Vitamin C

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Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription dietary supplement. As a therapy, it is used to prevent and treat scurvy, a disease caused by vitamin C deficiency.

Vitamin C is an essential nutrient involved in the repair of tissue, the formation of collagen, and the enzymatic production of certain neurotransmitters. It is required for the functioning of several enzymes and is important for immune system function.[1] It also functions as an antioxidant. Vitamin C may be taken by mouth or by intramuscular, subcutaneous or intravenous injection. Various health claims exist on the basis that moderate vitamin C deficiency increases disease risk, such as for the common cold, cancer or COVID-19. There are also claims of benefits from vitamin C supplementation in excess of the recommended dietary intake for people who are not considered vitamin C deficient. Vitamin C is generally well-tolerated. Large doses may cause gastrointestinal discomfort, headache, trouble sleeping, and flushing of the skin. The United States Institute of Medicine recommends against consuming large amounts.[2](pp155-165)

Most animals are able to synthesize their own vitamin C. However, apes (including humans) and monkeys (but not all primates), most bats, most fish, some rodents, and certain other animals must acquire it from dietary sources because a gene for a synthesis enzyme has mutations that render it dysfunctional.

Vitamin C was discovered in 1912, isolated in 1928, and in 1933, was the first vitamin to be chemically produced. Partly for its discovery, Albert Szent-Györgyi was awarded the 1937 Nobel Prize in Physiology or Medicine.

Chemistry[edit]

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The name "vitamin C" always refers to the [[Enantiomer|Template:Sm-enantiomer]] of ascorbic acid and its oxidized form, dehydroascorbate (DHA). Therefore, unless written otherwise, "ascorbate" and "ascorbic acid" refer in the nutritional literature to Template:Sm-ascorbate and Template:Sm-ascorbic acid respectively. Ascorbic acid is a weak sugar acid structurally related to glucose. In biological systems, ascorbic acid can be found only at low pH, but in solutions above pH 5 is predominantly found in the ionized form, ascorbate.[3]

Numerous analytical methods have been developed for ascorbic acid detection. For example, vitamin C content of a food sample such as fruit juice can be calculated by measuring the volume of the sample required to decolorize a solution of dichlorophenolindophenol (DCPIP) and then calibrating the results by comparison with a known concentration of vitamin C.[4][5]

Deficiency[edit]

Plasma vitamin C is the most widely applied test for vitamin C status.[3] Adequate levels are defined as near 50 μmol/L. Hypovitaminosis of vitamin C is defined as less than 23 μmol/L, and deficiency as less than 11.4 μmol/L.[6] For people 20 years of age or above, data from the US 2017-18 National Health and Nutrition Examination Survey showed mean serum concentrations of 53.4  μmol/L. The percent of people reported as deficient was 5.9%.[7] Globally, vitamin C deficiency is common in low and middle-income countries, and not uncommon in high income countries. In the latter, prevalence is higher in males than in females.[8]

Plasma levels are considered saturated at about 65 μmol/L, achieved by intakes of 100 to 200 mg/day, which are well above the recommended intakes. Even higher oral intake does not further raise plasma nor tissue concentrations because absorption efficiency decreases and any excess that is absorbed is excreted in urine.[3]

Diagnostic testing[edit]

Vitamin C content in plasma is used to determine vitamin status. For research purposes, concentrations can be assessed in leukocytes and tissues, which are normally maintained at an order of magnitude higher than in plasma via an energy-dependent transport system, depleted slower than plasma concentrations during dietary deficiency and restored faster during dietary repletion,[2](pp103-109) but these analysis are difficult to measure, and hence not part of standard diagnostic testing.[3][9]

Diet[edit]

Recommended consumption[edit]

Recommendations for vitamin C intake by adults have been set by various national agencies:

US vitamin C recommendations (mg per day)[2](pp134-152)
RDA (children ages 1–3 years) 15
RDA (children ages 4–8 years) 25
RDA (children ages 9–13 years) 45
RDA (girls ages 14–18 years) 65
RDA (boys ages 14–18 years) 75
RDA (adult female) 75
RDA (adult male) 90
RDA (pregnancy) 85
RDA (lactation) 120
UL (adult female) 2,000
UL (adult male) 2,000

In 2000, the chapter on Vitamin C in the North American Dietary Reference Intake was updated to give the Recommended Dietary Allowance (RDA) as 90 milligrams per day for adult men, 75 mg/day for adult women, and setting a Tolerable upper intake level (UL) for adults of 2,000 mg/day.[2](pp134-152) The table (right) shows RDAs for the United States and Canada for children, and for pregnant and lactating women,[2](pp134-152) as well as the ULs for adults.

For the European Union, the EFSA set higher recommendations for adults, and also for children: 20 mg/day for ages 1–3, 30 mg/day for ages 4–6, 45 mg/day for ages 7–10, 70 mg/day for ages 11–14, 100 mg/day for males ages 15–17, 90 mg/day for females ages 15–17. For pregnancy 100 mg/day; for lactation 155 mg/day.[15]

Cigarette smokers and people exposed to secondhand smoke have lower serum vitamin C levels than nonsmokers.[6] The thinking is that inhalation of smoke causes oxidative damage, depleting this antioxidant vitamin.[2](pp152-153) The US Institute of Medicine estimated that smokers need 35 mg more vitamin C per day than nonsmokers, but did not formally establish a higher RDA for smokers.[2](pp152-153) An inverse relationship between vitamin C intake and lung cancer was observed, although the conculsion was that more research is needed to confirm this observation.[16]

The US National Center for Health Statistics conducts biannual National Health and Nutrition Examination Survey (NHANES) to assess the health and nutritional status of adults and children in the United States. Some results are reported as What We Eat In America. The 2013–2014 survey reported that for adults ages 20 years and older, men consumed on average 83.3 mg/d and women 75.1 mg/d. This means that half the women and more than half the men are not consuming the RDA for vitamin C.[17] The same survey stated that about 30% of adults reported they consumed a vitamin C dietary supplement or a multi-vitamin/mineral supplement that included vitamin C, and that for these people total consumption was between 300 and 400 mg/d.[18]

Tolerable upper intake level[edit]

In 2000, the Institute of Medicine of the US National Academy of Sciences set a Tolerable upper intake level (UL) for adults of 2,000 mg/day. The amount was chosen because human trials had reported diarrhea and other gastrointestinal disturbances at intakes of greater than 3,000 mg/day. This was the Lowest-Observed-Adverse-Effect Level (LOAEL), meaning that other adverse effects were observed at even higher intakes. ULs are progressively lower for younger and younger children.[2](pp155-165) In 2006, the European Food Safety Authority (EFSA) also pointed out the disturbances at that dose level, but reached the conclusion that there was not sufficient evidence to set a UL for vitamin C,[19] as did the Japan National Institute of Health and Nutrition in 2010.[14]

Food labeling[edit]

For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin C labeling purposes, 100% of the Daily Value was 60 mg, but as of May 27, 2016, it was revised to 90 mg to bring it into agreement with the RDA.[20][21] A table of the old and new adult daily values is provided at Reference Daily Intake.

