by Steve Hickey
Dose-response curve for blood plasma concentration following a 1,250-mg dose of vitamin C in a depleted subject.
At vitamin C intakes below about 100–200 mg per day, the specialized tissues are protected from scurvy by accumulating high levels relative to normal tissues. In recommending 200 mg per day, Dr. Levine added that doses above 400 mg provide no additional benefit. At this suggested intake, most of the tissues in the body are in a state of depletion. Moreover, intakes of at least 18 grams of vitamin C per day are required to provide the maximum sustained blood levels.12
Molecular Pumps and Vitamin C
Vitamin C, or ascorbic acid, is a simple organic molecule similar to glucose. The glucose molecule constitutes a high proportion of the normal diet, typically many hundreds of grams each day. Notably, the abundant glucose competes with vitamin C, further limiting ascorbate’s benefits. When glucose (blood sugar) is high, less vitamin C is transported into cells,13 which may explain why many people do not report positive effects of vitamin C supplementation with the common cold and other illnesses.14 “Take more vitamin C and eat less sugar and carbohydrates” might be a new adage to replace the basic wisdom of the old one: “Starve a cold, lest you feed a fever.” Many high-dose vitamin C tablets or drinks that are laden with sugar in essence provide the antidote with the drug.
The specialized cells in the body that concentrate vitamin C have several types of molecular pump in the cell membrane to transport vitamin C. One type is called GLUT (glucose transporter) and pumps oxidized vitamin C into cells. Oxidized vitamin C (dehydroascorbate) has a similar molecular shape to glucose, hence GLUT pumps can transport either molecule. This pumping is competitive, which means that if there is a lot of glucose, then it will be pumped in preference to oxidized vitamin C.
Two other pumps transport vitamin C into tissues that have high need, including tissues in the intestines, kidney, liver, brain, eye, and other organs.15 While the pumps have a limited capacity for transporting vitamin C, the cells can become full at relatively low levels in the surrounding fluid. At higher plasma concentrations, the cells continue to accumulate ascorbate, but the rate is low. The possession of ascorbate pumps provides an indication that a cell is particularly sensitive to depletion of the vitamin.
The hormone insulin is able to move GLUT transporters from the interior of a cell to its surface, where more glucose can be transferred.16 Diabetics, who lack insulin, are unable to manage this increased absorption and sugar accumulates in their blood. One explanation for the long-term symptoms of diabetes is that the person’s cells are chronically short of vitamin C. Hormones such as insulin could also affect the body’s ability to absorb vitamin C.
We have already described the massive increase in absorption of ascorbate from the gut during stress and illness. Unfortunately, this response has not been investigated and the underlying control mechanisms are unknown.
Dynamic Flow
A single, large dose of vitamin C produces a brief response in the body. Gram-level doses produce a response above the background level (~70 μM/L) and this is rapidly excreted in urine. High concentrations in blood plasma are excreted with a half-life of about thirty minutes. However, when the dose is repeated, blood plasma levels can increase. A second dose adds to the blood levels before the previous dose is excreted. Separating doses by less than 3–4 hours can increase the levels to a plateau of about 250 μM/L in a previously deficient subject.
Repeated gram-level doses of vitamin C at hourly intervals produce a steady state in a depleted individual; a sustained maximum level requires an intake of about 20 grams per day.
As a simple analogy, consider a water barrel with a hole part way up the side. Left for a short period without filling, the barrel will settle down to a water level just below the hole (the baseline level). An attempt to fill the barrel with a bucket will only partly succeed. A single bucketful will raise the water level slightly, but it will soon escape through the hole. This is what happens when single doses of vitamin C are given once a day—the blood level is briefly increased, but soon falls back to the baseline. Dynamic flow is equivalent to filling the barrel from a continuously flowing tap. By increasing the flow, leakage from the hole can be overcome and the water level in the barrel can be increased indefinitely.
