Vitamin C

Vitamin C is an essential vitamin with antioxidant properties. It is frequently supplemented to ward off the common cold.

This page features 292 unique references to scientific papers.


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Vitamin C, or L-ascorbic acid, is a water-soluble essential vitamin. It is a very popular dietary supplement due to its antioxidant properties, safety, and low price.

Vitamin C is often supplemented to reduce the symptoms of the common cold.

However, vitamin C is unable to reduce the frequency of colds in a healthy population. An athlete supplementing vitamin C, on the other hand, can expect to cut the risk of getting a cold in half. Supplemental vitamin C is able to reduce the duration of a cold by 8-14% in any population, when it is taken as a daily preventative measure, or at the beginning of a cold. Though superloading vitamin C (5-10g daily) is said to be more effective, further research is needed to determine the accuracy of this claim.

Vitamin C is capable of being both an antioxidant and pro-oxidant, depending on what the body needs. This mechanism allows it to serve a variety of functions in the body.

Vitamin C sequesters free radicals in the body. It is replenished by antioxidant enzymes, and is often used as a reference drug in antioxidant research. Vitamin C’s structure allows it to act on neurology and depression, as well as interact with the pancreas and modulate cortisol. Its antioxidant properties mean vitamin C provides neuroprotective effects and benefits for blood flow. By protecting the testes from oxidative stress, vitamin C can also preserve testosterone levels.

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Also Known As

Ascorbic Acid, Ascorbate, 2-oxo-L-threo-hexono-1,4-lactone-2,3-enediol, L-ascorbic acid


Do Not Confuse With

L-Threonic Acid (a metabolite)


Is a Form of


Goes Well With

  • Zinc and Iron (may enhance absorption)

Caution Notice

  • Superloading vitamin C, particularly via intravenous injections, has repeatedly been demonstrated in case studies to cause oxalate nephrotoxicity. This is treatable (potentially lethal if not treated) and may be a reason to avoid injections of vitamin C if not supervised by a medical doctor.
Examine.com Medical Disclaimer

The Recommended Daily Intake (RDI) of vitamin C is 100-200mg. This is easily attained through the diet, so supplementation of such low doses is usually unnecessary. Higher doses of vitamin C, up to 2,000mg, are used to support the immune system (for athletes) or reduce the duration of the common cold.

Most studies on vitamin C prescribe one dose per day. The claim that taking 2,000mg up to five times a day to optimally reduce cold symptoms is not sufficiently tested and requires more evidence.


The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Vitamin C has in your body, and how strong these effects are.
GradeLevel of Evidence
ARobust research conducted with repeated double blind clinical trials
BMultiple studies where at least two are double-blind and placebo controlled
CSingle double blind study or multiple cohort studies
DUncontrolled or observational studies only
Level of Evidence
EffectChange
Magnitude of Effect Size
Scientific ConsensusComments
BGeneral Oxidation

Minor

Surprisingly mixed influences on biomarkers of oxidation, with either a decrease or no significant influence the majority of the time (with limited evidence to hint at... show

BLipid Peroxidation

Minor

Mixed and weak influences on lipid peroxidation, but a possible reduction exists

BBlood Flow

Minor

An increase in blood flow is seen in instances of impaired blood flow (smoking, obesity, etc.) which may be due to preservation of nitric oxide function (via reducing oxidation... show

BInflammation

No significant alterations seen in inflammatory cytokines associated with Vitamin C supplementation

BMuscle Damage

Minor

Although not acute, a possible reduction in biomarkers of muscle damage is sometimes noted with antioxidative supplementation which applies to Vitamin C; results are unreliable

BAerobic Exercise

No significant influence on aerobic exercise performance

BCortisol

Minor

Vitamin C (500-1,500mg daily) appears to be associated with both increases and decreases in exercise-induced cortisol spikes, depending on whether it acts as a prooxidant... show

BExercise-Induced Immune Suppression

More evidence suggests no significant effect than a possible protective effect, although the latter is possible

BHeart Rate

Minor

A decrease in heart rate has been noted in exercising obese adults, a per se effect of Vitamin C on heart rate (rather than secondary to the rate of percieved exertion)... show

BProtection from Smoking

There do not appear to be any inherent protective effects of Vitamin C against the oxidative and inflammatory changes associated with cigarette smoking, although the reduction... show

BPlasma Vitamin C

Strong

For the purpose of increasing plasma Vitamin C concentrations, orally supplemented Vitamin C appears to be the best decision (second only to intravenous vitamin C).

CGlycemic Control

No significant influence on glycemic control in diabetics with Vitamin C supplementation

CTriglycerides

No significant influence on fasting or postprandial triglycerides seems apparent with Vitamin C

CHeart Palpitations

No significant influence on heart palpitations

CSymptoms of Bacterial Vaginosis

Minor

Vaginal bacterial infections are somewhat treatable with directly applied (via silicon coated tablets), as Vitamin C exerts some antioxidant effects against those bacterial strains

CMicrocirculation

Minor

An increase in microcirculation has been noted secondary to increased blood flow, thought to be a general property of antioxidants

CFat Mass

Does not appear to significantly influence fat mass

CWeight

Vitamin C does not appear to have a weight reducing effect

CAdaptations to Exercise

Minor

It is thought that, secondary to reducing the rate of muscular damage, that adaptations gained from exercise are attenuated; there is mixed evidence to support this, but... show