European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of Daily Values, amounts are shown as percent of Reference Intakes (RIs). For vitamin C, 100% RI was set at 80 mg in 2011.[22]

Sources[edit]

Although also present in other plant-derived foods, the richest natural sources of vitamin C are fruits and vegetables.[23][1] Vitamin C is the most widely taken dietary supplement.[1]

Plant sources[edit]

Lua error in Module:Hatnote_list at line 44: attempt to call field 'formatPages' (a nil value). The following table is approximate and shows the relative abundance in different raw plant sources.[23][1][24] The amount is given in milligrams per 100 grams of the edible portion of the fruit or vegetable:

Raw plant source[25] Amount
(mg / 100g)
Kakadu plum 1000–5300[26]
Camu camu 2800[27]
Acerola 1677[28]
Indian gooseberry 445[29][30]
Rose hip 426
Common sea-buckthorn 400[31]
Guava 228
Blackcurrant 200
Yellow bell pepper/capsicum 183
Red bell pepper/capsicum 128
Kale 120
Broccoli 90
Kiwifruit 90
Raw plant source[25] Amount
(mg / 100g)
Green bell pepper/capsicum 80
Brussels sprouts 80
Loganberry, redcurrant 80
Cloudberry, elderberry 60
Strawberry 60
Papaya 60
Orange, lemon 53
Cauliflower 48
Pineapple 48
Cantaloupe 40
Passion fruit, raspberry 30
Grapefruit, lime 30
Cabbage, spinach 30
Raw plant source[25] Amount
(mg / 100g)
Mango 28
Blackberry, cassava 21
Potato 20
Honeydew melon 20
Tomato 14
Cranberry 13
Blueberry, grape 10
Apricot, plum, watermelon 10
Avocado 8.8
Onion 7.4
Cherry, peach 7
Apple 6
Carrot, asparagus 6

Animal sources[edit]

Compared to plant sources, animal-sourced foods do not provide so great an amount of vitamin C, and what there is, is largely destroyed by the heat used when it is cooked. For example, raw chicken liver contains 17.9 mg/100 g, but fried, the content is reduced to 2.7 mg/100 g. Vitamin C is present in human breast milk at 5.0 mg/100 g. Cow's milk contains 1.0 mg/100 g, but the heat of pasteurization destroys it.[32]

Food preparation[edit]

Vitamin C chemically decomposes under certain conditions, many of which may occur during the cooking of food. Vitamin C concentrations in various food substances decrease with time in proportion to the temperature at which they are stored.[33] Cooking can reduce the vitamin C content of vegetables by around 60%, possibly due to increased enzymatic destruction.[34] Longer cooking times may add to this effect.[35] Another cause of vitamin C loss from food is leaching, which transfers vitamin C to the cooking water, which is decanted and not consumed.[36]

Supplements[edit]

Vitamin C dietary supplements are available as tablets, capsules, drink mix packets, in multi-vitamin/mineral formulations, in antioxidant formulations, and as crystalline powder.[37] Vitamin C is also added to some fruit juices and juice drinks. Tablet and capsule content ranges from 25 mg to 1500 mg per serving. The most commonly used supplement compounds are ascorbic acid, sodium ascorbate and calcium ascorbate.[37] Vitamin C molecules can also be bound to the fatty acid palmitate, creating ascorbyl palmitate, or else incorporated into liposomes.[38]

Food fortification[edit]

Countries fortify foods with nutrients to address known deficiencies.[39] While many countries mandate or have voluntary programs to fortify wheat flour, maize (corn) flour or rice with vitamins,[40] none include vitamin C in those programs.[40] As described in Vitamin C Fortification of Food Aid Commodities (1997), the United States provides rations to international food relief programs, later under the asupices of the Food for Peace Act and the Bureau for Humanitarian Assistance.[41] Vitamin C is added to corn-soy blend and wheat-soy blend products at 40 mg/100 grams. (along with minerals and other vitamins). Supplemental rations of these highly fortified, blended foods are provided to refugees and displaced persons in camps and to beneficiaries of development feeding programs that are targeted largely toward mothers and children.[36] The report adds: "The stability of vitamin C (L-ascorbic acid) is of concern because this is one of the most labile vitamins in foods. Its main loss during processing and storage is from oxidation, which is accelerated by light, oxygen, heat, increased pH, high moisture content (water activity), and the presence of copper or ferrous salts. To reduce oxidation, the vitamin C used in commodity fortification is coated with ethyl cellulose (2.5 percent). Oxidative losses also occur during food processing and preparation, and additional vitamin C may be lost if it dissolves into cooking liquid and is then discarded."[36]

Food preservation additive[edit]

Ascorbic acid and some of its salts and esters are common additives added to various foods, such as canned fruits, mostly to slow oxidation and enzymatic browning.[42] It may be used as a flour treatment agent used in breadmaking.[43] As food additives, they are assigned E numbers, with safety assessment and approval the responsibility of the European Food Safety Authority.[44] The relevant E numbers are:

  1. E300 ascorbic acid (approved for use as a food additive in the UK,[45] US[46] Canada,[47] Australia and New Zealand[48])
  2. E301 sodium ascorbate (approved for use as a food additive in the UK,[45] US,[49] Canada,[47] Australia and New Zealand[48])
  3. E302 calcium ascorbate (approved for use as a food additive in the UK,[45] US[46] Canada,[47] Australia and New Zealand[48])
  4. E303 potassium ascorbate (approved in Australia and New Zealand,[48] but not in the UK, US or Canada)
  5. E304 fatty acid esters of ascorbic acid such as ascorbyl palmitate (approved for use as a food additive in the UK,[45] US,[46] Canada,[47] Australia and New Zealand[48])

The stereoisomers of Vitamin C have a similar effect in food despite their lack of efficacy in humans. They include erythorbic acid and its sodium salt (E315, E316).[45]

Pharmacology[edit]

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Pharmacodynamics is the study of how the drug – in this instance vitamin C – affects the organism, whereas pharmacokinetics is the study of how an organism affects the drug.

Pharmacodynamics[edit]

Pharmacodynamics includes enzymes for which vitamin C is a cofactor, with function potentially compromised in a deficiency state, and any enzyme cofactor or other physiological function affected by administration of vitamin C, orally or injected, in excess of normal requirements. At normal physiological concentrations, vitamin C serves as an enzyme substrate or cofactor and an electron donor antioxidant. The enzymatic functions include the synthesis of collagen, carnitine, and neurotransmitters; the synthesis and catabolism of tyrosine; and the metabolism of microsomes. In nonenzymatic functions it acts as a reducing agent, donating electrons to oxidized molecules and preventing oxidation in order to keep iron and copper atoms in their reduced states.[3] At non-physiological concentrations achieved by intravenous dosing, vitamin C may function as a pro-oxidant, with therapeutic toxicity against cancer cells.[50][51]

Vitamin C functions as a cofactor for the following enzymes:[3]

As an antioxidant, ascorbate scavenges reactive oxygen and nitrogen compounds, thus neutralizing the potential tissue damage of these free radical compounds. Dehydroascorbate, the oxidized form, is then recycled back to ascorbate by endogenous antioxidants such as glutathione.[2](pp98-99) In the eye, ascorbate is thought to protect against photolytically generated free-radical damage; higher plasma ascorbate is associated with lower risk of cateracts.[52] Ascorbate may also provide antioxidant protection indirectly by regenerating other biological antioxidants such as α-tocopherol back to an active state.[2](pp98-99) In addition, ascorbate also functions as a non-enzymatic reducing agent for mixed-function oxidases in the microsomal drug-metabolizing system that inactivates a wide variety of substrates such as drugs and environmental carcinogens.[2](pp98-99)

Pharmacokinetics[edit]

Ascorbic acid is absorbed in the body by both simple diffusion and active transport.[53] Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1,000 mg/day, absorption falls to less than 50% as the active transport system becomes saturated.[23] Active transport is managed by Sodium-Ascorbate Co-Transporter proteins (SVCTs) and Hexose Transporter proteins (GLUTs). SVCT1 and SVCT2 import ascorbate across plasma membranes.[54] The Hexose Transporter proteins GLUT1, GLUT3 and GLUT4 transfer only the oxydized dehydroascorbic acid (DHA) form of vitamin C.[55][56] The amount of DHA found in plasma and tissues under normal conditions is low, as cells rapidly reduce DHA to ascorbate.[57]

SVCTs are the predominant system for vitamin C transport within the body.[54] In both vitamin C synthesizers (example: rat) and non-synthesizers (example: human) cells maintain ascorbic acid concentrations much higher than the approximately 50 micromoles/liter (µmol/L) found in plasma. For example, the ascorbic acid content of pituitary and adrenal glands can exceed 2,000 µmol/L, and muscle is at 200–300 µmol/L.[58] The known coenzymatic functions of ascorbic acid do not require such high concentrations, so there may be other, as yet unknown functions. A consequence of all this high concentration organ content is that plasma vitamin C is not a good indicator of whole-body status, and people may vary in the amount of time needed to show symptoms of deficiency when consuming a diet very low in vitamin C.[58]

