Vitamin C

This article will describe the biochemistry of vitamin C. For the chemical properties of ascorbic acid, please see Ascorbic acid.

Unlike other vitamins, which are required by the majority of animal species, vitamin C is only required by a minority of animal species, including humans and higher primates. It is also the only water-soluble vitamin whose exact function remains unknown, although it has numerous physiological effects and eight different well characterized roles. As research advances, it appears that its first name, ignose, meaning "I don't know", or "godnose," describes it best.

Once described as the vitamin that prevents scurvy (hence its chemical name, ascorbic acid), vitamin C is now recognized as an important factor in the maintenance of good health and as a rationale for the consumption of more fruits and vegetables. It is the vitamin of many superlatives, as it is the most sold supplement in the world, the vitamin required for the maintenance of the most abundant protein in the body, the most "luminously controversial of all biological, alternative cancer therapies", the vitamin which intake has declined the most drastically in the course of Human evolution, and the vitamin which requirements have been debated for the most time and with the most intensity.

This article describes the debate on the vitamin's requirements (and, in some cases, lack thereof), presents the state-of-the-art in vitamin c therapeutics and presents the context in which knowledge on this nutrient has been produced. In this evolving field of medical research, epistemological considerations provide clues to the future developments in vitamin C.

Vitamin C

Description

Vitamin C is produced from glucose in the liver of most mammals and in the kidneys of most birds. The fact that most vertebrate species produce it endogenously as well as the fact that this production is massive (see Vitamin C in evolution, below) disqualify it as a vitamin, but it continues to be known as such. In contrast, other vitamins are indeed required in small amounts in the diet by most animal species, including humans. The molecule is also known as ascorbic acid, which suggests that vitamin C is to scurvy what vitamin B1 is to beri-beri, for instance, which is inexact as well (see Daily requirements, below).

Role as enzyme cofactor

Vitamin C is required by some enzymes called hydroxylases to add hydroxyl radicals (O-H) to specific molecules.

Collagen synthesis

Collagen hydroxylase uses vitamin C to make the long collagen fibers hold together. Collagen is the most abundant protein in the human body. (in progress)

Norepinephrine synthesis

Norepineprine, (aka noradrenaline), is obtained from dopamine by the action of the enzyme dopamine beta-hydroxylase. Dopamine and norepinephrine are neurotransmitters which have different functions but which are closely involved in mood, learning, and movement. Many antidepressants raise dopamine and norepinephrine concentrations, by different mechanisms.

Carnitine synthesis

Carnitine is the molecule that allows most fat molecules to be carried in the mitochondria where they will be transformed into energy. Carnitine is also required to carry excess organic acids out of mitochondria, where they would otherwise impair energy production. The metabolic pathway that leads from the amino acid lysine to the conditionnaly essential vitamin carnitine requires vitamin C twice. The steps are the enzymes gamma-butyrobetaine hydroxylase and epsilon-N-trimethyl-lysine hydroxylase. Low vitamin C causes a decreases in carnitine production, which contributes to fat deposition and overweight. At present, the exact role of low vitamin C in the obesity epidemic is not clarified, but the normalisation of vitamin C levels in people with low vitamin C status was shown to raise their ability to burn fat 4-fold during submaximal exercise. Future studies should determine to what extent fruits and vegetables contibute to carnitine synthesis and weight management.

Antioxidant functions

(in progress)

Vitamin C is also a major water phase low-molecular weight antioxidant.

In oxidation process the molecule of vitamin C step by step oxidazed with built up some active prooxidant substances. .

Biosynthesis

Yeasts do not synthesize vitamin C, but produce another antioxidant, erythorbic acid. However, metabolic engineering of yeasts such as Saccharomyces cerevisiae can be used for the industrial production of vitamin C.

Plants, Humans' first source of vitamin C, obviously produce it, in large amounts. Plants use vitamin C in such great amounts as a defense to survive to viruses, bacteria and other environmental challenges and to cope with the internal challenges associated with photosynthesis.

In animals, vitamin C synthesis is achieved through a sequence of four enzyme-driven steps, which convert glucose to ascorbic acid. It is carried out either in the kidneys, in reptiles and birds, or the liver, in mammals and perching birds. The last enzyme in the process, l-gulonolactone oxidase, cannot be made by humans because the gene for this enzyme is defective (Pseudogene ΨGULO). The loss of an enzyme concerned with ascorbic acid synthesis has occurred quite frequently in evolution and has affected most fish; many birds; some bats; guinea pigs; and most primates, including humans. The mutations have not been lethal because ascorbic acid is so prevalent in the environement or because oxidative stress is less prevalent in the environment (as for fishes, who are not exposed to high oxygen concentrations).

In addition to those species who lost vitamin C synthesis during evolution, it is worth mentioning the Shionogi rat, which is used in laboratories (much like the guinea pig) to study the inability to produce vitamin C and its consequences.

Evolution

The evolution of all vertebrate species is, in short, the history of how they responded to the "the call for oxygen" -- for "the fire of life". Most important is the need to use this fire without being "burnt" by it. The development of antioxidant machineries is closely intertwined with the development of species. An analysis of the evolutionary record reveals that the aquatic animals which would become amphibians did not significantly increase their concentrations of superoxide dismutase (SOD), the first line of defense against oxygen toxicity, but developed a highly functioning machinery transforming glucose into ascorbic acid, in order to cope with the sharp, 30-fold, increase in oxygen exposure. The further evolution of heavier four-legged animals, from reptiles to mammals, was marked by a gradual increase in superoxide dismutase, which was favoured to the expense of the vitamin C-producing machinery. This trend led, in exceptional cases, to the complete loss of vitamin C production: anthropoideans afforded to do without endogenous vitamin C by living in an environment providing great amounts of this metabolite, and expressed roughly twice the amount of SOD that other mammals express. Amongst those species, Humans have the best SOD defense.

According to the Online Mendeleian Inheritance in Man database, hypoascorbemia is a "public" inborn error of metabolism, as it affects all members of the human race.

It is agreed that the loss of the ability to produce vitamin C, due to a mutation in the L-gulono-gamma-lactone oxidase gene, some 25 to 45 million years ago, occurred because the natural environment of the common ancestor of primates provided great amounts of vitamin C. Primates, who still live in this environment, consume 2000 to 6000 mg of vitamin C per day, which are indeed great amounts, compared to recommended doses for Modern man, which are at least 20 times lower.

The ODS rat

The newly developed model of hypoascorbemia, the Osteogenic Disorder Shionogi rat (ODS rat), provides a unique occasion to analyze the early adaptative changes occuring when a species loses endogenous vitamin C synthesis. Contrary to the long held belief that the high vitamin C intake of early anthropoideans was alone sufficient to compensate for the mutation, ODS rats compensate this metabolic disease through several different mechanisms, some of which are not well characterized yet.

Uric acid

It was noted in 1970 that the inability of Higher primates to break down uric acid, which is due to a mutation in the enzyme uricase, strikingly parallels the well-known metabolic disease of Higher primates. Uric acid and ascorbate are both strong reducing agents (electron-donors). The hypothesis by Proctor that uric acid has taken over some of the functions of ascorbic acid received strong experimental support thirty years later, when it was shown that ODS rats spontaneously develop high plasma uric acid (without the help of a mutation in the uricase gene), amongst many other compensatory mechanisms. In further support of this hypothesis, uric acid was shown to protect different superoxide dismutases against peroxide-mediated inactivation. Hence, uric acid further improves the expression of SODs, that already tend to greater expression with the evolution of heavier animals.

(in progress)

Linus Pauling specified that the machinery for producing vitamin C was a burden that handicapped vitamin C-synthecizing individuals. In times of stress, the synthesis of vitamin C from glycogen can raise sharply: an adult goat, who manufactures more than 13,000 mg of vitamin C per day in normal health, will produce as much as 100,000 mg daily when faced with life-threatening disease, trauma or stress.