In dynamic flow, vitamin C is abundant in blood plasma and diffuses slowly into other body compartments. A typical adult human has a blood volume of about five liters. Cells take up somewhat less than half of this volume, with plasma making up the remaining fluid. Red cells are the predominant cell type and slowly absorb vitamin C by diffusion from the plasma. Given time, the concentrations in the plasma and the red blood cells will reach equilibrium. At this point, the blood concentration will have increased to the dynamic flow plateau level or above.
Blood makes up only a small fraction of the tissue volume. In a typical 150-pound (70 kg) human body, about 7 percent of the total volume is blood. High plasma ascorbate levels can diffuse slowly into other tissue compartments. Given time, the body will reach equilibrium, with the tissue levels being equal to or above the mean plasma concentration. When this occurs, the total amount of vitamin C in the body is much greater than that of a person who is not taking regular doses.
If a person who has been in dynamic flow for a considerable period stops taking vitamin C, blood levels remain high until the kidneys excrete the vitamin C. As a result, the vitamin C concentration in the large tissue volume is at a higher level than in the blood plasma, so vitamin C diffuses from the tissues into the blood. Such flow from the tissues sustains the plasma concentration for some time. Moreover, people in dynamic flow who become ill with a common cold or similar infection have a large advantage. Their blood levels are maintained by the frequent oral doses, and at times of high demand, the reserves in their tissues will prevent the blood plasma from being depleted.
The Short Half-Life of Vitamin C
Vitamin C’s short plasma half-life means that a large oral dose will raise blood levels for only a few hours. For the rest of the day, the level in blood plasma drops back to the background level of 70 μM/L. For decades, investigations into the properties of vitamin C have been flawed. Many scientists considered a gram-level dose to be large and this idea confuses nutrition and pharmacology. Nutritional intakes are required to maintain optimal health, while pharmacological intakes involve the use of vitamin C as a medicine to treat illness. Nutritional doses are typically considered to be up to about 10 grams per day, whereas 10 grams would be only a small pharmacological dose. For example, Robert F. Cathcart III, M.D., and others have used 40 grams, 60 grams, or even 200 grams a day in divided doses to treat a wide variety of illnesses with apparently great success.17 Many studies on vitamin C and the common cold confuse prevention and treatment, and often doses below 1 gram are studied for both.18 The dominant error has been to study single daily doses. Healthy individuals who want protection from the common cold or other illnesses by taking vitamin C need to raise their blood levels by taking divided doses or slow-release formulations.
What is the Optimal Intake?
The optimal intake for a healthy person has not been established. As we’ve seen, much of the work underlying the government RDA is flawed and the recommended intakes of vitamin C are woefully inadequate. Recent developments have demonstrated that the assumptions upon which the RDA was based are unjustified and unsupportable. There is currently no evidence to support the idea that low doses of vitamin C are optimal. Indeed, low intakes may be the cause of much of the world’s chronic disease.
Recently, because of the NIH experiments into the uptake and excretion of vitamin C, the RDA was revised from 60 mg daily for adults to 90 mg for men and 75 mg for women. Smokers are recommended to take an extra 35 mg per day, as the toxins produced by inhaling cigarette smoke increase oxidative stress and smokers tend to have lower blood levels of vitamin C anyway. However, this recommendation may be a gross underestimate, leaving smokers with a false sense of security—re
cent observations with large intravenous infusions of sodium ascorbate suggest that smoking can produce a high degree of oxidation, resulting in lowered plasma ascorbate levels.19
A person starting to take vitamin C supplements is starting from a level of relative deficiency. By taking repeated doses, the levels in the tissues and blood plasma increase and more can be tolerated. Human requirements for vitamin C appear to be more variable than previously realized. The key point is that people need more, far more, than previously assumed. Using the criteria used to set the RDA, and removing the errors, leads to a suggestion that the intake for a healthy adult should be in the range of about 500 mg to 20 grams (20,000 mg), or even more. Some people would require low doses and would not tolerate higher intakes; others need higher levels, above 10 grams.