CVO2 Max

Does not appear to have a role in altering VO2 max

CTotal Cholesterol

No significant influence on total cholesterol seems apparent with vitamin C supplementation

CSymptoms of Charcot-Marie-Tooth Disease

Insufficient evidence to support a role

CInsulin Sensitivity

No significant influence on insulin sensitivity

CPre-Eclampsia Risk

No significant influence on pre-eclampsia risk

CRisk of Cataracts

No significant influence on the risk of cataracts

CSpontaneous Birth Risk

No significant influence on spontaneous birthing

CUpper Respiratory Tract Infection Risk

No significant influence on the rate of acquiring sickness

CLength of Sickness

Mixed influences on the length one is sick for, with possibly no effect

CSubjective Well-Being

Minor

An improvement in mood has been noted in hospitalized persons

CBone Mineral Density

Minor

The rate of bone mineral density loss over time in elder women appears to be reduced with dietary antioxidants, and as such applies to Vitamin C supplementation. The protective... show

CAnti-Oxidant Enzyme Profile

Minor

An increase in antioxidant enzymes have been noted in elderly persons

COxygenation Cost of Exercise
CC-Reactive Protein

Minor

A possible reduction in C-Reactive Protein exists with Vitamin C supplementation

CDNA Damage

No significant influences on DNA damage

CExercise-Induced Oxidation

Highly mixed interactions with the exercise:oxidation axis with Vitamin C, with both increases and decreases being noted. Unlikely to have a reliable role

CMuscle Soreness

Minor

A possible reduction in muscle soreness the day after exercise may result when preloading exercise with Vitamin C

CHbA1c

No significant influence of Vitamin C supplementation on HbA1c levels

COxidation of LDL

No significant influence on the oxidation rates of LDL cholesterol

CHDL-C

No significant influence on HDL cholesterol

CLDL-C

No significant alterations in LDL cholesterol seen with Vitamin C supplementation

CRate of Perceived Exertion

Minor

The rate of percieved exertion in obese adults appears to be attenuated with Vitamin C supplementation

CFatigue

Minor

A decrease in fatigue has been noted in obese adults given Vitamin C in conjunction with exercise

CFat Oxidation

No significant influence on fat oxidation

CMineral Bioaccumulation
CSperm Quality
CSeminal Motility
CDepression
CFrequency of Intercourse

Minor

Supplementation of 3,000mg Vitamin C appears to increase sexual frequency from 4 times monthly to 14 times. No influence on masturbation frequency

DSymptoms of Osteoarthritis

No significant influence on the symptoms of osteoarthritis

DInterleukin 6

Studies Excluded from Consideration


Disagree? Join the Vitamin C Discussion

Table of Contents:


Edit1. Sources and Structure

1.1. Sources

Vitamin C (officially known as L-ascorbic acid, its prolonged name being 2-oxo-L-threo-hexono-1,4-lactone-2,3-enediol) is an Essential Vitamin, first structurally identified by Szent-Gyorgyi, Waugh, and King in 1932-1935[4][5] and first synthesized by Haworth and Hirst in 1933.[6] It has been popularized mostly by Linus Pauling for prevention of the common cold[7][8][9] and has since been said to be the most popular supplement in the world.[10]

Vitamin C is most commonly supplemented because of its potential protection against the common cold,[11] and purported anticancer effects.[12] Athletes report using vitamin C for both the antioxidant properties and potential immune support.[13]

The current recommendations for Vitamin C intake (according to the FDA) appears to be 75-90mg daily (females and males, respectively) for adults with increases of 10mg for pregnancy, 45mg for lactation, and 35mg for smokers.[14] Children require around 15-45mg daily and adolescents 65-75mg, while infants (12 months or less) appears to require 40-50mg daily; youth do not have differences in dosage based upon gender until adolescence is reached.[14]

Average dietary intakes have been reported to be 152+/-83.7mg in spain,[15]

Vitamin C is a relatively safe micronutrient that is a common supplement for its antioxidant properties and reported benefits against the common cold. Average dietary intakes are in the sufficiency range (above what the RDA recommends) although the lowest groups of vitamin C intake are under the recommendations

Particularly rich sources of Vitamin C include:

  • Kiwi fruits (290-800mg/kg in the deliciosa (common) species and 370-1850mg/kg in argutafruit[16])

Whereas the most common or significant dietary sources of Vitamin C include:

  • Citrus Fruits (29.6% in spain,[15] usually oranges[17]) and 9% in the US (all fruits inclusive[18])
  • Noncitrus fruits (21.5% in spain,[15] usually apples[17])
  • Juices (6.3% in spain[15] and 25-34% in the US[19][18])
  • Fruiting vegetables (usually peppers and sweet peppers) at 20% in spain[15] and 23% in the US (all vegetables inclusive[18])
  • Potatoes (3.9% in spain[15])
  • Leafy green vegetables (6.7% in spain[15])
  • Cruciferous vegetables (2.9% in spain[15])
  • Fortified cereals (4% in US[18])
Fruits tend to be the highest food source of vitamin C, and in mediterraean countries they also appear to be a predominant source of vitamin C in the average diet. In the US, juices appear to contribute a significant amount of vitamin C to the diet

1.2. Biological Significance

Vitamin C appears to be a cofactor for proper collagen synthesis, L-Carnitine biosynthesis (interestingly not mandatory[20]), and some neurotransmitters (particularly catecholamines).[10] In the body it maintains an overall pool of around 1,500-2,000mg that can be maintained with 75mg daily intake and saturated with 140mg daily.[10] In the body, Vitamin C has a half-life of 10–20 days with a bodily turnover of 1mg/kg and at the serum concentration of 50μM it has a bodily pool of approximately 22mg/kg[21][22] (50μM is right in the middle of the 40-60μM range found in humans[23][24]).

