Stephen Lawson
Administrative Officer

Last year, a group of scientists led by Dr. Mark Levine in the National Institutes of Health reported the results of their study on the optimal intake of vitamin C in the Proceedings of the National Academy of Sciences with the title, "Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance." Their careful study concluded that the current RDA for vitamin C of 60 mg/day should be increased to 200 mg/day, exactly the same recommendation proposed by chemistry Nobel laureate Linus Pauling nearly twenty years ago. Dr. Levine gave vitamin C in doses ranging from 30 mg/day to 400 mg/day to seven healthy young men, 20 to 26 years old, who were hospitalized for four to six months. The largest doses, 1,000 mg/day and 2,500 mg/day, were given near the end of the study. Due to attrition, only six men received 1,000 mg/day (1 gram/ day) and only three received the largest dose of 2,500 mg/day. It is, therefore, difficult to draw strong conclusions about the effect of the highest doses.

The researchers measured some critical physiological and biochemical parameters, including bioavailability, absorption, and excretion. For bioavailability, doses of vitamin C were given orally and intravenously and the difference between resultant plasma concentrations was calculated. Absorption was complete at 200 mg and then declined with increasing doses, so that less than 50% of the 1,250 mg dose was absorbed. Urinary excretion of vitamin C was determined after oral and intravenous administration of the vitamin. About 25% of a 100 mg dose given either orally or intravenously was excreted within 24 hours. Excretion increased as the dose increased; at the higher doses, about half of the orally administered vitamin was excreted within 24 hours and nearly all of the vitamin given intravenously was excreted.

Plasma concentrations of vitamin C increased rapidly with doses up to 400 mg/day, but increased much more slowly at higher doses. For instance, blood levels achieved at 60 mg/day (the present RDA) nearly tripled after a dose of 400 mg/day. While increasing the dose from 400 mg/day to 2,500 mg/day resulted in an average increase in the blood level of vitamin C of about 20%, the physiological relevance of an increase of this magnitude is not known.

Dr. Levine's group measured the level of vitamin C attained in immune cells, such as neutrophils, monocytes, and lymphocytes, as a function of the dose. The maximum concentration in these cells was reached at the dose of 100 mg/day.

Adverse effects?
The researchers also discussed the possible adverse consequences of high doses of vitamin C. Since their subjects were apparently normal healthy men, no information about the effect of vitamin C supplementation in people suffering from hemochromatosis, or iron overload, could be determined. Due to the limited length of the study, conclusions about longer-term ingestion of vitamin C could not be reached. The only potentially adverse effects that were observed in the NIH study concerned the excretion of uric acid and oxalate. The intake of 1,000 mg/day of vitamin C resulted in an increase in the excretion of uric acid of about 50% and oxalate of about 25% compared to the excretion at an intake of 400 mg/day or less of vitamin C. Increased excretion of oxalate may be correlated with the development of oxalate kidney stones, although no reliable reports have been published in the medical literature to substantiate the influence of supplemental vitamin C in stone formation. Studies completed by Dr. Constance Tsao at the Linus Pauling Institute of Science and Medicine showed that doses of 10 grams/day of vitamin C in six subjects (three men and three women, 24 to 59 years old) resulted in slightly elevated levels of oxalic acid in the urine, but that these levels were comparable to those attained by the consumption of normal diets. Dr. Tsao also found that doses of 3 to 10 grams/ day of vitamin C taken by ten subjects for 2 to 10 years did not produce abnormal plasma oxalic acid levels. While the NIH team concluded that "high doses of vitamin C had no adverse clinical impact," people prone to this type of stone formation may be advised to limit their intake of supplemental vitamin C, just as they restrict their intake of foods rich in oxalic acid, such as strawberries, chocolate, rhubarb, and spinach.

Other investigators have suggested that large doses of vitamin C may be contraindicated in cases of renal insufficiency and chronic hemodialysis. Not much is known about possible interactions between drugs, such as those used in cancer chemotherapy, and vitamin C, although some evidence suggests that large doses of vitamin C may not be advisable for patients taking anticoagulant drugs. However, the results of studies have been inconsistent and often inconclusive.

Other effects and therapy
Dr. Levine's group did not measure many of the crucial biochemical and physiological functions of vitamin C, such as its important role in the synthesis of hormones (neurotransmitters), enzymes, and antibodies; immunological function; cyclic AMP concentration (involved in gene regulation and rate modulation of enzyme reactions); regulation of cholesterol metabolism; and hydroxylation reactions required to produce collagen (present in connective tissue) and carnitine (needed to transport fatty acids to the mitochondria, where they are oxidized for energy). Vitamin C levels in many tissues or organs were not measured, nor was the efficacy of large doses of vitamin C administered therapeutically addressed. (The intake of vitamin C for prophylaxis may be significantly less than the amount that may have benefit in the treatment of certain chronic and acute illnesses or to enhance healing after injury or surgery.) Clinical work has already established the benefit of large amounts of vitamin C to ameliorate symptoms and shorten the duration of the common cold (reviewed by Drs. Harri Hemila and Zelek Herman in the Journal of the American College of Nutrition, 1995). Other work by Drs. Ewan Cameron and Linus Pauling in Scotland, Dr. Abram Hoffer in Canada, and Drs. Fukumi Morishige and Akira Murata in Japan has shown vitamin C to be a valuable adjunct to the appropriate conventional treatment of cancer (see the 1993 edition of Cancer and Vitamin C by Drs. Cameron and Pauling for references).