Excretion (via urine) is as ascorbic acid and metabolites. The fraction that is excreted as unmetabolized ascorbic acid increases as intake increases. In addition, ascorbic acid converts (reversibly) to DHA and from that compound non-reversibly to 2,3-diketogulonate and then oxalate. These three metabolites are also excreted via urine. During times of low dietary intake, vitamin C is reabsorbed by the kidneys rather than excreted. This salvage process delays onset of deficiency. Humans are better than guinea pigs at converting DHA back to ascorbate, and thus take much longer to become vitamin C deficient.[3][56]

Synthesis[edit]

Most animals and plants are able to synthesize vitamin C through a sequence of enzyme-driven steps, which convert monosaccharides to vitamin C. Yeasts do not make Template:Sm-ascorbic acid but rather its stereoisomer, erythorbic acid.[59] In plants, synthesis is accomplished through the conversion of mannose or galactose to ascorbic acid.[60][61] In animals, the starting material is glucose. In some species that synthesize ascorbate in the liver (including mammals and perching birds), the glucose is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process.[62] In humans and in animals that cannot synthesize vitamin C, the enzyme [[gulonolactone oxidase|Template:Sm-gulonolactone oxidase]] (GULO), which catalyzes the last step in the biosynthesis, is highly mutated and non-functional.[63][64][65][66]

Animal synthesis[edit]

There is some information on serum vitamin C concentrations maintained in animal species that are able to synthesize vitamin C. One study of several breeds of dogs reported an average of 35.9 μmol/L.[67] A report on goats, sheep and cattle reported ranges of 100–110, 265–270 and 160–350 μmol/L, respectively.[68]

The biosynthesis of ascorbic acid in vertebrates starts with the formation of UDP-glucuronic acid. UDP-glucuronic acid is formed when UDP-glucose undergoes two oxidations catalyzed by the enzyme UDP-glucose 6-dehydrogenase. UDP-glucose 6-dehydrogenase uses the co-factor NAD+ as the electron acceptor. The transferase UDP-glucuronate pyrophosphorylase removes a UMP and glucuronokinase, with the cofactor ADP, removes the final phosphate leading to [[glucuronic acid|Template:Sm-glucuronic acid]]. The aldehyde group of this compound is reduced to a primary alcohol using the enzyme glucuronate reductase and the cofactor NADPH, yielding Template:Sm-gulonic acid. This is followed by lactone formation—utilizing the hydrolase gluconolactonase—between the carbonyl on C1 and hydroxyl group on C4. Template:Sm-Gulonolactone then reacts with oxygen, catalyzed by the enzyme L-gulonolactone oxidase (which is nonfunctional in humans and other Haplorrhini primates; see Unitary pseudogenes) and the cofactor FAD+. This reaction produces 2-oxogulonolactone (2-keto-gulonolactone), which spontaneously undergoes enolization to form ascorbic acid.[61][69][56] Reptiles and older orders of birds make ascorbic acid in their kidneys. Recent orders of birds and most mammals make ascorbic acid in their liver.[61]

Non-synthesizers[edit]

Some mammals have lost the ability to synthesize vitamin C, including simians and tarsiers, which together make up one of two major primate suborders, Haplorhini. This group includes humans. The other more primitive primates (Strepsirrhini) have the ability to make vitamin C. Synthesis does not occur in some species in the rodent family Caviidae, which includes guinea pigs and capybaras, but does occur in other rodents, including rats and mice.[70]

Synthesis does not occur in most bat species,[71] but there are at least two species, frugivorous bat Rousettus leschenaultii and insectivorous bat Hipposideros armiger, that retain (or regained) their ability of vitamin C production.[72][73] A number of species of passerine birds also do not synthesize, but not all of them, and those that do not are not clearly related; it has been proposed that the ability was lost separately a number of times in birds.[74] In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases.[75] The ability to synthesize vitamin C has also been lost in about 96% of extant fish[76] (the teleosts).[75]

On a milligram consumed per kilogram of body weight basis, simian non-synthesizer species consume the vitamin in amounts 10 to 20 times higher than what is recommended by governments for humans.[77] This discrepancy constituted some of the basis of the controversy on human recommended dietary allowances being set too low.[78] However, simian consumption does not indicate simian requirements. Merck's veterinary manual states that daily intake of vitamin C at 3–6 mg/kg prevents scurvy in non-human primates.[79] By way of comparison, across several countries, the recommended dietary intake for adult humans is in the range of 1–2 mg/kg.

Evolution of animal synthesis[edit]

Ascorbic acid is a common enzymatic cofactor in mammals used in the synthesis of collagen, as well as a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). Given that ascorbate has these important functions, it is surprising that the ability to synthesize this molecule has not always been conserved. In fact, anthropoid primates, Cavia porcellus (guinea pigs), teleost fishes, most bats, and some passerine birds have all independently lost the ability to internally synthesize vitamin C in either the kidney or the liver.[80][75] In all of the cases where genomic analysis was done on an ascorbic acid auxotroph, the origin of the change was found to be a result of loss-of-function mutations in the gene that encodes L-gulono-γ-lactone oxidase, the enzyme that catalyzes the last step of the ascorbic acid pathway outlined above.[81] One explanation for the repeated loss of the ability to synthesize vitamin C is that it was the result of genetic drift; assuming that the diet was rich in vitamin C, natural selection would not act to preserve it.[82][83]

In the case of the simians, it is thought that the loss of the ability to make vitamin C may have occurred much farther back in evolutionary history than the emergence of humans or even apes, since it evidently occurred soon after the appearance of the first primates, yet sometime after the split of early primates into the two major suborders Haplorrhini (which cannot make vitamin C) and its sister suborder of non-tarsier prosimians, the Strepsirrhini ("wet-nosed" primates), which retained the ability to make vitamin C.[84] According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago.[85] Approximately three to five million years later (58 million years ago), only a short time afterward from an evolutionary perspective, the infraorder Tarsiiformes, whose only remaining family is that of the tarsier (Tarsiidae), branched off from the other haplorrhines.[86][87] Since tarsiers also cannot make vitamin C, this implies the mutation had already occurred, and thus must have occurred between these two marker points (63 to 58 million years ago).[84]

It has also been noted that the loss of the ability to synthesize ascorbate strikingly parallels the inability to break down uric acid, also a characteristic of primates. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that, in higher primates, uric acid has taken over some of the functions of ascorbate.[88]

Plant synthesis[edit]

File:Vitamin C Biosynthesis in Plants.svg
Vitamin C biosynthesis in plants

There are many different biosynthesis pathways to ascorbic acid in plants. Most proceed through products of glycolysis and other metabolic pathways. For example, one pathway utilizes plant cell wall polymers.[63] The principal plant ascorbic acid biosynthesis pathway seems to be via Template:Sm-galactose. The enzyme [[L-galactose 1-dehydrogenase|Template:Sm-galactose dehydrogenase]] catalyzes the overall oxidation to the lactone and isomerization of the lactone to the C4-hydroxyl group, resulting in Template:Sm-galactono-1,4-lactone.[69] Template:Sm-Galactono-1,4-lactone then reacts with the mitochondrial flavoenzyme [[Galactonolactone dehydrogenase|Template:Sm-galactonolactone dehydrogenase]][89] to produce ascorbic acid.[69] Template:Sm-Ascorbic acid has a negative feedback on Template:Sm-galactose dehydrogenase in spinach.[90] Ascorbic acid efflux by embryos of dicot plants is a well-established mechanism of iron reduction and a step obligatory for iron uptake.[lower-alpha 1]

All plants synthesize ascorbic acid. Ascorbic acid functions as a cofactor for enzymes involved in photosynthesis, synthesis of plant hormones, as an antioxidant and regenerator of other antioxidants.[92] Plants use multiple pathways to synthesize vitamin C. The major pathway starts with glucose, fructose or mannose (all simple sugars) and proceeds to Template:Sm-galactose, Template:Sm-galactonolactone and ascorbic acid.[92][93] This biosynthesis is regulated following a diurnal rhythm.[93] Enzyme expression peaks in the morning to supporting biosynthesis for when mid-day sunlight intensity demands high ascorbic acid concentrations.[93][94] Minor pathways may be specific to certain parts of plants; these can be either identical to the vertebrate pathway (including the GLO enzyme), or start with inositol and get to ascorbic acid via Template:Sm-galactonic acid to Template:Sm-galactonolactone.[92]