The biosynthesis of L-Carnitine (β-hydroxy butyric acid) that requires Vitamin C is not as a substrate, but as a necessary cofactor (iron and alpha-ketoglutarate are also required cofactors).[25] This is similar to the biosynthesis of catecholamines, as the dopamine-β-hydroxylase enzyme that converts dopamine into noradrenaline (which subsequently converts into adrenaline) is Vitamin C dependent.[26] Other enzymes that Vitamin C is known to positively modulate include those involved in the synthesis of oxytocin, vasopressin, cholecystokinin and α-Melanocyte-stimulating hormone.[27]

Vitamin C is required in the human body since it is required by some critical enzymes, particular those that synthesize L-Carnitine and the neurotransmitters known as catecholamines (dopamine and adrenaline). It also influences a few other neurotransmitters, and is required for proper collagen (joint) synthesis rates

Biosynthesis of Vitamin C can normally occur from either glucose or galactose being converted to glucose-6-phosphate, which then is converted to Uridine diphosphate glucose and (via uridine diphosphate glucuoronic acid) into L-glucuronic acid. This molecule is then converted into L-glucuronolactone, L-gulono-γ-lactone, and then via the enzyme known as gulonolactone oxidase it is converted into L-keto-gulono-γ-lactone and Vitamin C.[10] Humans (as well as guinea pigs, fruit eating bats, and apes) cannot follow the above biosynthetic pathway as the gulonolactone oxidase enzyme does not exist within us.[10][28]

Due to the inability to synthesize Vitamin C, it needs to be obtained via the diet. A failure to get sufficient Vitamin C in the diet results in scurvy,[29][30] and the ability of a molecule to prevent scurvy (of which Vitamin C is the reference drug) is known as being anti-scorbutic.[31]

Vitamin C can normally be synthesized in animals such as canines and felines, but humans do not have an ability to synthesize Vitamin C. If Vitamin C is not obtained via the diet, then a human will eventually get scurvy

While scurvy is the clinical deficiency state (and is true 'Vitamin C deficiency'), there are various states associated with excessive oxidation which serum vitamin C tends to be reduced (or at least the REDOX balanced altered suggesting a prooxidative state) relative to healthy cohorts. This includes fever and viral infections, stress, alcoholism,[10] smoking,[32][33] type II diabetes[34][35] despite consuming adequate vitamin C,[36] and in persons who have very recently suffered a myocardial infarction[37][38] or acute pancreatitis (these last two normalizing after some time).[39][40]

It has been noted[41] that it is still unclear whether the disease state causes a depletion in vitamin C or vice versa (vitamin C depletion exacerbates the progression of the above states) or whether it is merely a biomarker of a poor diet (this is seen in smokers[42]); at least in myocardial infarction[43] and acute pancreatitis,[44] there is a drastic increase in oxidation rapidly and both diabetes[45] and smoking[32] are associated with elevated chronic oxidation.

Vitamin C depletion (not to a clinical state where scurvey results) is associated with a variety of disease states. The reason for these observations is not fully clear, and the role vitamin C therapy could play in these states is similarly not clear

1.3. Structure and Properties

Vitamin C appears to stable in food (as the form of L-ascorbic acid) in the pH range of 4-6[10]

1.4. Supplement Variants and Specifications

European regulation state that any supplement with the label 'Vitamin C' may be one of five compounds; L-Ascorbic Acid (actual vitamin C), Sodium-L-Ascorbate, Potassium-L-Ascorbate, Calcium-L-Ascorbate, and L-Ascorbyl-6-Palmitate.[46] For vitamin-related purposes, they are equipotent.

They differ on some parameters such as DNA oxidation where Sodium Ascorbate and Ascorbic Acid (the main dietary form) could exert pro-oxidative effects on DNA, Calcium Ascorbate acting neutral on DNA and Ascorbyl-6-Palmitate being protective on DNA.[47] Due to this, it appears that Ascorbyl-6-Palmitate is used often in antioxidant supplements,[10] but does not have water solubility.

'Vitamin C' on the label may refer to one of five different molecules, but all of them are able to act as a vitamin in the body. There may be some small differences between the molecules

Ester-C is a brand name product (patented by Zila Nutraceuticals) for Vitamin C that consists of Vitamin C metabolites (the aldonic acids L-lyxonic, L-xylonic, and L-Threonic acid) with Calcium, and is labelled as Calcium Ascorbate. It is touted to be non-acidic and may be better tolerated by persons with acid reflux, as one study in persons sensitive to acidic foods noted that while 53.6% of the Vitamin C group experienced gastric upset, only 14.3% of the Ester-C group did.[48]

Beyond this, Ester-C appears to be more effective at treating scurvy (Vitamin C deficiency)[49] and at decreasing oxalate levels (a metabolite of Vitamin C),[50][51] Ester-C has been reported to reduce the common cold, but was not compared to basic Vitamin C and has not been replicated.[52]

Studies conducted using Ester-C that have been funded by Zila Nutraceuticals are cited following this sentence.[48]