When vitamin C-synthecizing species are exposed to high dietary levels of vitamin C, vitamin C concentrations decrease disproportionately in various organs, suggesting that endogenous synthesis of the vitamin is downregulated (it responds by decreasing) and/or that catabolism (destruction) or elimination of the vitamin are increased. Whether this "overreaction", in an environment providing large amounts of vitamin C, contributed to the selection of individuals with low or absent vitamin C synthesis is an open question.

Another possible compensatory mechanism is the synthesis of lipoprotein(a). Lipoprotein(a), which is almost exclusively present in primates, might strengthen the extracellular matrix and compensate to some extent the relative lack of collagen and elastin synthesis. In addition, evidence suggests that, in some circumstances, lp(a), like vitamin C, delays lipid oxidation (peroxidation).

Transport

Vitamin C, being a water soluble molecule that exists as a ion in body fluids (as the ascorbate anion), does not cross lipid-rich membranes easily: it has to follow specific paths through plasma membranes to enter and leave cells. It is thus very important to understand the transport of vitamin C in the different types of cells of the body to comprehend its role in health and disease. When describing the movements of vitamin C in body compartments, two different molecules must be taken into account: vitamin C and dehydroascorbic acid (DHAA; vitamin C which has undergone oxidation).

Active transport requires energy. Two transporters with extreme specificity for vitamin C, sodium-dependent vitamin C transporters 1 and 2 (SVCT1 and SVCT2) have been characterized. Recently, the sodium dependence of the SVCT2 transporter has been questioned. It appears that at least this transporter subtype is calcium/magnesium dependent. Intracellular and extracellular concentrations of both divalent ions thus condition the transport of vitamin C through these transporters. The presence of sodium at a certain threshold makes the SVCT2 transporter more efficient: vitamin C and sodium work cooperatively to achieve a high rate of transport of both molecules. The SVCTs have limited capacities, as they tend to decrease in number the more vitamin C is accumulated in cells, and with increasing concentrations of the vitamin in circulation. The SVCT1 transporters are mostly found in the liver and the kidneys (worthy of note, these are the two sites for vitamin C synthesis in the animal kingdom). The SVCT2 isoform dominates in the brain, skeletal muscles, and the spleen.

A lesser known, but important, mode of transport of vitamin C is exocytosis. In this process, vesicles or "sacs" filled with vitamin C are broken open, so vitamin C can be used to assist in specialized functions of neighboring cells. The secretion of vitamin C appears to be coordinated with the secretion of biologically active polypeptides from various glands, notably the pituitary gland; the metabolism of those polypeptides requires vitamin C as a cofactor (peptidyl-glycine α-amidating mono-oxygenase, vitamin C-requiring).

Facilitated diffusion is the process whereby molecules move from the compartment where there is more of the molecule to the compartment where there is less of it. Facilitated diffusion lets DHAA enter cells, but not vitamin C, and lets vitamin C, but not DHAA, leave cells. The latter process is less understood than the former, but what is certain, however, is that this latter mode of transport is essential in cells which deliver and keep vitamin C in the blood, i.e. the enterocytes (intestinal cells) and renal tubular cells (kidney cells), respectively. Once DHAA has entered a given cell, it is recycled back to vitamin C.

The fact that glucose transporters also transport the glucose derivative DHAA explains a paradoxical finding made my James Lind in his Treatise of the Scurvy:

(Victims of scurvy had) ravaged bodies (but) what was very surprising, the brains of those poor creatures were always sound and entire (...)

It thus appears that the glucose transporters, by transporting oxidized vitamin C, allow important organs to quickly store vitamin C in times of increased oxidative stress. Once dehydroascorbic acid has crossed the blood-brain barrier and is in the brain, it is recycled (reduced) back to vitamin C, and retained in this compartment. Conversely, conditions associated with low insulin, insulin resistance, high glucose and/or inflammation (diabetes, type 1 and 2, trauma, sepsis) impact on DHAA uptake and intracellular vitamin C status (also see Therapeutic uses). Adipocytes, astrocytes, endothelial cells, erythrocytes, granulosa cells, hepatocytes, neutrophils, osteoblasts and smooth muscle cells are known to accumulate DHAA for the accumulation of vitamin C.

Distribution

In the blood

Vitamin C concentrations in the blood generally are between 10 and 160 micromol/L, with values generally not exceeding 80 micromol/L after most meals Oral supplementation can raise levels to 220 micromol/L, while intravenous infusion of the vitamin can raise concentrations to 13 400 micromol/L.

• White blood cells

Leukocytes are cells which use oxidants to destroy microbes. For this reason, they have evolved mechanisms to tolerate great levels of oxidative stress and, notably, transport systems that allow for a quick and ample mobilization of vitamin C (concentrations of the vitamin can reach 50 times those found in the blood). Although lymphocytes are presently used to evaluate the body's need for vitamin C, they are not viewed as especially representative of the needs of organs and tissues (also see The pharmacokinetics debate, below).

In urine and feces

(in progress)

Determining the concentrations of vitamin C in urine and feces (excreta) allows for a basic evaluation of the amounts that were absorbed by the body. It is known, however, that vitamin C-synthecizing species continually urinate vitamin C. The mere urinary excretion of vitamin is a normal part of its metabolism and cannot be taken as a sign of excess consumption. The relationship between the intake of the vitamin and its fecal excretion varies very widely: Cathcart observed that up to 200 grams vitamin C could be tolerated in some diseases (cancer, aids, some viral diseases) and that the varying tolerance of the digestive tract to oral doses of vitamin C could be considered an index of the body's need for antioxidant protection, and for vitamin C in particular. Since the UL for vitamin C is based on gastrointestinal side-effects, the fact that these side-effects frequently appear at levels higher than 2000 mg calls for a revision of the ULs.

In organs and tissues

Some glands, organs and tissues contain 100 times more vitamin C than the blood, including adrenal glands, pituitary gland, thymus, retina, corpus luteum, and various types of neurons.

Adrenal glands

High concentrations of vitamin C are required for the adequate synthesis of catecholamines and steroids in the adrenal gland (adrenal cortex and adrenal medulla). In addition, in response to stress, adrenals secrete vitamin C locally, creating high concentrations acting in a paracrine manner.

Thymus

(in progress)

Corpus luteum

The corpus luteum produces the steroid progesterone, which is required to achieve a normal pregnancy. Different enzymes involved in progesterone synthesis are enhanced by vitamin C at concentrations of 100 micromol/L (in the higher nutritional range). Also see Therapeutic uses - Pregnancy. Conversely, the prostaglandin PGF2, which is known to injure the corpus luteum, increases the secretion of vitamin C by the corpus luteum and its consecutive depletion.

The brain

The brain contains on average 10 times more vitamin C than the blood. Species that are exceptionally tolerant to oxygen deprivation and to reoxygenation concentrate even higher amounts of vitamin C. The fact that the brain has specific mechanisms to accumulate vitamin C (see Transport, above), prompted researchers to investigate the effect of (oxidized, brain transportable) vitamin C on experimental stroke (see Therapeutic uses, below). Conversely, in animal models of diabetes, where blood glucose levels are abnormally high, a drastic inhibition of vitamin C transport to the brain (through its oxidized form) is observed.

• Hippocampus

The hippocampus, which is involved in memory and learning, concentrates more vitamin C than other brain regions. A recent study in an animal model of Alzheimer's disease and dementia showed vitamin C to be a "potent" memory enhancer, especially in aged animals.

• Hypothalamus and the pituitary gland

The hypothalamus concentrates high concentrations of vitamin C using its glial cells (tanycytes), which highly express the specialized transporter SVCT2 (also see Transport, above).