A person wishing to estimate his or her own requirement needs to determine their bowel tolerance level. To do this, start with a low dose and repeat it each hour until unpleasant bowel effects (gas, distension, and loose stools) are observed. This level of intake is your bowel tolerance level and the optimal intake is 50–90 percent of this maximum. Keep in mind that a high carbohydrate intake can interfere with the bowel tolerance test and falsely indicate a lower limit. Vitamin C requirements change with the state of health and need to be re-checked in this way from time to time. Perhaps more importantly, the level that a person can tolerate increases with time, as dynamic flow is maintained.
People vary in their requirements and it is not possible to provide a definitive statement about intakes that applies to all. Furthermore, a person’s requirement will vary, increasing with even a slight illness. The minimum intake required to raise a typical adult’s blood plasma levels consistently is 2–3 grams (2,000–3,000 mg) per day, in divided doses of about 500 mg. For some, this will be too high and they may need to lower the dose slightly. For many, this intake will be too low to provide resistance to infections and chronic disease.
Forms of Vitamin C
Vitamin C is available in many formulations and there are numerous claims for more effective supplement brands. Often, the claim is that their particular form of vitamin C has improved absorption when taken orally. Most forms of vitamin C are absorbed at comparable rates, although sustained release forms result in delayed absorption.20 In some cases, manufacturers claim that they have a more “natural” form of the vitamin, suggesting that theirs is the real vitamin C and ascorbic acid is not the genuine vitamin. Such claims are spurious. Vitamin C is defined as L-ascorbic acid, and in general, this is the vitamin C of choice, which is readily available at low cost. However, there are caveats and advantages associated with other forms.
Natural Vitamin C
Natural vitamin C is the same molecule as synthetic L-ascorbic acid.21 They are chemically identical with no known differences, whether physical, chemical, or biological, so there is no advantage to supplementing with “natural” vitamin C over L-ascorbic acid.22 As we have explained, occasionally epidemiological papers and clinical trials suggest that vitamin C in food is more effective than the vitamin C in supplements. However, such suggestions are misplaced, as the molecule is identical.23 Indeed in some foods, such as broccoli, the absorption may be impaired.24 Despite suggestions that there may be “magic” factors associated with vitamin C in foods, the differences between vitamin C in foods and supplements can be explained more easily as experimental error, such as underestimating the vitamin C in food. Furthermore, absorption of vitamin C from food can occur more slowly than from supplements, thus increasing average blood levels more effectively.
Natural vitamin C is often found in combination with plant pigments called bioflavonoids. Bioflavonoids are often antioxidants and are found in citrus and other fruits and vegetables with a high vitamin C content. There is some evidence that bioflavonoids increase the availability of vitamin C. However, to be effective, this requires a higher intake of bioflavonoids than is commonly found in vitamin C tablets.25 At low doses, vitamin C is well absorbed, so the benefits of bioflavonoids are unclear.
Mineral Forms
Since pure vitamin C is a weak acid, combining it with minerals, such as sodium, calcium, or magnesium, produces a non-acidic salt. Several forms of mineral ascorbate are common in supplements, with sodium ascorbate and calcium ascorbate being the most frequent. Some people find mineral forms are easier on the stomach, as they are less acidic. People taking massive doses of vitamin C as a mineral ascorbate may also end up consuming large amounts of the mineral. Sodium ascorbate contains 131 mg of sodium and calcium ascorbate has 114 mg of calcium per gram. Consuming many grams of vitamin C in this form may be contraindicated in some conditions, such as kidney disease.
However, there is a more critical restriction to the consumption of massive doses of mineral ascorbate—these forms are less effective. Sick people can often take massive amounts of vitamin C without significant oral discomfort. At a threshold point, close to bowel tolerance, the symptoms of a common cold, for example, often disappear. However, this threshold effect appears to be limited to vitamin C as ascorbic acid and it is not found with mineral ascorbates. Dr. Cathcart was the first to describe this greater response to ascorbic acid over other forms, which has been confirmed by others. This could be because vitamin C contains two available antioxidant electrons, but in mineral forms of ascorbate this number is lower. In sodium ascorbate, the sodium atom replaces one antioxidant electron. Once absorbed, a molecule of sodium ascorbate needs to gain an electron from the body’s metabolism in order to function. This effect may be one reason why some people experimenting with massive doses of ascorbate do not achieve the claimed benefits.