Ester-C is a form of Vitamin C supplementation that may have benefit in persons who are sensitive to acid containing foods, but beyond that its supposed benefits over standard Vitamin C have not been thoroughly proven


Edit2. Pharmacology

2.1. Serum

Normal circulating concentrations of Vitamin C (as L-ascorbic acid) are in the range of 40-60μM while the reduced form of dehydroascorbate is around 2μM;[23][24] the difference is possibly due to a short half-life of dehydroasorbate of 2-6 minutes.[53] The half-life of ascorbate at a concentration below 70μM is much more prolonged (somewhere between 8 and 40 days) whereas a serum concentration of ascorbate above this threshold (seen with supplementation of over 1,000mg vitamin C) is met with a 30 minute half-life.[54]

Supplemental ascorbate appears to follow a dual phase pharmacokinetic profile. When serum levels are below (within the physiological range) the body tends to regulate ascorbate via resorption in the kidneys (via sodium dependent vitamin C transporters[55]) and have a prolonged half-life of 8-40 days.[56] Serum concentrations

Oral intake of 1,250mg vitamin c is able to increase plasma vitamin C to 134.8+/-20.6μM and is calculated to exceed 220μM when taken at 3,000mg every four hours (in accordance with megadosing therapy for the common cold).[57]

2.2. Metabolism

Vitamin C appears to be metabolized into primarly one of three metabolites after it turns into a free radical (ascrobyl radical); dehydroascorbic acid, 2,3-diketogulonic acid and oxalic acid which convert into one another in that order. Dietary supplementation does not necessarily increase urinary levels of these metabolites, as there is a lack of metabolism of L-ascorbic acid before it is urinated out.[10][53]

As the first stage of metabolism is turning into a free radical, conditions characterized by excessive oxidation deplete circulating L-ascorbic acid (which acts in a protective but sacrifical manner); this is best shown with studies on smoking[58][59] which usually requires a higher Vitamin C intake.

Vitamin C is metabolized into a free radical (via a sacrifical and protective antioxidant effect) and then converted into dehydroascobic acid. From here, vitamin C then proceeds along to produce oxalic acid via 2,3-diketogulonic acid


Edit3. Neurology

3.1. Kinetics and Distribution

Vitamin C is actively transported into the brain via the Sodium-dependent Vitamin C Transporter-2 (SVCT2 or Slc23a1) transporter, whereas the oxidized version of Vitamin C (Dehydroascorbic acid) is transported by GLUT transporters.[60][61] Due to this, it is known to be transported across the blood brain barrier.[62][63] While from systemic circulation (through the blood brain barrier) the oxidized form of dehydroascorbate appears to be required to be transported through GLUT transporters,[63] the choroid plexus epithelium (connection of cerebrospinal fluid to the brain) expresses SVCT2[64][65] and this appears to be the majority route of entry.[65][66][67]

There appears to be a 4-fold higher cerebrospinal fluid concentration of ascorbate relative to plasma in rats,[68][67] resulting in a cerebrospinal concentration of around 200-400μM when plasma are 60μM or less[69][70] although human measurements are more modest at 160μM relative to the same plasma level of 40-60μM.[71][72]

Vitamin C can cross the blood brain barrier, but the rate of entry is somewhat limited and and it needs to be in the oxidized form of dehydroascorbate for this to occur. The majority of Vitamin C entry into the brain occurs via cerebrospinal fluid

Within the brain, Vitamin C appears to be in highest concentrations in the hippocampus, parietal cortex, and the cerebellum[73][74][75] with slightly lower concentrations in the frontal cortex, thalamic nuclei, olfactoy bulb, and striatum with lowest detected in the spinal cord and pons (lowest).[73][76] It is thought that distribution of Vitamin C in the brain mirrors that of where the SVCT2 transport is expressed (noted to be high in the cerebellum, hippocampus, olfactory bulb[77] and frontal cortex[78]), although this does not fully explain the distribution as the parietal cortex does not possess SVCT2.[78]

Vitamin C seems to be in highest concentrations in the hippocampus, cerebellum, and frontal/parietal cortices

3.2. Mechanisms

As mentioned elsewhere (Biological Significance), Vitamin C is a cofactor in the production of catecholamines (via the enzyme dopamine-β-hydroxylase[26][79][80]) and other neurohormones such as oxytocin, vasopressin, and α-Melanocyte-stimulating hormone.[27][81] Another area that Vitamin C facilitates is supporting HIF-1α production, which uses a prolyl and lysyl hydroxylation similar to what is seen with collagen.[60][82] These enzymatic interactions rely on the ability of L-ascorbic acid to transfer a single electron, and may involve the Vitamin C metabolites as well.

Vitamin C interacts with a variety of enzymes involved in cognition. It does not inherently induce these enzymes (increase their activity or the amount of them), but its existence is required for optimal enzyme functioning; this likely means that for enzymatic benefits perhaps only avoiding a deficiency is required

3.3. Acetylcholine

In isolated rat synaptic vesicles, vitamin C appears to cause acetylcholine release with an EC50 value of 2-2.5µM and appears to be dependent on calcium as it was inhibited with EGTA.[83]

Injections of 60mg/kg vitamin C to mice appears to have acetylcholinesterase inhibiting properties by reducing its activity 17.1% (comparable to 50mg/kg Metrifonate and 150mg/kg oral Licorice).[84]

3.4. Neuroprotection

Vitamin C has been found to, in vitro, protect cerebellar granule cells from glutamate induced excitotoxicity[85][86] which is thought to be related to how NDMA receptors can respond to REDOX modulation.[87][88] This is more of a general phenomena that applies to reducing agents (antioxidants), and is abolished by prooxidants.[88]

Vitamin C appears to have putative neuroprotective roles against excitotoxicity (toxicity from excessive cell stimulation) through inhibiting the NMDA receptor. This does not appear to be a unique role for Vitamin C, but something that is attributable to antioxidants in general

3.5. Stress

There appears to be an increase in oxidative stress within cells following percieved stressors (both physical[89] and mental[90][91]), and this increased oxidative state is known to lead to cellular death.