Retina

The retina, like the brain, accumulates high concentrations of vitamin C using GLUT1 glucose transporters, which are distributed on the blood-retinal barrier. An experimental model of diabetes showed vitamin C concentrations in the retina to be drastically reduced by the high concentrations of glucose seen in diabetes, as a result of the competition of glucose with dehydroascorbic acid for entry in the retina (in this study, the transport of DHA was decreased by two thirds).

Food sources

The richest natural sources are fruits and vegetables, and of those, the camu camu fruit , the billygoat plum and the Indian gooseberry or amla (Emblica officinalis) contain the highest concentration of the vitamin (about 30 times the amount found in oranges). It is also present in some cuts of meat, especially liver. Vitamin C as ascorbic acid is the most widely taken nutritional supplement and is available in a variety of forms from tablets and drink mixes to pure ascorbic acid crystals in capsules or as plain powder.

Plants

There exists an enormous difference in vitamin C content between cultivated fruits and fruits found in the wild, especially those that Human's ancestors consumed when they got rid of endogenous capacity. Since vitamin C, in plants like in animals, is used to resist many environmental challenges, it is logical that cultivation, with its associated pest control and controlled environment, lessened the need for endogenous vitamin C production in plants. It is well known that cultivated fruits, although more tasty, are less resistant than wild species.

With the gradual recognition that vitamin C prevents more than the sailor's disease, and in response to the general trends in consumer demands, the biotechnological industry has realized the enormous financial gains that it could expect from creating new, patented, plant species reproducing the capabilities that many natural species already have.

Amongst fruits commonly found on the market, citrus fruits and small fruits (such as strawberries or blueberries) are relatively good sources of vitamin C. The amount of vitamin C in foods of plant origin depends on the variety of the plant, the soil condition and the climate in which it grew, the length of time since it was picked and the storage conditions, and the method of preparation. Cooking in particular is often said to destroy vitamin C — but see Food preparation, below.

Animals

Some cuts of meat are sources of vitamin C for humans. The muscle and fat that make up the modern western diet are, however, poor sources. As with fruit and vegetables, cooking degrades the vitamin C content.

Vitamin C is present in mother's milk and in less amounts in raw cow's milk (but pasteurized milk contains only trace amounts of the vitamin).

Food preparation

Recent observations suggest that the impact of temperature and cooking on vitamin C may have been overestimated, since it decomposes around 190–192°C, well above the boiling point of water:

• Since it is water soluble, vitamin C will strongly leach into the cooking water, but this doesn't necessarily mean the vitamin is destroyed.
• Contrary to what is commonly assumed, it can take much longer than two or three minutes to destroy vitamin C at boiling point.
• Cooking doesn't leach vitamin C in all vegetables at the same rate; for instance, it has been suggested that the vitamin is not destroyed when boiling broccoli. This may be a result of vitamin C leaching into the cooking water at a slower rate from this vegetable.

Consistent with the interaction of vitamin C with copper metals in physiology, pots made with alloys of this metal will destroy the vitamin.

Fresh-cut fruit may not lose much of its nutrients when stored in the refrigerator for a few days.

Supplements

Vitamin C is the most widely taken dietary supplement. It is available in many forms including caplets, tablets, capsules, drink mix packets, in multi-vitamin formulations, in multiple anti-oxidant formulations, as chemically pure crystalline powder, time release versions, and also including bioflavonoids such as quercetin, hesperidin and rutin. Tablet and capsule sizes range from 25 mg to 1500 mg. Vitamin C (ascorbic acid) crystals are typically available in bottles containing 300 g to 1 kg of powder (a teaspoon of vitamin C crystals equals 5,000 mg). Other forms of Vitamin C as sodium ascorbate, magnesium ascorbate, calcium ascorbate, mixed mineral ascorbates (e.g. Na, K, Mg, Ca, Zn), and Ester-C are also available, though less popular.

Vitamin C-enriched teas and infusions are increasingly appearing in markets. If boiling temperatures did indeed destroy vitamin C at the rate that had previously been suggested, using such products would be nonsensical. As note above, boiling is not as potently detrimental to the integrity of the vitamin C as was previously assumed.

History

Vitamin C was first isolated in 1928, and in 1932 it was shown to prevent scurvy. Both Charles Glen King at the University of Pittsburgh and Albert Szent-Györgyi (working with ex-Pittsburgh researcher Joseph Svirbely) came to discover what is now known as vitamin C around April of 1932. Although Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine, many feel King is as responsible for its development.

Recommended daily requirements

The daily requirement of vitamin C can be determined using three different paradigms. As a result, at present, the daily requirement for vitamin C is unclear. To illustrate the situation: the United States and Canada recommend about twice the amount that the World Health Organization recommends. The amount that the WHO suggests is roughly the same as what veterinarians recommend for guinea pigs (but these vitamin C-dependent animals weight only 1 kg on average). The Linus Pauling Institute recommends more than four times the amount that the US and Canada recommend, or ten times what the WHO recommends. However, after the death of Pauling, the Linus Pauling Institute came to diverge from Linus Pauling himself, who recommended doses in the same range as what other primates consume in the wild (also see Biosynthesis, above).

	Guinea pigs	United Kingdom	United States	World Health Organization	Linus Pauling Institute	Vitamin C Foundation	Linus Pauling	Other primates
Daily vitamin C intake (in milligrams)	10-30	40	95	45	400	3000	6000-18000	2000-6000

The antiscorbutic range

Achieving scurvy in humans requires much patience. Although the traditional cafeteria diet provides a convenient basis for the experiment and allows, if some supplementary vitamins and essential fats are provided, for the achievement of very low or undetectable blood vitamin C concentrations, after about 5 weeks, many more weeks are required to finally witness abnormal wound healing. In his experiment on his own self, which is not significantly different from other experimental scurvies, John Crandon, a medical intern, was disappointed to see that vitamin C persisted in his white blood cells until week 11. Only on day 134, did he witnessed the first skin abnormalities, but other symptoms such as fatigue, mental confusion had already appeared. Clearly, minimal concentrations of vitamin C were tenaciously retained in his body. After 6 months on his regime, a sense of imminent death, cooccuring with frank wounding abnormalities, led him to stop the experiment. Ten days of intravenous vitamin C were sufficient to normalize wound healing.

The sailors' disease, which is mostly of historical significance, has little physiological relevance, but remains however the basis of some recommended dietary allowances throughout the world. In 1999, arguing that 10 mg of vitamin C are antiscorbutic, the World Health Organisation and the United Kingdom were recommending 30 mg as a safeguard for most of the population. RDAs have been slightly raised since, but no epistemological shift was undertaken.

In 1974, in the Proceedings of the National Academy of Sciences (USA), Linus Pauling pointed out that amounts of recommended vitamin C in the range of 45 mg per day (for adults) should be renamed Minimum Dietary Allowances to reflect the fact that they were only intended to prevent a deficiency disease. Although this suggestion was not accepted by health authorities, more recent recommandations reflect the notion that vitamin C not only prevents scurvy but contributes to the attainment of the "best of health".

Based on pharmacokinetics

In line with Pauling's suggestion, Mark Levine and colleagues, from the National Institute of Diabetes and Digestive and Kidney diseases (US NIH), pioneered the use of pharmacokinetic studies in order to determine recommended dietary allowances based on physiological requirements. This approach influenced many countries across the world (Japan, Canada, many European countries) and gave solid support to the 5 servings of fruits and vegetables a day recommandation made by the World Health Organization.