Industrial synthesis[edit]

Lua error in Module:Hatnote_list at line 44: attempt to call field 'formatPages' (a nil value). Vitamin C can be produced from glucose by two main routes. The no longer utilized Reichstein process, developed in the 1930s, used a single fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. The Reichstein process and the modern two-step fermentation processes both use glucose as the starting material, convert that to sorbitol, and then to sorbose using fermentation.[95] The two-step fermentation process then converts sorbose to 2-keto-l-gulonic acid (KGA) through another fermentation step, avoiding an extra intermediate. Both processes yield approximately 60% vitamin C from the glucose starting point.[96] Researchers are exploring means for one-step fermentation.[97][98]

China produces about 70% of the global vitamin C market. The rest is split among European Union, India and North America. The global market is expected to exceed 141 thousand metric tons in 2024.[99] Cost per metric ton (1000 kg) in US dollars was $2,220 in Shanghai, $2,850 in Hamburg and $3,490 in the US.[100]

Medical uses[edit]

Rows and rows of dietary supplement bottles on shelves
Vitamin C supplements among other dietary supplements at a US drug store

Vitamin C has a definitive role in treating scurvy, which is a disease caused by vitamin C deficiency. Beyond that, a role for vitamin C as prevention or treatment for various diseases is disputed, with reviews often reporting conflicting results. No effect of vitamin C supplementation reported for overall mortality.[101] It is on the World Health Organization's List of Essential Medicines and on the World Health Organization's Model Forumulary.[102] In 2021, it was the 255th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[103]

Scurvy[edit]

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Scurvy is a disease resulting from a deficiency of vitamin C. Without this vitamin, collagen made by the body is too unstable to perform its function and several other enzymes in the body do not operate correctly. Early symptoms are malaise and lethargy, progressing to shortness of breath, bone pain and susceptibility to bruising. As the disease progressed, it is characterized by spots on and bleeding under the skin and bleeding gums. The skin lesions are most abundant on the thighs and legs. A person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there is fever, old wounds may become open and suppurating, loss of teeth, convulsions and, eventually, death. Until quite late in the disease the damage is reversible, as healthy collagen replaces the defective collagen with vitamin C repletion.[1][37][104]

Notable human dietary studies of experimentally induced scurvy were conducted on conscientious objectors during World War II in Britain and on Iowa state prisoners in the late 1960s to the 1980s. Men in the prison study developed the first signs of scurvy about four weeks after starting the vitamin C-free diet, whereas in the earlier British study, six to eight months were required, possibly due to the pre-loading of this group with a 70 mg/day supplement for six weeks before the scorbutic diet was fed. Men in both studies had blood levels of ascorbic acid too low to be accurately measured by the time they developed signs of scurvy. These studies both reported that all obvious symptoms of scurvy could be completely reversed by supplementation of only 10 mg a day.[105][106] Treatment of scurvy can be with vitamin C-containing foods or dietary supplements or injection.[37][2](p101)

Sepsis[edit]

People in sepsis may have micronutrient deficiencies, including low levels of vitamin C.[107] An intake of 3.0 g/day, which requires intravenous administration, appears to be needed to maintain normal plasma concentrations in people with sepsis or severe burn injury.[108][109] Sepsis mortality is reduced with administration of intravenous vitamin C.[110][111]

Common cold[edit]

1955 black-and-white photo of Nobel Prize winner, Linus Pauling.
The Nobel Prize winner Linus Pauling advocated taking vitamin C for the common cold in a 1970 book.

Research on vitamin C in the common cold has been divided into effects on prevention, duration, and severity. Oral intakes of more than 200 mg/day taken on a regular basis was not effective in prevention of the common cold. Restricting analysis to trials that used at least 1000 mg/day also saw no prevention benefit. However, taking a vitamin C supplement on a regular basis did reduce the average duration of the illness by 8% in adults and 14% in children, and also reduced the severity of colds.[112] Vitamin C taken on a regular basis reduced the duration of severe symptoms but had no effect on the duration of mild symptoms.[113] Therapeutic use, meaning that the vitamin was not started unless people started to feel the beginnings of a cold, had no effect on the duration or severity of the illness.[112]

Vitamin C distributes readily in high concentrations into immune cells, promotes natural killer cell activities, promotes lymphocyte proliferation, and is depleted quickly during infections, effects suggesting a prominent role in immune system function.[114] The European Food Safety Authority concluded there is a cause and effect relationship between the dietary intake of vitamin C and functioning of a normal immune system in adults and in children under three years of age.[115][116]

COVID-19[edit]

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During March through July 2020, vitamin C was the subject of more US FDA warning letters than any other ingredient for claims for prevention and/or treatment of COVID-19.[117] In April 2021, the US National Institutes of Health (NIH) COVID-19 Treatment Guidelines stated that "there are insufficient data to recommend either for or against the use of vitamin C for the prevention or treatment of COVID-19."[118] In an update posted December 2022, the NIH position was unchanged:

  • There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19 in nonhospitalized patients.
  • There is insufficient evidence for the Panel to recommend either for or against the use of vitamin C for the treatment of COVID-19 in hospitalized patients.[119]

For people hospitalized with severe COVID-19 there are reports of a significant reduction in the risk of all-cause, in-hospital mortality with the administration of vitamin C relative to no vitamin C. There were no significant differences in ventilation incidence, hospitalization duration or length of intensive care unit stay between the two groups. The majority of the trials incorporated into these meta-analyses used intravenous administration of the vitamin.[120][121][122] Acute kidney injury was lower in people treated with vitamin C treatment. There were no differences in the frequency of other adverse events due to the vitamin.[122] The conclusion was that further large-scale studies are needed to affirm its mortality benefits before issuing updated guidelines and recommendations.[120][121][122]

Cancer[edit]

There is no evidence that vitamin C supplementation reduces the risk of lung cancer in healthy people or those at high risk due to smoking or asbestos exposure.[123] It has no effect on the risk of prostate cancer,[124] and there is no good evidence vitamic C supplementation affects the risk of colorectal cancer[125] or breast cancer.[126]

There is research investigating whether high dose intravenous vitamin C administration as a co-treatment will suppress cancer stem cells, which are responsible for tumor recurrence, metastasis and chemoresistance.[127][128]

Cardiovascular disease[edit]

There is no evidence that vitamin C supplementation decreases the risk cardiovascular disease,[129] although there may be an association between higher circulating vitamin C levels or dietary vitamin C and a lower risk of stroke.[130] There is a positive effect of vitamin C on endothelial dysfunction when taken at doses greater than 500 mg per day. (The endothelium is a layer of cells that line the interior surface of blood vessels.)[131]

Blood pressure[edit]

Serum vitamin C was reported to be 15.13 μmol/L lower in people with hypertension compared to normotensives. The vitamin was inversely associated with both systolic blood pressure (SBP) and diastolic blood pressure (DBP).[132] Oral supplementation of the vitamin resulted in a very modest but statistically significant decrease in SBP in people with hypertension.[133][134] The proposed explanation is that vitamin C increases intracellular concentrations of tetrahydrobiopterin, an endothelial nitric oxide synthase cofactor that promotes the production of nitric oxide, which is a potent vasodilator. Vitamin C supplementation might also reverse the nitric oxide synthase inhibitor NG-monomethyl-L-arginine 1, and there is also evidence cited that vitamin C directly enhances the biological activity of nitric oxide, a vasodilator.[133]

Type 2 diabetes[edit]

There are contradictory reviews. From one, vitamin C supplementation cannot be recommended for management of type 2 diabetes.[135] However, another reported that supplementation with high doses of vitamin C can decrease blood glucose, insulin and hemoglobin A1c.[136]

Iron deficiency[edit]

One of the causes of iron-deficiency anemia is reduced absorption of iron. Iron absorption can be enhanced through ingestion of vitamin C alongside iron-containing food or supplements. Vitamin C helps to keep iron in the reduced ferrous state, which is more soluble and more easily absorbed.[137]

Topical application to prevent signs of skin aging[edit]