A rat study has noted that oral ingestion of low dose vitamin C (1mg/kg; 0.16mg/kg in humans) was able to suppress an increase in biomarkers of stress in rats, namely oxidation.[92]

3.6. Depression

Vitamin C appears to have antidepressant effects, associated with potassium channels (can be read up on under the depression section on the Agmatine page).[93] In short, potassium channel blockers appear to have anti-depressant effects[94] while potassium channel openers have pro-depressive effects and inhibit the actions of potassium channel blockers[95][94] and vitamin C appears to be synergistically antidepressive with potassium channel blockers.[93]

Vitamin C appears to have antidepressant effects. While the direct mechanism of action is not known, it appears to ultimately work via potassium channels (like most antidepressants) and is synergistic with potassium channel blockers

In regards to animal research, administration of Vitamin C has shown an antidepressant effect in a tail suspension test,[96][93] chronic unpredictable manageable stress,[97] and acute stress[92] at a dosage range of 1-10mg/kg oral administration.

In humans, there is an old case study where depression in a child (induced by ACTH administration) was alleviated with vitamin C[98] but more importantly, a study using a product known as Cetebe (3,000mg vitamin C) in otherwise healthy adults for two weeks noted a reduction in depressive symptoms (Becks Depression Inventory) and increase in the frequency of intercourse (no influence on masturbation);[99] this study was funded by the producer of Cetebe, GlaxoSmithKline.

Preliminary evidence in humans to support antidepressant effects in humans, with the lone controlled trial having a notable conflict of interest

3.7. Dementia

Serum concentrations of Vitamin C appear to be inversely related with risk of Dementia, with an Odds Ratio (OR) of 0.29 after controlling for school education, intake of dietary supplements, smoking habits, body mass index, and alcohol consumption.[100]

3.8. Alzheimer's

In regards to Alzheimer's, oxidative stress is thought to play a major role in the pathogenesis of the disease[101] with byproducts of peroxidation being detected in higher than normal levels in neurofibrillary tangles[102][103][104] and lower serum vitamin C concentrations despite adequate dietary intake[105] although due to a higher cerebrospinal fluid to plasma ratio in alzheimer's (5.1 relative to 3.1 in controls[106]) it is thought the lower serum concentration reflects increased uptake by the brain to counter increaed oxidative stress;[107] this would position the decrease in Vitamin C as a consequence of Alzheimer's rather than a cause.

Vitamin C and oxidative kinetics appear to be altered in persons with Alzheimer's disease

In rat studies, orally ingested Vitamin C (25mg/kg in rats) alongside intracerebral injections of fibrillar amyloid-β was able to reduce oxidative and inflammatory biomarkers (the former comparable to Melatonin at 20mg/kg but weaker than Vitamin E at 50mg/kg; the latter similar to vitamin E but less than melatonin)[108] although elsewhere in an older APP/PSEN1 transgenic mouse model injected with 125mg/kg vitamin C failed to find evidence for neuroprotection or beneficial changes in oxidation (despite slightly improving memory).[109]

Mixed evidence as to whether vitamin C can be of help. It may be neuroprotective but not rehabilitative, and the benefits appear to extend to other antioxidant compounds as well


Edit4. Cardiovascular Health

4.1. Blood Flow

There appear to be several disease states or metabolic conditions of which ascorbate deficiency in the endothelium is associated with endothelial dysfunction.[110]

The endothelial variant of the NOS enzyme (eNOS) appears to be susceptible to oxidative damage, including both translation of the enzyme itself[111] and the required cofactor tetrahydrobiopterin is readily oxidized and rendered inactive.[112] Due to this, supplemental antioxidants are thought to preserve the actions of eNOS in instances of excessive oxidative stress and vitamin C has been said to augment nitric oxide production[113] secondary to 'recycling' (preserving) tetrahydrobiopterin.[114][115] As this is an antioxidative effect and other studies in animals have noted comparable benefits with other antioxidants (such as Melatonin[116][117]) this is likely just an antioxidative effect rather than a unique property of vitamin C.

Other possible mechanisms that may contribute (also general to antioxidants) include scavenging superoxide[118] which would otherwise reduce nitric oxide into peroxynitrate[119] and directly reducing nitrite (product of Nitrate) into nitric oxide[120] or producing nitric oxide from S-nitrosothiols.[121]

Vitamin C appears to promote nitric oxide secondary to its antioxidant properties preventing a unnecessarily rapid decline of nitric oxide. This is not a unique mechanism of action, and is thought to underlie the effects of other potent antioxidants such as melatonin or Pycnogenol (both demonstrated to act similarly)

4.2. Artherosclerosis

Vitamin C is known to be required for microsomal 7α-hydroxylation (rate limiting step of the catabolism of cholesterol), and a deficiency of Vitamin C results in excess cholesterol in the liver and increased risk for gallstones.[10][122][123] This increase in cholesterol retention (by reducing its elimination rate) also appears to be a risk factor for cardiovascular diseases and particularly artherosclerosis.[124][125]