In 2004, Pr. Steve Hickey, of the Manchester Metropolitan University, pointed out some limitations in the methodology used by Levine and colleagues and questioned the conclusions inferred from the data. The study by Padayatty, Levine et al. evidenced that subjects could achieve concentrations in the range of 180-220 micromol/L when taking grams of vitamin C throughout the day. The closest living relatives of humans, like our common ancestor, consume 2 to 6 grams of vitamin C a day, in divided doses, evidently. This study thus provided a framework to understand the effects of daily gram amounts of ascorbic acid comparable to those that the ancestor of man took when he could lose the ability to produce vitamin C. A 1.25 gram dose of vitamin C was estimated to raise blood concentrations to 187 micromol/L, or roughly 4.5 times the average level found in the blood of United States citizens. A plateau effect was observed: there was relatively little difference between taking one gram of vitamin C or three (if we assume that bowel tolerance doesn't vary between individuals -- see Transport, above). The larger the doses, the greater the losses, but the data indicated, with a curve of vitamin C concentrations plateauing for a couple of hours after consumption of primate doses of vitamin C, that significantly high blood levels could be maintained during a whole day, if consumption is not limited to a massive single dose, but if this dose is spread during the whole day (as can be expected from a primate species picking vitamin C-rich fruits most of the day, or a species having about 6 periods of food intake, like man).

The authors derived different conclusions from the data. While it is clear, based on the concentration curve, that the blood rise in vitamin C concentrations lasts for a fraction of a day, the researchers recommended a daily allowance from it, without further calculations, arguing that "plasma values return to (...) steady-state concentrations in 24 hours." For this reason, the term recommended daily allowance poses problems: it could be called, more logically but less elegantly, a "recommended 2-hour infradian allowance."

In conclusion, after oral intake, vitamin C concentrations in the blood behave much like those of glucose, from which it is derived (in most other animal species). A continuous exogenous provision of glucose is required to achieved the concentrations desired to sustain common daily activities, and taking a day's portion of glucose all at once in the morning is ill-advised, as it will draw on reserves and cause sickness.

Despite of the pharmacokinetics evidence, single daily doses continue to be applied to replenish vitamin C in disease, with predictably poor results.

The critique is widely publicized, but is met with a mix of skepticism and curiosity : "(we are not) persuaded by the arguments of (...) critics that frequent large doses would necessarily result in substantially greater benefits than earlier trials have demonstrated. (but) we look forward to incorporating such trials when they have been carried out, in future versions of the Cochrane review."] Evidence-based medicine thus cannot resolve the issue, as trials are not conducted. This objection questions the value of several earlier trials and could modify the way metanalyses are conducted (see the Future directions in vitamin C research).

While tradidional evidence-based medicine is confined to review incomplete evidence, single-subject randomized trials, as advocated by Sackett, the founder of evidence-based medicine, can be conducted by physicians at relatively low cost, for the sake of patients.

Hickey also questioned the use of white blood cell saturation as a measure of tissue saturation in the rest of the body on the grounds that those types of cells, due to their higher need for antioxidants, rapidly and massively accumulate vitamin C, and thus couldn't be representative (also see Distribution, above). This critique is not of the utmost importance because Levine & al, by showing that intravenous infusions of vitamin C allow to reach concentrations orders of magnitude higher than what is considered the level of saturation, readily provide a contradiction this hypothetical threshold, as emphacized by Hickey as well.

Despite of the current shortcomings in the pharmacokinetic modelling of vitamin C intake, Levine and Padayatty, using the available data, were able to show that a common way to supplement patients was uneffective and provided false negative results. In a recent study of a combination of Vitamin E and vitamin C for the prevention of the oxidative stress leading to pre-eclampsia, failure to show significant results was attributed to poor methodology and to the absence of a valid endpoint, blood vitamin C: (researchers and commentators) "overlooked a key reason for the lack (of effectiveness) of vitamin C in the prevention of preeclampsia. Because plasma ascorbate concentrations were not reported, we estimated them from known data, the placebo and treatment groups in the study probably had similar plasma and tissue ascorbate concentrations. Doses of 1 g per day have little effect on plasma or intracellular ascorbate concentrations." Although it would be more accurate to say that doses of 1 g per day only have a transient effect on plasma ascorbate concentrations and, in part for this reason, still unknown effects on tissues, Levine and his critics agree on the notion that many earlier trials are of questionable significance and that conclusions have to be revised.

Based on evolutionary biology

The notion that the genome of Man has not evolved as rapidly as his methods to produce food is commonly recognized, in particular in evolutionary biology and evolutionary medicine. The thrifty gene hypothesis is an example of an evolutionary biology theory that is based on the discrepancies between genetic evolution and historical evolution.

As early as 1949, Bourne pointed out the magnitude of the decrease in vitamin C intake that occurred as the human lineage left the environment in which the vitamin C machinery had been lost. Most recent data confirm the initial statements by Bourne, Stone and Pauling that the environment in which vitamin C production was lost provided (and still provides) gram amounts of vitamin C (between 2000 mg and 6000mg).

Stone called hypoascorbemia, the inability to produce vitamin C, an inborn error of metabolism, comparable to lactose intolerance, for example. The Online Mendeleian Inheritance in Man database (National Center for Biotechnology Information) considers this analysis to be valid, and adds that it could be called a "public inborn error of metabolism".

Vitamin C intake recommandations are now set to levels necessary to attain the "best state of physical and mental health,". The international consensus is that increasing fruit and vegetable consumption is an essential part of the prevention and management of chronic diseases (cardiovascular diseases, cancer, diabetes and obesity)

Future research will tell if Bourne, Stone, Pauling and Milton were right to suggest, in Milton's terms, that our closest living relatives "have lessons for us."

Therapeutic uses

Viral diseases

Vitamin C has a very interesting therapeutic index in virus infections. Much like common household products such as sprays, vitamin C kills or inactivates a very broad variety of viruses, including herpes simplex, vaccinia, rabies, herpes zoster (shingles), measles, influenza, foot-and-mouth, hepatitis, rabies, HIV, polio virus and so forth (reviewed in ). Many of the antiviral effects of vitamin C have been demonstrated shortly after the discovery of the molecule, in the 1930's, by Jungeblut.

Vitamin C acts in conjunction with copper (and perhaps other transition metals such as iron) and oxygen to produce hydroxyl radicals, which are the most toxic free radicals. As emphacized above (see Description -- Antioxidant properties of vitamin C), most of the enzymatic and non-enzymatic effects of vitamin C are due to its antioxidant properties, and in particular to its ability to reduce iron and copper. In viruses, transition metal chemistry is not regulated in the same way as in mammalian cells. Concentrations of vitamin C that will lead to viral DNA damage (through copper reduction and subsequent generation of hydroxyl radical from hydrogen peroxide) can be attained in the body through supplementation.

The question is not whether vitamin C is a broad spectrum antiviral, but rather how it should be used to reach this effect. Pharmacokinetics, once again (also see Daily requirements -- Recommendations based on vitamin C pharmacokinetics) are of crucial importance.

(WP content under revision: Ascorbate usage in studies of up to several grams per day, have been associated with decreased cold duration and severity of symptoms, possibly as a result of an antihistamine effect . The highest dose treatments, published clinical results of specific orthomolecular therapy regimes pioneered by Drs. Klenner (repeated IV treatments, 400–700+ (mg/kg)/day [5][6]) and Cathcart (oral use to bowel tolerance, up to ~150 grams ascorbate per day for flu), have remained experimentally unaddressed by conventional medical authorities for decades.

The Vitamin C Foundation recommends an initial usage of up to 8 grams of vitamin C every 20–30 minutes [7] in order to show an effect on the symptoms of a cold infection that is in progress. Most of the studies showing little or no effect employ doses of ascorbate such as 100 mg to 500 mg per day, considered "small" by vitamin C advocates. Equally importantly, the plasma half life of high dose ascorbate is approximately 30 minutes, which implies that most high dose studies have been methodologically defective and would be expected to show a minimum benefit. Clinical studies of divided dose supplementation, predicted on pharmacological grounds to be effective, have only rarely been reported in the literature. Essentially all the claims for high dose vitamin C remain to be scientifically refuted. The clinical effectiveness of large and frequent doses of vitamin C is an open scientific question.

In 2002 a meta-study into all the published research on effectiveness of ascorbic acid in the treatment of infectious disease and toxins was conducted, by Thomas Levy, Medical Director of the Colorado Integrative Medical Centre in Denver. He claimed that evidence exists for its therapeutic role in a wide range of viral infections and for the treatment of snake bites.

