The conclusion is that two conditions are necessary to elevate vitamin C excretion continuously: a dose of at least 500 mg and a dose every 12 hr. This is substantially higher than the U.S. recommended daily allowance and more frequent than administration being used in clinical trials."

2. Levine, M. , Conry-Cantilena, C., Wang, Y., Welch, R.W., and Cantilena, L.R., "Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance," PNAS USA 93: 3704-9 (1996)

"Based on these data and Institute of Medicine criteria, the current RDA of 60 mg daily should be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1000 mg daily, and vitamin C daily doses above 400 mg have no evident value."

"At the vitamin C dose of 1000 mg daily, urine uric acid and oxalate were elevated...If high doses were administered longer, it is unclear whether the elevations would remain and whether renal calculi would result. When patients ingested more than 1000 mg of vitamin C daily, unexpected calculi were not reported."

3. Blanchard, J., Tozer, T.N., and Rowland, M., "Pharmacokinetic perspectives on megadoses of ascorbic acid", Am. J. Clin. Nutr. 66: 1165-71 (1997). [see also editorial with it, Barry Shane]

"The analysis indicates that both saturable gastrointestinal absorption and nonlinear renal clearance act additively to produce the ceiling effect in plasma concentrations. As a consequence of this ceiling effect, there is no pharmacokinetic justification for the use of megadoses of ascorbic acid" "Jacob et al...reported that the body pool of ascorbic acid approaches an upper limit...[which] can be achieved with an average intake of about 138 mg/d"

4. Curhan, GC, Willett, WC, Rimm, EB, and Stampfer, MJ, "A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men", J Urol 155: 1847-51 (1996)

"We conducted a prospective study of the relationship between the intake of vitamins C and B6 and the risk of symptomatic kidney stones in a cohort of 45,251 men 40 to 75 years old with no history of kidney calculi...For vitamin C the age-adjusted relative risk for men consuming 1,500 mg daily or more compared to less than 250 mg daily was 0.78...After adjusting for other potential stone risk factors the relative risks did not change significantly."

5. HemilÑ H, "Vitamin C supplementation and common cold symptoms: problems with inaccurate reviews", Nutrition 12: 804-9 (1996).

"Studies carried out since then have consistently found that vitamin C (> or = 1 g/d) alleviates common cold symptoms, indicating that the vitamin does indeed have physiologic effects on colds. However, widespread conviction that the vitamin has no proven effects on the common cold still remains. Three of the most influential reviews drawing this conclusion are considered in the present article. Two of them are cited in the current edition of the RDA nutritional recommendations as evidence that vitamin C is ineffective against colds. In this article, these three reviews are shown to contain serious inaccuracies and shortcomings, making them unreliable sources on the topic"

6. Johnston, C.S. and Luo, B., "Comparison of the absorption and excretion of three commercially available sources of vitamin C", J Am Diet Assoc 94: 779-84 (1994)

"vitamin C from Ester-C or in association with bioflavonoids was not more bioavailable than simple ascorbic acid"

7. Schorah, CJ, et al, "Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients," Am J Clin Nutr 63: 760-5 (1996)

"[vitamin C was measured] in critically ill patients in whom the excessive generation of reactive oxygen species could compromise antioxidant defense mechanisms. Median concentrations...were less than 25% of the values found in healthy control subjects and in subjects in two other disease groups (diabetes, gastritis)...The findings indicate that antioxidant defenses could be considerably compromised in these very sick patients."

8. . Chandra, R. K. "Graying of the immune system: Can nutrient supplements improve immunity in the elderly?", JAMA 277: 1398-99 (1997)

"nutrient supplements may be important for health promotion and prevention of certain chronic diseases. This view goes against the prevailing dogma in nutritional science that a balanced diet is sufficient to achieve all nutritional objectives."