Edit5. Interactions with Glucose Metabolism

5.1. Pancreas

Ascorbate appears to be important to a pancreatic β-cell due in part to its antioxidant properties[126] (these cells tend to have low levels of antioxidant enzymes[127][128]) and its presence is required for proper secretion of insulin.[129] In rats that are able to synthesize vitamin C, it accumulates to high levels in these cells.[130] Furthermore, there is possible competitive inhibition of ascorbate acid metabolites (dehydroascorbate) with glucose as they use the same transporter.[131]

Two grams of vitamin C daily for 2 weeks in otherwise healthy adults has been noted to delay the postprandial insulin spike and prolong the increase in serum glucose when measured at one hour (but not beyond that),[132] hypothesized to be due to competitive inhibition with glucose into pancreatic β-cells.

Not substantial amounts of evidence at this moment in time, but vitamin C may be protective of pancreatic beta-cells. However, supplementation of vitamin C with glucose may cause a transient state of insulin resistance by increasing circulating glucose and suppressing insulin secretion


Edit6. Exercise and Physical Performance

6.1. Mechanisms

Skeletal muscle is known to be a large store of bodily vitamin C (around two thirds[133]) and responsive to dietary vitamin C intake, with one study noting baseline concentrations of 19nmol/g being increased to 53 and 61nmol/g following consumption of 0.5 or 2 kiwi fruits (conferring 53 and 212mg respectively[134]). Vitamin C is readily taken up via SVCT transporters in skeletal muscle tissue.[135]

The main mechanism of concern with Vitamin C supplementation and muscle metabolism would be the antioxidant properties of Vitamin C,[136] although both the collagen and carnitine synthesis roles are thought to be useful.

Vitamin C appears to be readily taken up and stored in skeletal muscle tissue, where it is thought to confer antioxidant protection and support carnitine and collagen biosynthesis

6.2. Exercise Immunology

The post exercise spike in cortisol is known to suppress activity of T-cells and B-cells, which would limit antibody production such as IgA.[137] Despite an interaction with cortisol following exercise with Vitamin C supplemenation (1,500mg for 7-12 days)[138][139][140][141] a few studies measuring IgA have failed to find any significant influence, with similar decreases in both placebo and Vitamin C.[139][140] One study has noted a significant increase in post-exercise lymphocyte counts associated with a decrease in cortisol,[141] whereas another has reported a relative suppression.[138]

For studies measuring cytokines, there has been no reported influence on IL-6, IL-10, IL-1ra, IL-2, IFN-γ, and IL-8 following an ultramarathon[142] nor any influence on IL-6 following short-term exercise.[141] IL-6 is particularly notable as despite there being no significant influence on circulating levels following oral supplementation of Vitamin C (1,000-1,500mg), a combination supplement of Vitamin C (500mg) and Vitamin E (400 IU) for 28 days has once been shown to prevent IL-6 release from contracting skeletal muscle (associated with antioxidant effects).[143]

For studies that measure upper respitatory tract infection risk following exercise, no significant effects are seen with 1,500mg Vitamin C for 12 days prior to a simulated half marathon in the heat.[140]

Usage of supplemental vitamin C in the 1,500-2,000mg range before short duration exercise is able to attenuate the increase in cortisol. However, this does not appear to significantly mediate immune responses to exercise

In contrast to the suppression of cortisol mentioned above with short term exercise, longer and more strenuous exercise such as ultramarathons are known to have an augmentation of cortisol with vitamin C.[142][139] This is thought to be related to the observation that the risk of colds is only reduced in populations subject to strenous exercise (where vitamin C halves the risk of cold symptoms) according to meta-analyses on the topic.[144][145]

Strenous and prolonged exercise such as marathons or skiing appear to be affected differently with supplemental vitamin C, as they increase cortisol rather than decrease it. This type of exercise also appears to be the type that does experience reductions in cold frequency with supplemental vitamin C

6.3. Delayed Onset Muscle Soreness (DOMS)

DOMS is a soreness and tenderness of the muscle tissue that arises after exercise, usually with a delay where it does not suface immediately but usually the next day or 48 hours afterwards.

One study using Vitamin C at 400mg (with Vitamin E at 264mg) failed to notice any benefit to soreness with treatment relative to placebo.[1]

6.4. Power Output

Vitamin C (400mg), in conjunction with Vitamin E (286mg) as a mixed anti-oxidant supplement for 6 weeks in otherwise healthy men, is not significantly better than placebo at attenuating an exercise-induced reduction of power output seen during the recovery phase of exercise.[1]

6.5. Endurance Performance

It is generally accepted that the state of obesity, relative to a non-obese state, makes the same amount of exercise more tiring to the body (perception) and uses more caloric reserves for the same amount of work.[146] Ingestion of 500mg Vitamin C via supplementation when paired with both an exercise regimen and a caloric restriction diet was able to significantly reduce heart rate during exercise and the rate of perceived exertion, although it didn't affect success on the diet.[147]


Edit7. Skeletal and Bone Metabolism

7.1. Bone Mass

At least one rat study notes that supplementation with Vitamin C (5mg) is associated with an attenuation of bone loss due to ovariectomy, an animal model of menopause.[148] After 8 weeks of supplementation, the control ovariectomy group experienced bone loss while the ovariectomy group with Vitamin C was not significantly different than control.[148]


Edit8. Inflammation and Immunology

8.1. Cold and Flu

According to meta-analyses on the topic assessing doses of 200mg vitamin C or more, vitamin C has failed to reduce the frequency of colds in the normal population but was successful in reducing the duration of colds (on average 8-14%);[149][145] when looking at studies investigating extreme physical stress (marathoners and skiiers), the risk of getting a cold was halved (which has been noted in past meta-analyses[144])

It has been noted[150] that the observations from Linus Pauling on vitamin C interactions with the common cold may have been influenced by athletic cohorts, as one of the more convincing studies he wrote about[151] was in regards to children in a skiing school (German PDF[152]).