Colds A recent 55-study review found little positive effect of a vitamin C intake on common cold at low doses, but indication of prophylaxis benefits at higher doses especially where the subjects were in stressful situations.

At least 29 controlled clinical trials (many double-blind and placebo-controlled) involving a total of over 11,000 participants have been conducted into vitamin C and the Common cold. These trials were reviewed in the 1990s and again more recently. The trials show that vitamin C reduces the duration and severity of colds but not the frequency. The data indicate that there is a normal dose-response relationship. Vitamin C is more effective the higher the dose.

The vast majority of the trials were limited to doses below 1 g/day. As doses rise, it becomes increasingly difficult to keep the trials double blind because of the obvious gastro-intestinal side effects of heavy doses of Vitamin C. So, the most effective trials at doses between 2 and 10 g/day are generally met with skepticism.

The controlled trials and clinical experience prove that vitamin C in doses ranging from 0.1 to 2.0 g/day have a relatively small effect. The duration of colds was reduced by 7% for adults and 15% for children. The studies provide ample justification for businesses to encourage their employees to take 1 to 2 g/day during the cold season to improve workplace productivity and reduce sick days. The clinical reports provide the strongest possible evidence that vitamin C at higher doses is significantly more effective. However, the effectiveness typically comes at the price of gastro-intestinal side effects. It is easy for physicians to minimize these side effects since they cause no lasting harm. Adult patients, however, have proven reluctant to subject themselves to gas and cramping to deliver an unknown benefit (the duration and severity of colds is highly variable so the patient never knows what he/she is warding off). It is well worth the effort of identifying the small subset of individuals who can benefit from high daily doses (>10 g/day) of vitamin C without side effects and training them to regularly take 5 g/day during cold season and to increase the dose at the onset of a cold.

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Hepatitis C virus infection A phase I clinical trial was conducted to determine whether antioxidants could be beneficial in hepatitis C virus infection (HCV infection). This infection leads to a lack of antiviral defenses and to oxidative stress in the liver. Ultimately, oxidative stress, notably lipid-mediated oxidative stress (lipid peroxidation), causes liver cells to degenerate and die. Vitamin C was part of the protocol. The trial yielded favourable changes : normalization of liver enzymes (ALT returned to normal in 44 % of those who had abnormal ALT); decrease in viral load (25 % of patients); tissue changes (36.1 % had improvements histologic parameters); and 58 % of patients saw their quality of life improve with the antioxidant treatment (increase in the SF-36 score). It is impossible, using this trial, to determine the respective contribution of the antioxidants used, and whether changes in dosages and posology could yield better outcomes.

Polio Most notable was Fred R. Klenner, a doctor in general practice in Reidsville, North Carolina. He utilized both oral and intravenous vitamin C to treat a wide range of infections and poisons. He published a paper in 1949 that described how he had seen poliomyelitis yield to vitamin C in sufficiently large doses.[8] No controlled clinical trials have been conducted to confirm effectiveness.[9]

Toxics

Lead

(in progress)

There is also evidence that vitamin C is useful in preventing lead poisoning, possibly helping to chelate the toxic heavy metal from the body. [10]

Common pesticides and contaminants

There exists great concern about the impact of pesticides and other contaminants on the reproductive capabilities on animals, including humans. The toxicity of pesticides and contaminants can occur, notably, through endocrine disruption and/or oxidative stress.

The oxidative toxicity of bisphenol A to the epididymis and its effect on sperm motility and sperm count have been shown to be lessened by vitamin C. The oxidative toxicities of endosulfan, phosphamidon,mancozeb and PCB (Aroclor 1254) were also neutralized by vitamin C. It is important to note that the protective effects occurred irrespective of the chemical structure of the toxics, but rather addressed a common pathway of injury, i.e. oxidative stress, considering the very broad variety of chemical properties of toxics commonly encountered in the environment and in humans.

Medications (reduction of adverse effects)

Reduction of gentamicin nephrotoxicity

Vitamin C has been found to be effective in reducing or protecting against nephrotoxicity caused by the aminoglycoside antibiotic gentamicin.

Heart disease

After a high-fat meal, triglycerides raise and the flow of blood through the arteries is impaired. Two grams of vitamin C largely suppress the impairment in flow-mediated dilatation in people with coronary heart disease as well as in healhty persons. This finding implies that studies on the consumption of vitamin C (and possibly other nutrients and foods) must be reinterpreted in function of the timing of the supplementation and in function of the amount of fat consumed.

(Under revision: Nobel laureate chemist Linus Pauling stated that "chronic scurvy" or "subclinical scurvy" is a condition of vitamin C deficiency which is not as easily noticeable as acute scurvy (because chronic scurvy is mostly internal), characterized by micro lesions of tissues (such as that caused by blood pulsing through arteries, which stretches the arterial walls causing them to tear slightly), due to suboptimal collagen synthesis (see Collagen synthesis, above). Pauling and Rath stated that cardiovascular disease is primarily a collagen defect in the vasculature, and that plaque deposits were consequences. In support of this notion, the Proceedings of the National Academy of Sciences published in 2000 evidence that Shionogi rats (see Biosynthesis, above), a scurvy-prone species like Man, had a tendency to develop damage to the aorta, low HDL cholesterol and high total cholesterol, in a manner akin to typical human heart disease, under suboptimal vitamin C nutriture.

Vitamin C is the main component of the three ingredients in Pauling and Rath's patented preventive cure for Lp(a) related heart disease, the other two being the amino acid lysine and nicotinic acid (a form of Vitamin B3). Lp(a) as an atherosclerotic, evolutionary substitute for ascorbate is still discussed as a hypothesis by mainstream medical science and the Rath-Pauling related protocols have not been rigorously tested and evaluated as conventional medical treatment by the FDA. )

Cancer

Prevention

As noted above, vitamin C at physiologically attainable concentrations limits or suppresses the deleterious effects resulting from oxidative stress of several common contaminants that are involved in the genesis of cancer (see Toxics -- Common pesticides and contaminants).

(in progress)

Lung cancer

A major issue in cancer prevention is lung cancer prevention. 90 % of lung cancers, the world's most common form of cancer, are caused by tobacco. While tobacco cessation campaigns and therapies are logical responses to this major public health issue, the treatment of tobacco addiction, a psychiatric disorder, is still in its infancy, with a success rate of less than 30%. Harm reduction strategies, although seemingly antagonistic in their goals to cessation campaigns and therapies, adress the ultimate issue of cancer prevention, and are likely to have, in this respect, greater success. The cancer-causing mechanism of tobacco, though complex because it involved thousands of carcinogenics, is well characterized. The common pathway to the genesis of lung cancer is considered to be an attack by the oxidant mixture of proteins of lung cells. Vitamin C, at concentrations in the higher physiological range (100 micromol/L), almost totally suppresses these effects in vivo while other antioxidants are uneffective or poorly effective.

As more than 70% of smokers remain unsuccessful in their attempts to stop smoking, even with the help of powerful antidepressants, a fundamental public health issue arises: if smokers are informed that high plasma vitamin C can protect them from the most deleterious effects of smoking, what will be the consequences on public health administrations, who mostly support cessation campaigns and therapies (with less than ideal results)? Obviously any attempt to reduce the harm from tobacco faces great challenges, and active opposition, as evidenced by the fact that no clinical trials have yet beeen conducted to validate an adapted use of vitamin-C rich fruits or supplements for lung cancer chemoprevention, despite of the tantalizing evidence.

(in progress)

Treatment

In 1979 and 1985, two placebo-controlled trials could not show any positive effect of vitamin C in cancer patients, and as a result, caused a marked decline in interest for vitamin C in cancer. Concerning the methodology of those two trials, Mark Levine, chief of molecular and clinical nutrition at the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, declared: "Nobody ever realized the difference between intravenous and oral. It's a huge difference. It's a medical-student, pharmacology 101 kind of error." For the details of the history of the evaluation of vitamin C in cancer, see Sociology and Future research.