Human skin contains vitamin C, which supports collagen synthesis, decreases collagen degradation, and assists in antioxidant protection against UV-induced photo-aging, including photocarcinogenesis. This knowledge is often used as a rationale for the marketing of vitamin C as a topical "serum" ingredient to prevent or treat facial skin aging, melasma (dark pigmented spots) and wrinkles. The purported mechanism is that it functions as an antioxidant, neutralizing free radicals from sunlight exposure, air pollutants or normal metabolic processes.[138] The efficacy of topical treatment, as opposed to oral intake is poorly understood.[139][140] The clinical trial literature is characterized as insufficient to support health claims, one reason being put forward was that "All the studies used vitamin C in combination with other ingredients or therapeutic mechanisms, thereby complicating any specific conclusions regarding the efficacy of vitamin C."[141] More research is needed.[142]

Cognitive impairment and Alzheimer's disease[edit]

Lower plasma vitamin C concentrations were reported in people with cognitive impairment and Alzheimer's disease compared to people with normal cognition.[143][144][145]

Eye health[edit]

Higher dietary intake of vitamin C was associated with lower risk of age-related cataracts.[146][147] Vitamin C supplementation did not prevent age-related macular degeneration.[148]

Periodontal disease[edit]

Low intake and low serum concentration were associated with greater progression of periodontal disease.[149][150]

Adverse effects[edit]

Oral intake as dietary supplements in excess of requirements are poorly absorbed,[23] and excesses in the blood rapidly excreted in the urine, so it exhibits low acute toxicity.[1] More than two to three grams, consumed orally, may cause nausea, abdominal cramps and diarrhea. These effects are attributed to the osmotic effect of unabsorbed vitamin C passing through the intestine.[2](p156) In theory, high vitamin C intake may cause excessive absorption of iron. A summary of reviews of supplementation in healthy subjects did not report this problem, but left as untested the possibility that individuals with hereditary hemochromatosis might be adversely affected.[2](p158)

There is a longstanding belief among the mainstream medical community that vitamin C increases risk of kidney stones.[151] "Reports of kidney stone formation associated with excess ascorbic acid intake are limited to individuals with renal disease".[2](pp156-157) A review states that "data from epidemiological studies do not support an association between excess ascorbic acid intake and kidney stone formation in apparently healthy individuals",[152] although one large, multi-year trial did report a nearly two-fold increase in kidney stones in men who regularly consumed a vitamin C supplement.[153]

There is extensive research on the purported benefits of intravenous vitamin C for treatment of sepsis,[108] severe COVID-19[120][121] and cancer.[154] Reviews list trials with doses as high as 24 grams per day.[120] Concerns about possible adverse effects are that intravenous high-dose vitamin C leads to a supraphysiological level of vitamin C followed by oxidative degradation to dehydroascorbic acid and hence to oxalate, increasing the risk of oxalate kidney stones and oxalate nephropathy. The risk may be higher in people with renal impairment, as kidneys efficiently excrete excess vitamin C. Second, treatment with high dose vitamin C should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency as it can lead to acute hemolysis. Third, treatment might interfere with the accuracy of glucometer measurement of blood glucose levels, as both vitamin C and glucose have similar molecular structure, which could lead to false high blood glucose readings. Despite all these concerns, meta-analyses of patients in intensive care for sepsis, septic shock, COVID-19 and other acute conditions reported no increase in new-onset kidney stones, acute kidney injury or requirement for renal replacement therapy for patients receiving short-term, high-dose, intravenous vitamin C treatment. This suggests that intravenous vitamin C is safe under these short-term applications.[155][156][157]

History[edit]

Scurvy was known to Hippocrates, described in book two of his Prorrheticorum and in his Liber de internis affectionibus, and cited by James Lind.[158] Symptoms of scurvy were also described by Pliny the Elder: (i) Pliny. "49". Naturalis historiae. 3.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>; and (ii) Strabo, in Geographicorum, book 16, cited in the 1881 International Encyclopedia of Surgery.[159]

Scurvy at sea[edit]

Limes, lemons and oranges identified as preventing scurvy
Limes, lemons and oranges were among foods identified early as preventing or treating scurvy on long sailing voyages.

In the 1497 expedition of Vasco da Gama, the curative effects of citrus fruit were known.[160] In the 1500s, Portuguese sailors put in to the island of Saint Helena to avail themselves of planted vegetable gardens and wild-growing fruit trees.[161] Authorities occasionally recommended plant food to prevent scurvy during long sea voyages. John Woodall, the first surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his 1617 book, The Surgeon's Mate.[162] In 1734, the Dutch writer Johann Bachstrom gave the firm opinion, "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens."[163][164] Scurvy had long been a principal killer of sailors during the long sea voyages.[165] According to Jonathan Lamb, "In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;...all mainly to scurvy."[166]

File:James Lind by Chalmers.jpg
James Lind, a British Royal Navy surgeon who, in 1747, identified that a quality in fruit prevented scurvy in one of the first recorded controlled experiments[167]

The first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the Royal Navy, James Lind. While at sea in May 1747, Lind provided some crew members with two oranges and one lemon per day, in addition to normal rations, while others continued on cider, vinegar, sulfuric acid or seawater, along with their normal rations, in one of the world's first controlled experiments.[167] The results showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.[168]

Fresh fruit was expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles).[35] It was 1796 before the British navy adopted lemon juice as standard issue at sea. In 1845, ships in the West Indies were provided with lime juice instead, and in 1860 lime juice was used throughout the Royal Navy, giving rise to the American use of the nickname "limey" for the British.[167] Captain James Cook had previously demonstrated the advantages of carrying "Sour krout" on board, by taking his crew on a 1772-75 Pacific Ocean voyage without losing any of his men to scurvy.[169] For his report on his methods the British Royal Society awarded him the Copley Medal in 1776.[170]

The name antiscorbutic was used in the eighteenth and nineteenth centuries for foods known to prevent scurvy. These foods included lemons, limes, oranges, sauerkraut, cabbage, malt, and portable soup.[171] In 1928, the Canadian Arctic anthropologist Vilhjalmur Stefansson showed that the Inuit avoided scurvy on a diet of largely raw meat. Later studies on traditional food diets of the Yukon First Nations, Dene, Inuit, and Métis of Northern Canada showed that their daily intake of vitamin C averaged between 52 and 62 mg/day.[172]

Discovery[edit]

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Vitamin C was discovered in 1912, isolated in 1928 and synthesized in 1933, making it the first vitamin to be synthesized.[173] Shortly thereafter Tadeus Reichstein succeeded in synthesizing the vitamin in bulk by what is now called the Reichstein process.[174] This made possible the inexpensive mass-production of vitamin C. In 1934, Hoffmann–La Roche bought the Reichstein process patent, trademarked synthetic vitamin C under the brand name Redoxon, and began to market it as a dietary supplement.[175][176]

In 1907, a laboratory animal model which would help to identify the antiscorbutic factor was discovered by the Norwegian physicians Axel Holst and Theodor Frølich, who when studying shipboard beriberi, fed guinea pigs their test diet of grains and flour and were surprised when scurvy resulted instead of beriberi. Unknown at that time, this species did not make its own vitamin C (being a caviomorph), whereas mice and rats do.[177] In 1912, the Polish biochemist Casimir Funk developed the concept of vitamins. One of these was thought to be the anti-scorbutic factor. In 1928, this was referred to as "water-soluble C", although its chemical structure had not been determined.[178]

Albert Szent-Györgyi was awarded the Nobel Prize in Medicine in part for his research on vitamin C
Albert Szent-Györgyi, pictured here in 1948, was awarded the 1937 Nobel Prize in Medicine "for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid".[179]