Most of the literature uses dosages within the range of 200mg to 2,000mg, and while this does appears to be ineffective for preventing or reducing the occurrence of the common cold it does appear to slightly reduce the duration thereof. There are more marked benefits in athletic populations, where risk may be halved

8.2. Bacterial Interactions

One study has noted that drug resistant Mycobacterium tuberculosis (bacteria that causes tuberculosis) is highly sensitive to being destroyed by Vitamin C, which was fairly unique as other bacteria tested were not affected.[153] This was due to a large iron content in this bacteria, which is reduced (from Fe3+ to Fe2+) and causes prooxidative effects after reacting with oxygen.

Although there is no human evidence at this moment in time, Vitamin C supplementation holds promise for being able to destroy the tuberculosis bacteria despite being drug resistant


Edit9. Interactions with Oxidation

9.1. Mechanisms

Vitamin C (L-Ascorbic acid) is a single electron donor, and can be reduced into an ascorbyl radical (AFR) via either oxidative stressors or being used as a cofactor in enzymes. This sacrificial antioxidant activity (antioxidant being somewhat synonymous with 'reduction' when looking at REDOX equations) can be reversed by NADH and NADPH dependent reductases.[154][155][156] Another possible reaction occurs when excessive accumulation of AFR occurs, where two molecules of AFR react with one another to form L-ascorbic acid and Dehydroascorbic acid.[157] Although conversion of the two AFR molecules into dehydroascorbic acid is also reversible (various antioxidant enzymes such as glutathione or thiol reductases[158]), it can possibly not occur due to a short half-life of around 2-6 minutes under physiological conditions[53] the dehydroascorbic molecule and spontaenous formation of 2,3-diketogulonic acid which is irreversible and cannot be converted back into L-ascorbic acid.[53] Production of 2,3-diketogulonic acid then proceeds to create oxalic acid and get excreted from the body via urine.

The above reduction conducted by L-ascorbic acid that converts it to AFR is the main antioxidative effect of Vitamin C, and is known to be 'sacrificial' as the L-ascorbic acid molecule is changed when the reaction occurs. This scavenging applies to most reactive oxygen species (ROS) including superoxide (O2-)[159] and some reactive nitrogen species such as peroxynitrate either directly[160] or reducing an O2- induced conversion of Nitric Oxide into peroxynitrate.[159]

Vitamin C gets reduced (absorbs oxidation) in a sacrifical manner to either protect other things from being oxidized or to facilitate enzymes in the body. The molecules created have the potential to be restored back into Vitamin C, and if this does not occur then Vitamin C is metablized to oxalic acid and then urinated out

It is wholly possible for Vitamin C to also act as a prooxidant depending on context, although the ascorbyl radical itself (technically a prooxidant) is not overly potent due to the position of the free radical group.[161][162] Dietary minerals in vitro are able to oxidize ascorbate as ascorbate is oxidized in the presence of minerals such as iron or copper[163][164] while chelating the minerals prevents autooxidation;[165] this reduction of minerals via ascorbate produces reduced minerals that are better able to exert prooxidative effects. It has been noted[162] that prooxidative effects appear to predominate in vitro at low concentrations of vitamin C relative to minerals (usually iron), and antioxidative effects at higher concentrations of vitamin C relative to minerals.

9.2. Antioxidant Enzymes

Exercise is known to reduce oxidation levels in serum[166][167] possibly associated with an increase in antioxidant enzymes,[168][169] which is said to be an adaptation to the initial increase in oxidative damage induced by exercise. Vitamin C supplementation has been reported to increase activity of these antioxidant enzymes (when acting as a prooxidant).[2]


Edit10. Interactions with Hormones

10.1. Cortisol

A deficiency of vitamin C in rodents tends to result in elevated plasma cortisol without influencing ACTH concentrations,[170][171] and ACTH stimulation appears to be somewhat hindered despite higher serum cortisol concentrations.[172]

In rats unable to synthesize vitamin C, injections (500mg per rat) are able to delay the turnover of cortisol and enhance its actions in the body[173] and has been found to enhance ACTH-induced cortisol production.[174]

In animal studies, injections of vitamin C can enhance glucocorticoid activity by delaying turnover and enhancing secretion while cortisol activity is also enhanced during deficiency

Supplementation of Vitamin C has been shown to reduce exercise-induced spikes in cortisol after both acute[138][141] and up to 12 days supplementation[140] in the dosage range of 1,000-1,500mg. These studies tend to note either no significant changes in lipid peroxides (a parameter of oxidation in the body) relative to placebo,[140] or a relative decrease.[141] These results are not unanimous as some studies note only a trend towards a reduction in cortisol that fails to reach significance,[175] and similar effects have been noted when a Vitamin C and Vitamin E combination supplement has reduced oxidative parameters.[1]