In 2005 in vitro (test tube) research by the National Institutes of Health indicated that vitamin C administered in pharmacological concentrations (i.e. intravenous) was preferentially toxic to several strains of cancer cells. The authors noted: "These findings give plausibility to intravenous ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H₂O₂ may be beneficial." This research appeared to support Linus Pauling's claims that vitamin C can be used to fight cancer.

Vitamin C inhibits key pathways in the proliferation of cancer cells as well. The PI3K/AKT pathway is a central mechanism of cancer proliferation that raises intense interest in the field of cancer research. Vitamin C inhibits this pathway in vitro as well as in vivo. The form of vitamin C used to demonstrate these effects is ascorbyl stearate, a lipophilic, vitamin C derivative, which is termed a nutraceutical. Although there is no reason to think that a lipophilic form of vitamin C is better than vitamin C properly administered in accordance with its pharmacokinetics, it can be expected that knowledge about the anticancer role of vitamin C will progress faster with the incentive of developping a "novel" anticancer nutraceutical.

Hypoxia-inducible factor-1 (HIF-1) is another well known protein involved in carcinogenis. Vitamin C inhibits its expression, a fact that lead researchers to challenge the hypothesis that it is the antioxidant and DNA-protective effect of vitamin C that explain its anticancer effects.

In 2006 the Canadian Medical Association Journal published in vivo research that demonstrated that intravenous vitamin C can subdue advanced-stage cancer in humans.

Neurological and psychiatric conditions

Stroke

Vitamin C is transported in its oxidized form (dehydroascorbic acid, DHA) to the brain at a high rate through glucose transporters (also see transport and distribution, above). In a study published in the Proceedings of the National Academy of Sciences, the administration of DHA to experimental models of thromboembolic stroke enhanced blood flow and decreased morbidity and mortality. Considering the lack of safe and accessible treatment for stroke, and because of the greater safety of DHA, which would allow early intervention, the authors concluded that increasing "cerebral levels of ascorbate in stroke has tremendous potential to represent the timely translation of basic research into a relevant therapy for thromboembolic stroke in humans".

Autism

(Explain the role of vit C in catecholamines biosynthesis; comparison with drugs for autism spectrum disorders) One study has shown that vitamin C can help treat behavioral problems associated with autism. While this small double-blind trial performed in 1993 found that 2 grams of vitamin C in divided doses (for 40-pound children; 8 g for 70 kg of weight) had a significant positive effect on behavior in children with autism, it has not been replicated ever since. A recent internet survey found that 30.8% of parents use vitamin C as a therapy for their child with autism., although not necessarily at a dosage replicating the 1993 protocol.

Cataracts

A decrease in lens vitamin C concentrations in the course of cataract progression was shown.

The Jean Mayer USDA Human Nutrition Research Center on Aging showed that, in the Nurses' Health Study cohort, practically all older women who consumed vitamin C supplements for more than 10 years were protected from lense opacities, thus confirming earlier epidemiological evidence on the benefits of vitamin C supplementation in the prevention of cataracts.

While evidence indicates that cataracts could be termed a state of "lens scurvy", researchers tried to discover the effects of disproportionately high vitamin C in the lens (5 to 15 times more vitamin C than normals). The study in rat mutants accumulating grossly supraphysiological lens levels of vitamin C evidences that such an overdose causes lens aging through a Maillard reaction (biological "browning" comparable to the browning of food in gastronomy). The authors, acknowledging the evidence in favour of vitamin C's protective role in humans, concluded that vitamin C was joining "the ranks of those metabolites that are essential for life, such as glucose, fatty acids, and oxygen, but can inflict damage when the cell's defenses are weakened by diabetes, end-stage renal disease, poor nutrition, exposure to UV light, or old age itself." One of the main authors of this study speculated "that quantities above the widely recommended 250 mg/day (as supplements) might have more detrimental than beneficial effects and accelerated (sic) the aging process by the Maillard reaction", without further explanations on how cataract, a disease associated with vitamin C depletion in the lens that is largely prevented by vitamin C supplementation, could become a disease associated with vitamin C supplementation (more than 250 mg per day, or the equivalent of 5 servings of fruits a day). Such wildy speculative conclusions, extrapolated from an irrelevant model of disease, were uttered by a specialist of the Maillard reaction who did not state, in the study's declaration of interest, that he holds a patent for a molecule, pentosidine, that can be used to develop "agents which inhibit the non-enzymatic browning reactions" (Maillard reactions)(also see Bias against vitamin C).

The finding, made in 1998, that cataract is associated with lens vitamin C deficiency received support in 2004. While concentrations of vitamin C in the healhty aqueous humour are between 60 to 85 mg/dL, about 20 to 30 times those found in plasma, they average 4.29 mg/dL in persons suffering from cataract, or 0,06 % of normals. This finding, added to the fact that the transport of the vitamin from the aqueous humour to the lens appears to be rather slow in humans, confirm that the lens is a tissue that benefits high intakes of vitamin C, in complete disagreement with the conclusions derived by Monnier from "Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model."

Obstetrics and gynaecology

(under revision)

Recent studies into the use of a combination of Vitamin E ("natural" source isomer moiety, d-alpha tocopheryl ester) and vitamin C (unspecified ascorbate) in preventing oxidative stress leading to pre-eclampsia have failed to show significant (p=0.05) positive benefit at the dosage tested, Drs. Padayatty and Levine with NIH in a "Letter to the Editor" stated that the studies and another "Letter to the Editor" overlooked a key reason for the lack of vitamin C on the prevention of preeclampsia. Because plasma ascorbate concentrations were not reported, we estimated them from known data, the placebo and treatment groups in the study probably had similar plasma and tissue ascorbate concentrations. Doses of 1 g per day have little effect on plasma or intracellular ascorbate concentrations. In another study the same dosage did decrease average gestational time resulting in a higher incidence of low birthweight babies in one study. Several other studies have been more favorable but large studies into antioxidants for pre-eclampsia are continuing.

Side effects and contraindications

Contraindications A Contraindication is a condition which makes an individual more likely to be harmed by a dose of vitamin C than an average person.

• A primary concern is people with unusual or unaddressed iron overload conditions, including hemochromatosis. Vitamin C enhances iron absorption. If sufferers of iron overload conditions take gram sized doses of vitamin C, they may worsen the iron overload due to enhanced iron absorption.

• Inadequate Glucose-6-phosphate dehydrogenase enzyme (G6PD) levels, a genetic condition, may predispose some individuals to hemolytic anemia after intake of specific oxidizing substances present in some food and drugs. This includes repeated, very large intravenous or oral dosages of vitamin C. There is a test available for G6PD deficiency [11]. High dose of Vitamin E has been proposed as a potential protective factor.

Side-effects

• Vitamin C causes diarrhea if taken in quantities beyond a certain limit, which varies by individual. Cathcart has called this limit the Bowel Tolerance Limit and observed that it is higher in people with serious illness than those in good health. It ranges from 5 to 25 grams per day in healthy individuals to 300 grams per day in the seriously ill people, such as those with AIDS and cancer. The diarrhea side-effect is harmless, though it can be inconvenient. The diarrhea will cease as soon as the dose is reduced.

• Large doses of vitamin C may cause acid indigestion, particularly when taken on an empty stomach. This unpleasant but harmless side-effect can be avoided by taking the vitamin along with meals or by offsetting its acidity by taking an antacid such as baking soda or calcium carbonate.