From 1928 to 1932, Albert Szent-Györgyi and Joseph L. Svirbely's Hungarian team, and Charles Glen King's American team, identified the anti-scorbutic factor. Szent-Györgyi isolated hexuronic acid from animal adrenal glands, and suspected it to be the antiscorbutic factor.[180] In late 1931, Szent-Györgyi gave Svirbely the last of his adrenal-derived hexuronic acid with the suggestion that it might be the anti-scorbutic factor. By the spring of 1932, King's laboratory had proven this, but published the result without giving Szent-Györgyi credit for it. This led to a bitter dispute over priority.[180] In 1933, Walter Norman Haworth chemically identified the vitamin as Template:Sm-hexuronic acid, proving this by synthesis in 1933.[181][182][183][184] Haworth and Szent-Györgyi proposed that L-hexuronic acid be named a-scorbic acid, and chemically Template:Sm-ascorbic acid, in honor of its activity against scurvy.[184][173] The term's etymology is from Latin, "a-" meaning away, or off from, while -scorbic is from Medieval Latin scorbuticus (pertaining to scurvy), cognate with Old Norse skyrbjugr, French scorbut, Dutch scheurbuik and Low German scharbock.[185] Partly for this discovery, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine,[179] and Haworth shared that year's Nobel Prize in Chemistry.[186]

In 1957, J. J. Burns showed that some mammals are susceptible to scurvy as their liver does not produce the enzyme [[L-gulonolactone oxidase|Template:Sm-gulonolactone oxidase]], the last of the chain of four enzymes that synthesize vitamin C.[187][188] American biochemist Irwin Stone was the first to exploit vitamin C for its food preservative properties. He later developed the idea that humans possess a mutated form of the Template:Sm-gulonolactone oxidase coding gene.[189] Stone introduced Linus Pauling to the theory that humans needed to consume vitamin C in quantities far higher than what was considered a recommended daily intake in order to optimize health.[190]

In 2008, researchers discovered that in humans and other primates the red blood cells have evolved a mechanism to more efficiently utilize the vitamin C present in the body by recycling oxidized Template:Sm-dehydroascorbic acid (DHA) back into ascorbic acid for reuse by the body. The mechanism was not found to be present in mammals that synthesize their own vitamin C.[191]

History of large dose therapies[edit]

Lua error in Module:Hatnote_list at line 44: attempt to call field 'formatPages' (a nil value). Vitamin C megadosage is a term describing the consumption or injection of vitamin C in doses comparable to or higher than the amounts produced by the livers of mammals which are able to synthesize vitamin C. An argument for this, although not the actual term, was described in 1970 in an article by Linus Pauling. Briefly, his position was that for optimal health, humans should be consuming at least 2,300 mg/day to compensate for the inability to synthesize vitamin C. The recommendation also fell into the consumption range for gorillas – a non-synthesizing near-relative to humans.[78] A second argument for high intake is that serum ascorbic acid concentrations increase as intake increases until it plateaus at about 190 to 200 micromoles per liter (µmol/L) once consumption exceeds 1,250 milligrams.[192] As noted, government recommendations are a range of 40 to 110 mg/day and normal plasma is approximately 50 µmol/L, so 'normal' is about 25% of what can be achieved when oral consumption is in the proposed megadose range.

Pauling popularized the concept of high dose vitamin C as prevention and treatment of the common cold in 1970. A few years later he proposed that vitamin C would prevent cardiovascular disease, and that 10 grams/day, initially administered intravenously and thereafter orally, would cure late-stage cancer.[193] Mega-dosing with ascorbic acid has other champions, among them chemist Irwin Stone[190] and the controversial Matthias Rath and Patrick Holford, who both have been accused of making unsubstantiated treatment claims for treating cancer and HIV infection.[194][195] The idea that large amounts of intravenous ascorbic acid can be used to treat late-stage cancer or ameliorate the toxicity of chemotherapy is – some forty years after Pauling's seminal paper – still considered unproven and still in need of high quality research.[196][197][154]

Dosage[edit]

An optimal daily dosage is 100-400 mg. Spread it out in two or more doses.

Optimal dosage for most people is 100-140 mg/d. Higher dosage of 250 mg/d for prevention of colds.[198]

Maximum dosage should be 400 mg/d.[199]

Sources include fruits and vegetables.

Vitamin C and viral infections[edit]

Used prophylactically, dosage is 200 mg to 500 mg per day. Higher dosages of 1000 or even 3000 to 5000 mg per day are not needed while healthy. The upper limit for vitamin C is 2,000 mg.

The I MASK protocol recommends 500 to 1000 mg twice daily.[200]

At first sign of illness use: Powdered Vitamin C ascorbates: Take 2000 mg every 2 hours until “bowel tolerance.”

To treat acute illness, much higher dosage is needed, upward of 6 grams of liposomal Vitamin C.[201]

Vitamin C megadosage[edit]

Vitamin C megadosage is a term describing the consumption or injection of vitamin C (ascorbic acid) in doses well beyond the current United States Recommended Dietary Allowance of 90 milligrams per day, and often well beyond the tolerable upper intake level of 2,000 milligrams per day.[2] There is no scientific evidence that vitamin C megadosage helps to cure or prevent cancer, the common cold, or some other medical conditions.[202][196]

Historical advocates of vitamin C megadosage include Linus Pauling, who won the Nobel Prize in Chemistry in 1954. Pauling argued that because humans lack a functional form of L-gulonolactone oxidase, an enzyme required to make vitamin C that is functional in most other mammals, plants, insects, and other life forms, humans have developed a number of adaptations to cope with the relative deficiency. These adaptations, he argued, ultimately shortened lifespan but could be reversed or mitigated by supplementing humans with the hypothetical amount of vitamin C that would have been produced in the body if the enzyme were working.

Vitamin C megadoses are claimed by alternative medicine advocates including Matthias Rath and Patrick Holford to have preventive and curative effects on diseases such as cancer and AIDS,[203][204] but the available scientific evidence does not support these claims.[196] Some trials show some effect in combination with other therapies, but this does not imply vitamin C megadoses in themselves have any therapeutic effect.[205]

Background[edit]

Vitamin C is an essential nutrient used in the production of collagen and other biomolecules, and for the prevention of scurvy.[206] It is also an antioxidant, which has led to its endorsement by some researchers as a complementary therapy for improving quality of life.[207] Certain animal species, including the haplorhine primates (which include humans),[78][208] members of the Caviidae family of rodents (including guinea pigs and capybaras),[209] most species of bats,[210] many passerine birds,[74] and about 96% of fish (the teleosts),[74] cannot synthesize vitamin C internally and must therefore rely on external sources, typically obtained from food.

For humans, the World Health Organization recommends a daily intake of 45 mg/day of vitamin C for healthy adults, and 25–30 mg/day in infants.[211]

Since its discovery, vitamin C has been considered almost a panacea by some,[212] although this led to suspicions of it being overhyped by others.[213] Vitamin C has long been promoted in alternative medicine as a treatment for the common cold, cancer, polio, and various other illnesses. The evidence for these claims is mixed. Since the 1930s, when it first became available in pure form, some physicians have experimented with higher-than-recommended vitamin C consumption or injection.[214] Orthomolecular-based megadose recommendations for vitamin C are based mainly on theoretical speculation and observational studies, such as those published by Fred R. Klenner from the 1940s through the 1970s. There is a strong advocacy movement for very high doses of vitamin C, yet there is an absence of large-scale, formal trials in the 10 to 200+ grams per day range.

The single repeatable side effect of oral megadose vitamin C is a mild laxative effect if the practitioner attempts to consume too much too quickly. In the United States and Canada, a tolerable upper intake level (UL) was set at 2,000 mg/day, citing this mild laxative effect as the reason for establishing the UL.[2] However, the European Food Safety Authority (EFSA) reviewed the safety question in 2006 and reached the conclusion that there was not sufficient evidence to set a UL for vitamin C.[215] The Japan National Institute of Health and Nutrition reviewed the same question in 2010 and also reached the conclusion that there was not sufficient evidence to set a UL.[216]

About 70–90% of vitamin C is absorbed by the body when taken orally at normal levels (30–180 mg daily). Only about 50% is absorbed from daily doses of 1 gram (1,000 mg). Even oral administration of megadoses of 3g every four hours cannot raise blood concentration above 220 micromol/L.[217]

Relative deficiency hypothesis[edit]

File:Pauling Vit C Book Cover.jpg
Linus Pauling's popular and influential 1986 book How to Live Longer and Feel Better advocated very high doses of vitamin C

Humans and other species that cannot synthesize their own vitamin C carry a mutated and ineffective form of the enzyme L-gulonolactone oxidase, the fourth and last step in the ascorbate-producing machinery. In the anthropoids lineage, this mutation likely occurred 40 to 25 million years ago.[citation needed] The three surviving enzymes continue to produce the precursors to vitamin C, but the absence of the fourth enzyme means the process is never completed, and the body ultimately disassembles the precursors.