Evolutionary evidence
Linus Pauling based his own intake of vitamin C on several factors, including the amount synthesized by animals that are able to do so, the amount consumed in the diet by wild animals that are biologically closely related to humans, and the estimated intake by our Paleolithic ancestors. In How to Live Longer and Feel Better, he reasoned that animals capable of the endogenous synthesis of vitamin C would not manufacture so much if it were not beneficial. For example, goats weighing about 50 kilograms, or 110 pounds, synthesize over 9,000 milligrams (9 grams) of vitamin C per day, or 13,000 mg/day per 70 kilograms (154 lbs) of body weight. The laboratory rat weighs about 325 grams and synthesizes 20 to 70 mg/day, or 4,000 to 15,000 mg/day per 70 kilograms of body weight. The optimal intake of vitamin C for guinea pigs, weighing about 700 grams and unable to synthesize vitamin C, was reported by Yew in 1973 to be about 35 mg/day, or 3,500 mg/day per 70 kilograms of body weight. Chimpanzees in captivity weigh about 55 kilograms and consume about 800 to 1,600 mg/day of vitamin C in their prepared diets; gorillas, weighing about 200 kilograms, ingest between 3,000 and 6,000 mg/day. These primates, our closest biological relatives, are not able to synthesize vitamin C and must depend upon dietary sources to prevent scurvy and optimize performance and health. In 1949, Dr. G.H. Bourne calculated that gorillas in the wild consume about 4,500 mg/day of vitamin C.

In an article in The New England Journal of Medicine in 1985, Drs. Eaton and Konner estimated that the Paleolithic diet provided about 400 mg/day of vitamin C to our human ancestors, much more than the 90 mg/day or less presently consumed dietarily by most Americans. Dr. Gladys Block has estimated that 40% of Americans have vitamin C blood levels about half of the level obtainable by consuming a diet abundant in fruits and vegetables. Supplementation is an economical, safe, and effective means to achieve higher blood levels.

In "Evolution and the Need for Ascorbic Acid" (published in the Proceedings of the National Academy of Sciences in 1970), Linus Pauling calculated the amount of several vitamins in 110 raw plant foods, based on the amount of each plant food that provides 2,500 kcal of energy, which is the average daily need for humans. The thiamine (vitamin B1), riboflavin (vitamin B2), and nicotinic acid (vitamin B3) content in the amount of these foods that provide 2,500 kcal of energy is about 3 times the RDA for these vitamins, but the average amount of vitamin C for the 110 plant foods providing 2,500 kcal of energy is 2,300 mg, or 38 times the present RDA. (Of course, the value for vitamin C would decrease somewhat if meat, poultry, or fish were included in the diet to provide food energy or if the consumption of nuts or grains is high.) It appears that Dr. Levine's recommendation to increase the RDA for vitamin C to 200 mg/day is a step in the right direction.

Many micronutrients in food have beneficial effects, and interactions between them may be important. Most epidemiologic studies correlate a high consumption of fruits and vegetables with a decreased risk of developing age-related diseases like cancer, cataract, and heart disease. Evidence also supports special roles for supplemental vitamins C and E in reducing the incidence of heart disease and cancer. Indeed, much of the protective effect can be related to antioxidant vitamins, while much is certainly related to beneficial phytochemicals and other substances. It is a fascinating and very complicated picture, and Dr. Levine's study has contributed to our understanding. However, much more research needs to be done to determine the optimal intake of vitamin C for children, women, the elderly, those under stress or exposed to environmental toxins, and those suffering from chronic or acute illness.

Dr. Albert Szent-Gyorgyi, 1937 Nobel laureate in Physiology or Medicine for discoveries of biological oxidation processes, confided to Linus Pauling in 1966 that he took about 1,000 mg/day of supplemental vitamin C. Dr. Pauling himself took much larger doses. Both Szent-Gyorgyi and Pauling recognized the importance of vitamins many decades ago--in 1938, Linus Pauling said that investigation of substances manufactured in the body or ingested in food would have "transcendent significance to mankind," and in 1939, Szent-Gyorgyi wrote, "Vitamins, if properly understood and applied, will help us to reduce human suffering to an extent which the most fantastic mind would fail to imagine." Based on new experimental evidence, we may be well on the way to proving them right.

For information on vitamin C and its role in health and disease, see the Linus Pauling's Institute's Micronutrient Information Center.

Last updated May, 1997

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