Toxicity

Vitamin C exhibits remarkably low toxicity. For example, in a rat, the LD50 (the dose that will kill 50% of a population) has been reported as 11900 mg/kg, or, for a 70 kg (155 pound) human, 833 grams of vitamin C would need to be ingested to stand a 50% chance of killing the person. However, as large amounts cause diarrhea and are not absorbed. An extremely large amount of vitamin C would need to be rapidly injected by IV to stand any chance of killing a person. Robert Cathcart, MD, has used intravenous doses of vitamin C of 250 grams and reports that he has had no problems. The Council for Responsible Nutrition has set an Upper Level (UL) of 2 grams, based on transient diarrhea. Their publication on vitamin C safety notes that

“

...very large doses of vitamin C have been taken daily over the course of many years, and only minor undesirable effects have been attributed with any certainty to the vitamin’s use[...] Clearly, vitamin C has a low order of toxicity.

”

Harmful effects

Reports of harmful effects of vitamin C tend to receive prominent media coverage. As such, these reports tend to generate much debate and more research into vitamin C. Some of the harmful effects described below were proven invalid in later studies, while other effects are still being analyzed.

• In April 1998, the journal Nature reported alleged carcinogenic and teratogenic effects of excessive doses of vitamin C. The effects were noted in test tube experiments and on only two of the 20 markers of free radical damage to DNA. These results have not been observed in living organisms.

• The authors of the "Nature" study later clarified their position, stating that their results "show a definite increase in 8-oxoadenine after supplementation with vitamin C. This lesion is at least ten times less mutagenic than 8-oxoguanine, and hence our study shows an overall profound protective effect of this vitamin".

• In April 2000, University of Southern California researchers reported a thickening of the arteries of the neck in persons taking high vitamin C doses. It was later pointed out by vitamin C advocates that this can be explained by vitamin C's collagen synthesising role leading to thicker and stronger artery walls. (ref. para 10)

• In June 2004, Duke University researchers reported an increased susceptibility to osteo-arthritis in guinea pigs fed a diet high in vitamin C. However, a 2003 study at Umeå University in Sweden, found that "the plasma levels of vitamin C, retinol and uric acid were inversely correlated to variables related to rheumatoid arthritis disease activity."

• A speculated increased risk of kidney stones may be a side effect of taking vitamin C in larger than normal amounts (>1 g). The potential mechanism of action is through the metabolism of vitamin C (ascorbic acid) to dehydroascorbic acid, which is then metabolized to oxalic acid, a known constituent of kidney stones. However, this oxalate issue is still controversial, with evidence being presented for and against the possibility of this side effect. Vitamin C has long been advocated, and used, by some less conventional physicians to prevent or alleviate some kinds of non-oxalate kidney stone formation. after addressing the oxalate issue. Vitamin B6 may mitigate the general risk of oxalate stones by decreasing oxalate production. Additionally, thiamine may inhibit oxalate formation. Furthermore, correcting any magnesium deficiency may decrease the risk of kidney stones by decreasing oxalate crystallization. Increasing one's fluid intake also helps to prevent oxalate crystallization in the kidney. There is evidence that certain intestinal flora influence how much oxalate is destroyed and that their absence is a significant causal risk factor in oxalate stone formers. Patients with a predispostion to form oxalate stones or those on hemodialysis are usually advised to avoid excess use of vitamin C. The most recent data lead to conclude that vitamin C is safe for hemodialysis patients, and trials are awaited to firmly establish this conclusion, since the management of the anemia associated with hemodyalisis is improved by vitamin C.

• "Rebound scurvy" is a theoretical, never observed, condition that could occur when daily intake of vitamin C is rapidly reduced from a very large amount to a relatively low amount. Advocates suggest this is an exaggeration of the rebound effect which occurs because ascorbate-dependent enzyme reactions continue for 24–48 hours after intake is lowered, and use up vitamin C which is not being replenished. The effect is to lower one's serum vitamin C blood concentration to less than normal for a short amount of time. During this period of time there is a slight risk of cold or flu infection through reduced resistance. Within a couple of days the enzyme reactions shut down and blood serum returns to the normal level of someone not taking large supplements. This is not scurvy, which takes weeks of zero vitamin C consumption to produce symptoms. It is something people who take large vitamin C supplements need to be aware of in order to gradually reduce dosage rather than quit taking vitamin C suddenly. (ref. para 4) This is a theoretical risk for those taking supplements, e.g., if they find themselves severely ill, and in a hospital without the supplements, at a time when they need normal or better levels of vitamin C to fight the disease (ref. and search for "The major problem"). At this time, many doctors and hospital staff do not know much about nor administer megadosing of supplements, so that patients may have to rely on friends or relatives to bring them their supplements.

• Some writers have identified a theoretical risk of poor copper absorption from high doses of vitamin C, although little experimental evidence supports this. However, ceruloplasmin levels seem specifically lowered by high vitamin C intake. In one study, 600 milligrams of vitamin C daily did not decrease copper absorption or overall body copper status in young men, but led to lower ceruloplasmin levels similar to those caused by copper deficiency. In another, ceruloplasmin levels were significantly reduced.

• There are stories circulating among some folk remedy proponents that doses of around 12 grams per day of vitamin C can induce an abortion in women under 4 weeks of pregnancy. This is not supported by scientific research however.

Conflicts with prescription drugs

Pharmaceuticals designed to reduce stomach acid such as the proton pump inhibitors (PPIs), are among the most widely-sold drugs in the world. One PPI, omeprazole, has been found to lower the bioavailability of vitamin C by 12%, independent of dietary intake. This means that one would have to consume 14% more vitamin C to counteract the use of 40 mg/day of omeprazole. The probable mechanism of vitamin C reduction, intragastric pH elevated into alkalinity, would apply to all other PPI drugs, though not necessarily to doses of PPIs low enough to keep the stomach slightly acidic.

Sociology

To fully comprehend the special perception that vitamin C enjoys, we must understand the role of Linus Pauling, one of the principle founders of modern chemistry, in the dissemination and popularization of information about this molecule.

Pauling, a two-time Nobel Prize winner who had received worldwide praise for his work on a common metabolic disease, sickle cell anemia, struggled for the recognition of an even more common metabolic disease, which was termed by OMIM our "public inborn error of metabolism." The response of the medical profession, by Pauling's account, was "astonishing." From being perhaps the major figure in modern chemistry, Pauling suddenly became, in the eyes of some, little more than a well-meaning but misguided eccentric or even a quack. Meanwhile, masses began to follow Pauling's advice in what became one of the most important movements of citizen science; when asked how to assess the value of the safety warnings and the skeptical responses issued by medical authorities, he responded: "I would trust the biochemistry of a goat over the advice of a doctor."

Goodwin and Tangum draw an interesting analogy with another case in the history of science. Based on the analysis by Giorgio de Santillana of Galileo's impact in XVIIth century Italy, Goodwin and Tangum proposed to their fellow doctors, in American Medical Association's Archives of Internal Medicine, that Pauling's crime, like Galileo's, was not so much that he proposed a new paradigm, but that he proposed it directly to the people. Pauling, by speaking to the population, just like he did when he fought to stop nuclear bomb trials (his success led him to receive his second Nobel Prize), committed the same crime as Galileo, who had chosen to write in the language of the masses (Italian), and who had to face the ire of the "scholarly elite, whom he had bypassed, usurped, and rendered irrelevant". They comment:

Of course, (speaking directly to the public) was precisely the course followed by many of the proponents of the benefits of micronutrients, the most famous of whom was Linus Pauling, the chemist who intruded into clinical matters. It is instructive to reread the review articles and editorials published in the 1970s ridiculing and condemning the ideas of Pauling. He was treated as a dangerous enemy, although a few years before his death, like Galileo, he was rehabilitated to the status of a genius with controversial ideas.

In effect, Pauling initiated one of the most significant critiques of the medical institution, perhaps even greater than Ivan Illich's critique.

By his own admission, Pauling's impetus was to communicate, as an educated citizen, the knowledge amassed by Irwin Stone, Abram Hoffer, Frederick Klenner and others before him. Pauling's "telescope" was his ability to read the literature that had been ignored by what could be called the pathocentric paradigm.