In the 1960s, the Nobel-Prize-winning chemist Linus Pauling, after contact with Irwin Stone,[218] began actively promoting vitamin C as a means to greatly improve human health and resistance to disease. His book How to Live Longer and Feel Better was a bestseller and advocated taking more than 10 grams per day orally, thus approaching the amounts released by the liver directly into the circulation in other mammals: an adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and much more when stressed.[citation needed]

Matthias Rath is a controversial German physician who worked with and published two articles discussing the possible relationship between lipoprotein and vitamin C with Pauling.[219][220] He is an active proponent and publicist for high-dose vitamin C. Pauling's and Rath's extended theory states that deaths from scurvy in humans during the Pleistocene, when vitamin C was scarce, selected for individuals who could repair arteries with a layer of cholesterol provided by lipoprotein(a), a lipoprotein found in vitamin C-deficient species.[221]

Stone[222] and Pauling[78] believed that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal per day. For comparison, the FDA's recommended daily allowance of vitamin C is only 90 milligrams.[2]

Adverse effects[edit]

Although sometimes considered free of toxicity, there are in fact known side effects from vitamin C intake, and it has been suggested that intravenous injections should require "a medical environment and trained professionals."[223]

For example, a genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD) can cause affected people to develop hemolytic anemia after using intravenous vitamin C treatment.[224] The G6PD deficiency test is a common laboratory test.

Because oxalic acid is produced during metabolism of vitamin C, hyperoxaluria can be caused by intravenous administration of ascorbic acid.[223] Vitamin C administration may also acidify the urine and could promote the precipitation of kidney stones or drugs in the urine.[223]

Although vitamin C can be well tolerated at doses well above what government organizations recommend, adverse effects can occur at doses above 3 grams per day. The common "threshold" side effect of megadoses is diarrhea. Other possible adverse effects include increased oxalate excretion and kidney stones, increased uric acid excretion, systemic conditioning ("rebound scurvy"), preoxidant effects, iron overload, reduced absorption of vitamin B12 and copper, increased oxygen demand, and acid erosion of the teeth when chewing vitamin C tablets.[2] In addition, one case has been noted of a woman who received a kidney transplant followed by high-dose vitamin C and died soon afterwards as a result of calcium oxalate deposits that destroyed her new kidney. Her doctors concluded that high-dose vitamin C therapy should be avoided in patients with kidney failure.[225]

Overdose[edit]

As discussed previously, vitamin C generally exhibits low toxicity. The Template:LD50 (the dose that will kill 50% of a population) is generally accepted to be 11,900 milligrams (11.9 grams) per kilogram in rat populations.[226] The American Association of Poison Control Centers has reported zero deaths from vitamin C toxicity[when?].[227]

Interactions[edit]

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 (Prilosec), has been found to lower the bioavailability of vitamin C by 12% after 28 days of treatment, independent of dietary intake. 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.[228] In another study, 40 mg/day of omeprazole lowered the fasting gastric vitamin C levels from 3.8 to 0.7 µg/mL.[229] Aspirin may also inhibit the absorption of vitamin C.[230][231]

Regulation[edit]

There are regulations in most countries that limit the claims regarding treatment of disease that can be placed on food and dietary supplement product labels. For example, claims of therapeutic effect with respect to the treatment of any medical condition or disease are prohibited by the United States Food and Drug Administration even if the substance in question has gone through well conducted clinical trials with positive outcomes. Claims are limited to "structure and function" phrasing (like "helps maintain a healthy immune system") and the following notice is mandatory on food and dietary supplement product labels that make these types of health claims: These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.[232]

Research[edit]

Cancer[edit]

The use of vitamin C in high doses as a treatment for cancer was promoted by Linus Pauling, based on a 1976 study published with Ewan Cameron which reported intravenous vitamin C significantly increased lifespans of patients with advanced cancer.[233][202] This trial was criticized by the National Cancer Institute for being designed poorly, and three subsequent trials conducted at the Mayo Clinic could not replicate the results.[202][234]

Preliminary clinical trials in humans have shown that it is unlikely to be a "miracle pill" for cancer and more research is necessary before any definitive conclusions about efficacy can be reached.[223] A 2010 review of 33 years of research on vitamin C to treat cancer stated "we have to conclude that we still do not know whether Vitamin C has any clinically significant antitumor activity. Nor do we know which histological types of cancers, if any, are susceptible to this agent. Finally, we don't know what the recommended dose of Vitamin C is, if there is indeed such a dose, that can produce an anti-tumor response."[234]

The American Cancer Society has stated, "Although high doses of vitamin C have been suggested as a cancer treatment, the available evidence from clinical trials has not shown any benefit."[202]

Burns[edit]

One clinical trial used high intravenous doses of vitamin C (66 mg/kg/hour for 24 hours, for a total dose of around 110 grams) after severe burn injury,[235] but despite being described as promising, it has not been replicated by independent institutions and thus is not a widely accepted treatment.[236] Based on that study, the American Burn Association (ABA) considers high-dose ascorbic acid an option to be considered for adjuvant therapy in addition to the more accepted standard treatments.[237]

Cardiac effects[edit]

Atrial fibrillation (AF) is a common cardiac rhythm disturbance associated with oxidative stress. Four meta-analyses have concluded that there is strong evidence that consuming 1–2 g/day of vitamin C before and after cardiac operations can decrease the risk of post-operative AF.[238][239][240][241] However, five randomized studies did not find any such benefit in the United States, so that the benefit was restricted to less wealthy countries.[241][242]

Exercise-induced bronchoconstriction[edit]

Exercise-induced bronchoconstriction (EIB) indicates acute narrowing of the airways as a result of vigorous exercise. EIB seems to be caused by the loss of water caused by increased ventilation, which may lead to the release of mediators such as histamine, prostaglandins, and leukotrienes, all of which cause bronchoconstriction. Vitamin C participates in the metabolism of these mediators and might thereby influence EIB.[243] A meta-analysis showed that 0.5 to 2 g/day of vitamin C before exercise decreased EIB by half.[244]

Endothelial function[edit]

A meta-analysis showed a significant positive effect of vitamin C on endothelial function. Benefit was found of vitamin C in doses ranging from 0.5 to 4 g/day, whereas lower doses from 0.09 to 0.5 g/day were not effective. No effect on endothelial function was seen in healthy volunteers or healthy smokers.[245]

Common cold[edit]

Lua error in Module:Hatnote_list at line 44: attempt to call field 'formatPages' (a nil value). A frequently cited meta-analysis calculated that various doses of vitamin C (daily doses under 0.2 grams were excluded) do not prevent the common cold in the general community, although 0.25 to 1 g/day of vitamin C halved the incidence of colds in people under heavy short-term physical stress.[246] Another meta-analysis calculated that, in children, 1–2 g/day vitamin C shortened the duration of colds by 18%, and in adults 1–4 g/day vitamin C shortened the duration of colds by 8%.[246] There is evidence of linear dose-dependency in the effect of vitamin C on common cold duration up to 6–8 g/day.[247]Template:Technical inline As noted above, there is an absence of large-scale, formal trials in the 10 to 200+ grams per day range, so no information is available for these higher dosages. Additionally, the cited studies of larger daily doses of vitamin C do not take into account the fast excretion rate of vitamin C at gram-level doses, which makes it necessary to give the total daily amount in smaller, more frequent doses to maintain higher plasma levels.[248] As of 2014, at least 16 studies had found that vitamin C supplements did not prevent the common cold and had minimal effect at best in shortening cold lengths.[196]

Intravenous ascorbic acid[edit]

Template:Short description Template:Infobox medical intervention Template:Alternative medicine sidebar

Intravenous Ascorbic Acid (also known as vitamin C or L-ascorbic acid), is a process that delivers soluble ascorbic acid directly into the bloodstream. It is not approved for use to treat any medical condition.[249]