Lipid-Soluble C
Another form of vitamin C, ascorbyl palmitate, is a lipid-soluble form of vitamin C. Unlike the proprietary brand of mineral ascorbates, Ester-C™, it is a true ester. A molecule of ascorbyl palmitate is vitamin C combined (esterified) with the fatty acid palmitate. Ascorbyl palmitate is used as a food additive, but is most commonly found as an ingredient of anti-aging cosmetics because of its antioxidant properties and its role in collagen synthesis.26 When taken orally, ascorbyl palmitate may be largely converted to L-ascorbic acid and palmitate in the liver, and it is unclear if it provides any advantage over L-ascorbic acid.27 Ascorbyl palmitate is frequently used in cosmetics and topical preparations.
Liposomal C
For healthy people and many with chronic disease, enough vitamin C is provided by dynamic flow levels attained with inexpensive vitamin C. However, some people with diseases such as cancer may not be able to achieve sufficient levels in the blood to combat the illness with normal vitamin C supplements. Intravenous infusion of sodium ascorbate is one option, but a new oral form, liposomal C, also allows greater blood levels to be attained.
A thin membrane surrounds every cell in the body, constructed of two layers of a fat-like substance called phospholipid. Phospholipids have some of the chemical properties of soap: they contain a polar (water-soluble) head and a non-polar (fat-soluble) tail. The head will dissolve in water and the tail in fat, an arrangement that, in soap, helps break up fat deposits during washing. This molecular arrangement means that phospholipids, like soap, can form bubbles when mixed in water.
Liposomes are formed from bubbles of phospholipids, often containing and protecting a liquid content. Commercially produced liposomes may be very small and can be filled with drugs or supplements as an aid to absorption into the body. They provide a method for overcoming the barrier to oral uptake of vitamin C. We have seen that if a person used to low intakes of vitamin C is given a single dose of 12 grams, only about 2 grams will be absorbed. However, if liposomes are filled with concentrated vitamin C, they can theoretically overcome this absorption limit, delivering most of the 12 grams to the body. The result of a large dose of liposomal vitamin C is a gradual increase in blood levels, similar to that obtained with a standard tablet. However, the peak level may be far higher, above 400 μM/L, and the response is sustained. These spectacularly high plas
ma levels of vitamin C are selectively toxic to cancer cells and liposomes extend the potential of oral doses to combat disease, including cancer.
Schematic comparison between the claimed maximal plasma response (to 1,250 mg of vitamin C; gray line) to that obtained with an oral dose of 36,000 mg of liposomal ascorbate (black line). (Hickey, S., et al. JNEM [2008])
Are High Doses of Vitamin C Safe?
The idea that people might want us to accept something false as fact is well-known, as we are bombarded daily with advertising. Much advertising aims at generating such misleading “facts” by frequent repetition. The word factoid refers to an item of unreliable information, which has been given credence by repeated exposure. Factoids are “facts” that had no existence before appearing in a magazine or newspaper. At its heart, a factoid is an assumption or speculation. For several decades, an odd medical and media campaign has generated a series of such factoids concerning the safety of vitamin C. Typically, these scare stories are given wide media publicity before they are subjected to scientific scrutiny.
Vitamin C is remarkably safe, which is not surprising considering it is essential to human life and is actively retained in the body. Vitamin C is a simple molecule, used by both animals and plants, often at high concentrations. Organisms have had hundreds of millions of years to evolve mechanisms for prevention of damage by vitamin C. But even allowing for such tolerance, the safety of vitamin C is outstanding. It is unusual in that it can be taken in massive doses, for long periods, without apparent harm.
Vitamins generally have an excellent safety profile—the harmful effects of overdosing are generally overstated. When the science is considered dispassionately, it becomes clear that people are in greater danger of deficiency than overdose. Nevertheless, vitamin intake needs to be considered carefully to ensure optimal nutrition, free from side effects.