In the preface of The Healing Factor, Vitamin C Against Disease, Stone's main opus, Pauling summarized:

As man has spread over the earth and increased in number, the supplies of ascorbic acid have decreased. It is possible that most people in the world receive only one or two percent of the amounts of ascorbic acid that would keep them in the best of health. The resulting hypoascorbemia may be responsible for many of the illnesses that plague mankind.

to what Albert Szent-Gyorgyi, the discoverer of vitamin C, added:

The medical profession itself took a very narrow and wrong view. Lack of ascorbic acid caused scurvy, so if there was no scurvy there was no lack of ascorbic acid. Nothing could be clearer than this. The only trouble was that scurvy is not a first symptom of lack but a final collapse, a premortal syndrome, and there is a very wide gap between scurvy and full health. But nobody knows what full health is! This could be found out by wide statistical studies, but there is no organization which could and would arrange such studies.

While the debate about the most "luminously controversial of all biological, alternative cancer therapies" is slowly resolving, and as Pauling is regaining his reputation, the philosophical questions raised by the Nobel laureates, that every Human may ask, remain largely unadressed: where is man coming from? what is health?

Consecration of amateurism is vitamin C research

The history of vitamin C research provides remarkable examples of amateursim. A few years after the discovery of vitamin C, Jungeblut provided evidence that it had remarkable antiviral activity, notably against the poliomyelitis virus. Sabin, who later developed the famous vaccine against polio, attempted to replicate the studies but failed to replicate them, despite of the careful and detailed instructions provided by Jungeblut. It was interpreted as a therapeutic failure of vitamin C by other incompent researchers and physicians. Jungeblut is still remembered by specialists as an authoritative source on the antiviral activity of vitamin C, while Sabin is not. Evidence-based medicine and the randomized controlled trial were promoted as means to free clinical practice from the empire of opinion. History shows that, in the case of vitamin C, the remedy was worse than the disease. Moertel, whose mission was to combat "uncontrolled quackery", was unable, and, according to Pauling, who tried to help him, unwilling to replicate the study. Whether Moertel's amateurism was deliberate or not, it had the effect of providing a tool to other amateurs who fought against quackery, "crude EBM practitioners (going) about using their favorite RCTs as clubs with which to beat up their supposedly less-informed colleagues." Still today, randomized controlled trials of controversial methodology abound, and allow "crude EBM practicioners" chasing quackery and self-medication to "avoid blame by wrapping themselves in the EBM mantle." Scientific criticisms based on strong pharmacokinetic evidence are responded to with non-scientific non-arguments ("(we are not) persuaded by the arguments of (...) critics that frequent large doses would necessarily result in substantially greater benefits"): in a paradoxical turn of events, the very behaviour that EBM was intended to minimize, guess work, is magnified and swiftly transmitted to the mass media as uncorruptible truth emanating from the golden standard of biomedical sciences.

The mass media, in turn, shape the opinion of the only stakeholders in vitamin C research, the citizens, who gradually cease to reclaim more research and abdicate to private interests the duty to determine what is best for them. And, since "the large quantities of trial data required to meet the standards of evidence based medicine are available for relatively few interventions" this restrictive or "crude" version of evidence-based medicine" does "introduce a systematic bias, resulting in allocation of resources to those treatments for which there is rigorous evidence of effectiveness, or towards those for which there are funds available to show effectiveness (such as new pharmaceutical agents)." and "impinges on the ethical principle of justice."

Citizens, philosophers of sciences and ethicists have been called to duty in the struggle for accountability in biomedical sciences. The contestation of EBM, which is reaching unprecendented intensity, is increasingly involving citizens and expert patients, as well as doctors who decide to publicly express their fear that "the next generation of doctors (is) being conditioned to function like a well-programmed computer that operates within a strict binary framework".

Future research

As noted above (see Therapeutic uses, Cancer), the study of vitamin C pharmacokinetics not only triggered changes in the recommended dietary allowance of this vitamin, but it also raised interest in the cancer-killing properties of the molecule when it is administered intravenously. Once again, however, a closer look at the past will allow to open "new" (forgotten) therapeutic perspectives. Levine declared, "Nobody ever realized the difference between intravenous and oral. It's a huge difference. It's a medical-student, pharmacology 101 kind of error" and underlined that it was justified to reopen the case about vitamin C in cancer because we are now aware of this "pharmacology 101 kind of error" that Pauling and Moertel altogether had committed.

However, a co-author of the same pharmacokinetic study disagrees: although Levine does not question the quality of the Mayo clinic study (and questions the value of Pauling and Cameron's study), Hugh Riordan declares the opposite: "The Mayo Clinic studies were done with the accepted experimental design used to clarify initial observations but did not truly replicate the Cameron and Pauling studies (used a lesser dosage,less time). This issue has been reviewed elsewhere (note: in Richardson, 1987 )." In other words, Riordan co-signed a government-funded research where it is said that Pauling and Moertel were both wrong and that oral vitamin C is uneffective, but declares in another journal, with different co-authors and independently (practically at the same time), that oral administration is not wrong per se, but that Mayo clinic's studies were, and refers to the famous sociological inquiry by Richardson published 15 years before to justify his claim. Manifestly, self-medication with (oral) vitamin C remains a politically sensitive issue.

Independent meta-analyses

The majority or trials with vitamin C use doses that are inferior to primate doses (less than a few grams, often a gram or less) and do not follow the proper dosing schedule (one or two admnistrations a day). Nonetheless, those are called trials of "high doses" because, from an anthropocentric and medicocentric point of view, these are doses that can only be afforded by the self-medicating populace -- galvanized by Pauling and his followers. Independent researchers will interpret the data for what they are worth, and take trials by Cathcart, Klenner, and others as the best currently available evidence. The fact that these authors were not made popular by the medico-academic industrial complex, is an interesting sociopolitical consideration, but it is not relevant in the assessment of vitamin C's therapeutic value. The advent of open access journals and, of course, authoritative online resources such as the Citizendium, allow researchers to bypass the taboos imposed by publishing conglomerates where conflict of interests, by their own admission, is the rule rather than the exception. It is interesting to note that the critique of the most recent meta-analyses on vitamin C in the common cold has entered the scientific discourse by the door of a PLoS (Public Library of Sciences) journal. Steve Hickey later blowed the whistle about the fact that the Journal of Orthomolecular Medicine, where Pauling and others published, is still rejected from the National Library of Medicine database, PubMed, with no valid explanations given by the referees of the database (ref,ref).

Neglected diseases and publications

The clinical and investigative works of Cathcart, Klenner, Jungeblut were made in a context of scarcity of resources that is not unlike the context in which the majority of clinicians throughout the world perform their work. The open access movement in sciences is viewed as an opportunity for clinicians and researchers to enter the scientific discourse by bypassing the systematic bias favouring the research agendas of developed countries(ref). A major part of the world's burden of disease and of world's mortality is represented by infant deaths. Multitudes of clinicians and researchers from the Third World and other poorer countries will be interested to know how Frederick Klenner was able to achieve an exceptional record in this respect (ref + cf obstetrics and gynaecology), in a context quite similar to present-day Africa and Asia -- in the post-segregationist United States.

In less favoured countries, the fear that the population could follow Pauling and colleagues and self-medicate with vitamin C is inexistant. While the myth that gram amounts of vitamin C are "megadoses" can be perpetuated in Northern countries where vitamin-C rich fruits are less common (worthy of note, rose hips, contain 20 times more vitamin C than commonly available fruits), in Southern Countries, fruits that provide such primate doses of vitamin C can be easily accessed. For instance, in Brazil, the nutritional data of a popular and affordable juice indicates a content of vitamin C equivalent to 15720 % of the RDA per bottle (3144 % of the RDA per 100 ml) (see photograph -- coming soon).