The use of intravenous ascorbic acid as a proposed cancer treatment or co-treatment has been a controversial topic since the emergence of misleading data in the 1970s.[250]

Contraindications[edit]

High doses of ascorbic acid administered by intravenous infusion have been shown to increase the absorption of iron.[251] In individuals with hemochromatosis (a genetic disorder where the body takes up and stores too much iron), intravenous ascorbic acid is contraindicated as high dosages of ascorbic acid may result in iron overloading and therefore, lead to life-threatening complications such as heart disease, diabetes, or tissue damage.[252]

High dosages of ascorbic acid (such as those used in intravenous therapy) have been reported to cause some intestinal discomfort, diarrhoea, as well as increased gas and urination.[253]

Alternative medicine and unproven applications[edit]

Sepsis[edit]

The "Marik protocol", or "HAT" protocol, as devised by Paul E. Marik, proposed a combination of intravenous vitamin C, hydrocortisone, and thiamine as a treatment for preventing sepsis for people in intensive care. Marik's own initial research, published in 2017,[254] showed a dramatic evidence of benefit, leading to the protocol becoming popular among intensive care physicians,[255] especially after the protocol received attention on social media and National Public Radio, drawing criticism of science by press conference from the wider medical community.[256][257] Subsequent independent research failed to replicate Marik's positive results, indicating the possibility that they had been compromised by bias.[257][258] A systematic review of trials in 2021 found that the claimed benefits of the protocol could not be confirmed.[259]

Pharmacology[edit]

File:Ascorbic acid structure.svg
Chemical structure of ascorbic acid (reduced form)

Mechanism of action[edit]

Ascorbic acid operates as an anti-oxidant and essential enzyme cofactor in the human body. In in vitro studies, the primary mechanism of high dosage intravenous ascorbic acid can be related to ascorbic acid's pro-oxidant activity, whereby hydrogen peroxide is formed.[260][261][262] In the extracellular fluid of cells, ascorbic acid dissociates into an ascorbate radical upon the reduction of transition metal ions, such as ferric or cupric cations.[260] These transition metal ions will then reduce dissolved oxygen into a superoxide radical – this will then react with hydrogen to form hydrogen peroxide.[261]

Furthermore, according to Fenton chemistry, these transition metal ions can be further oxidised by hydrogen peroxide to generate a highly reactive hydroxyl radical.[263] The formation of hydrogen peroxide and hydroxyl radicals is believed to induce cytotoxicity and apoptosis of cancer cells.[263] Although many in vitro studies have studied hydrogen peroxide generation by ascorbic acid, the pharmacological mechanism of intravenous ascorbic acid in vivo is still unclear.[263]

History[edit]

Pioneering research[edit]

Although the pharmacology of ascorbic acid had been studied since its discovery in the 1930s,[264] the method of administration and its medicinal potential to human patients was not investigated until the 1940s.[265] In 1949, American physician, Frederick Klenner, published his scientific report, “The Treatment of Poliomyelitis and Other Virus Diseases with ascorbic acid”,[266] which detailed the use of intravenous ascorbic acid to treat polio in children.[265] Klenner's research pioneered future studies investigating the medicinal role of intravenous ascorbic acid. Klenner's work was recognised by Linus Pauling in the foreword to the Clinical Guide: "Dr. Fred Klenner's early research reports provide much information on the use of high-dose ascorbic acid for the prevention and cure of many diseases, and these reports are still important."[267]

Black and white photo of Nobel Prize winner, Linus Pauling.
Nobel Prize winner, Linus Pauling, is recognised as one of the early pioneers of ascorbic acid research

Linus Pauling[edit]

Nobel Prize winner and biochemist, Linus Pauling, was pivotal in the re-emergence of intravenous ascorbic acid research. Over the course of the 1970s, Pauling would begin a long-term collaboration with fellow physician, Ewan Cameron, on the medical potential of intravenous ascorbate acid as cancer therapy in terminally ill patients. In 1976, Pauling and Cameron co-authored a study whereby a group of 100 terminal cancer patients underwent supplementary ascorbic acid therapy (10g/day by intravenous infusion and oral thereafter) and the control group of 1,000 patients did not.[268] Their findings reported that the survival rate of the terminal cancer patients increased by four-fold, compared to the control group, stating that: "the treatment of ascorbate in amounts of 10g/day or more is of real value in extending the life of patients with advanced cancer."[268]

Subsequent studies by Pauling and Cameron hypothesised that ascorbic acid's role in enhanced collagen production would lead to the encapsulation of tumours and thus, protect normal tissue from metastasis.[269] Following these findings, Pauling became a strong advocate for vitamin megadosing and continued to investigate the medicinal potential of intravenous ascorbic acid across a range of illnesses, including: HIV transmission, the common cold, atherosclerosis, and angina pectoris.[270][271][272]

Medical controversy[edit]

The efficacy of intravenous ascorbic acid therapy came under scrutiny of the medical and science community, following the numerous high-profile studies authored by Linus Pauling in the 1970s.[262] The experimental design of Pauling and Cameron's 1976 publication, "Supplemental ascorbate in the supportive treatment of cancer",[268] had garnered considerable criticism as it was neither randomised nor placebo controlled. To test the validity of Pauling and Cameron's findings, the Mayo Clinic conducted three independent experiments in 1979, 1983 and 1985, whereby terminal cancer patients were given doses of oral ascorbic acid under randomised, double bind and placebo-controlled conditions.[273][274][275] All studies concluded that high doses of oral ascorbic acid were not effective against cancer.

The use of intravenous ascorbic acid in the treatment of cancer has been a contentious issue. There is no evidence to indicate that intravenous ascorbic acid therapy can cure cancer.[276][275] According to the U.S. Food and Drug Administration (FDA), high-dose vitamin C (such as intravenous ascorbic acid therapy) has not been approved as a treatment for cancer or any other medical condition.[249]

There many been multiple studies devoted to investigating the medicinal properties of ascorbic acid. The use of high-dosage intravenous ascorbic acid as a cancer treatment was first promoted by Linus Pauling and Ewan Cameron in the 1970s;[268][269] however, these findings were not reproduced using oral administration by subsequent Mayo Clinic studies in the 1980s.[273][274][275] In 2010, an academic review which detailed 33 years of ascorbic acid and cancer research stated: "we still do not know whether Vitamin C has any clinically significant anti-tumor activity. Nor do we know which histological types of cancers, if any, are susceptible to this agent. Finally, we don't know what the recommended dose of Vitamin C is, if there is indeed such a dose, that can produce an anti-tumor response".[277]

Research[edit]

The turn of the 21st century saw a renewed interest in the medical potential of intravenous ascorbic acid therapy. In the early 2010s, in vitro preclinical and clinical trials were undertaken to investigate the pharmacological mechanism of action of intravenous ascorbic acid therapy.[278][279] These findings demonstrated ascorbic acid's pro-oxidant capabilities to produce hydrogen peroxide and thus, proposed a possible pharmacological mechanism of action against cancer cells. Nonetheless, ascorbic acid's potential as an anti-tumour therapy is still dubious, as other pro-oxidant substances (such as menadione[280][281]) have been unsuccessful in the treatment of cancer patients.[282]

Notes[edit]

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  1. Dicot plants transport only ferrous iron (Fe2+), but if the iron circulates as ferric complexes (Fe3+), it has to undergo a reduction before it can be actively transported. Plant embryos efflux high amounts of ascorbate that chemically reduce iron(III) from ferric complexes.[91]

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https://chrismasterjohnphd.substack.com/p/cancer-iv-drips-and-the-glutathione [archive]

https://www.americaoutloud.com/is-iv-vitamin-c-right-for-me/ [archive]

https://chrismasterjohnphd.substack.com/p/vitamin-c-whole-food-vs-synthetic [archive]

https://takecontrol.substack.com/p/vitamin-c-improves-effectiveness-chemo-radiation [archive]

https://chrismasterjohnphd.substack.com/p/330-is-whole-food-vitamin-c-really [archive]

https://unbekoming.substack.com/p/vitamin-c [archive]

https://takecontrol.substack.com/p/vitamin-c-health-benefits [archive]

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