Elsewhere, an increase in cortisol has been noted with ultramarathons using similar doses of Vitamin C (1,500mg for 7 days).[142][139] These studies either fail to report an increase in oxidative damage[139] or actually note increases in some oxidative biomarkers such as F2-Isoprostane,[142] and one study using Vitamin E alongside Vitamin C (400IU and 500mg, respectively) has noted the same effects.[2]

Vitamin C appears to have a bidirectional relationship with cortisol, with increases noted when Vitamin C is able to be a prooxidant and decreases noted when Vitamin C is able to be an antioxidant. The addition of Vitamin E does not appear to significantly influence the actions of Vitamin C

One study using 3,000mg Vitamin C prior to a non-exercise stressor has failed to find a significant influence on cortisol concentrations relative to control.[176]

Minimal studies assessing cortisol concentrations outside of exercise, none of which are promising

10.2. Testosterone

In instances where oxidative stressors damage testicular function (usually rat studies), vitamin C supplementation has been shown to preserve testosterone concentrations secondary to its antioxidant properties. This has been noted in response to lead toxicity,[177] Alcohol ingestion,[178] stressors such as noise or burns,[179][180] and various research toxins that act via pro-oxidative means.[181] These protective effects have been noted at oral doses as low as 20-40mg/kg in rats[181][177] and similar protective effects on the testicles has been noted in human males at 1,000mg vitamin C daily.[182]

It should be noted that these protective effects may not be unique to vitamin C, as various other antioxidant compounds have also been noted to exert protection against oxidative toxins (including but not limited to Quercetin, Vitamin E, Selenium, and Panax ginseng).

There may be protective effects of vitamin C (any antioxidant, actually) on testicular function. An impairment of testicular function normally suppresses testosterone concentrations, and preserving function would preserve testosterone concentrations; while this is a relative increase, it does not suggest that superloading Vitamin C increases testosterone beyond basal levels


Edit11. Interactions with Lungs

11.1. Smoking


Edit12. Interactions with other Organ Systems

12.1. Kidneys

Vitamin C is known to be metabolized into oxalic acid, which is known to contribute to the formation of calcium oxalate kidney stones.

It appears that men who take higher doses of Vitamin C (1,000mg) appear to be at a greater relative risk (approximate doubling) of forming kidney stones than do persons who are not deficient in vitamin C but who do not supplement.[183]

12.2. Adrenal Glands

Vitamin C appears to be involved in regulation of catecholamines (dopamine, adrenaline, noradrenaline) in the adrenal glands, as ascorbate in the chromaffin granule is oxidized (to ascorbyl radical) and gets reduced back to ascorbate when it reaches the granule membrane (via cytochrome b561)[156][184][185] where it is then secreted alongside catecholamines,[186] which has been detected in humans when stimulated by ACTH.[187] As mentioned elsewhere, vitamin C is also a requirement for the dopamine-β-hydroxylase enzyme which is in the catecholamine biosynthetic pathway, and vitamin C can support earlier stages of catecholamine biosynthesis by recycling tetrahydrobiopterin which is a cofactor for tyrosine hydroxylase (converts L-Tyrosine into L-DOPA).[188]

The importance of vitamin C in maintaining adrenal gland function and catecholamine secretion is thought to underlie why scurvy (Vitamin C deficiency) is associated with fatigue (the earliest observable symptom).[189][190][191] In rodent models where vitamin C deficiencies are induced, circulating catecholamines do appear to be reduced.[192]

Vitamin C is a mandatory cofactor for the synthesis of noradrenaline from dopamine, and subsequently adrenaline from noradrenaline. It is thought that a deficiency of vitamin C and lack of catecholamine secretion underlies fatigue symptoms associated with scurvy

Incubating adrenal chromaffin cells with vitamin C does not appear to increase the activity of the enzyme[193] but has been found to increase noradrenaline production from dopamine in SH-SY5Y neuroblastoma cells (50% increase with 1mM ascorbate over 6 hours,[194] with a later study noting 100-1000µM of ascorbate or 100-300µM dehydroascrobate also causing a similar increase but a plateau at around 500µM[195]). This reaction appeared to be unique to vitamin C (the other antioxidants trolox and N-acetylcysteine failed to mimic the results).[195]

In otherwise healthy humans with a relatively low intake of dietary vitamin C (did not have scurvy), oral ingestion of vitamin C (3,000mg) has been shown to reduce adrenaline secretion in response to stress without affecting noradrenaline nor dopamine.[176]

Vitamin C dose-dependently increases noradrenaline production from dopamine in the adrenalins up until around 0.5mM concentration, where it then plateaus. It appears that this concentration is near physiological concentrations already, as adding additional vitamin C to the diet does not appear to further increase urinary catecholamines

12.3. Testicles

In rats simultaneously exposed to lead, 40mg/kg vitamin C over 6 weeks is able to attenuate changes in oxidative parameters (to approximately half of the way between lead only and no lead control) which was associated with a minimization of lead accumulation and preservation of testicular Zinc content. Perhaps secondary to preserving zinc concentrations and testicular function (zinc playing important roles in testicular function[196][197]), vitamin C supplementation preserved testosterone concentrations that dropped with lead.[177]


Edit13. Pregnancy and Infancy

13.1. Requirements

In rat brains, Vitamin C concentrations in the brain approximately double during the last portion of pregnancy[198][199] which does not further increase after birth (slight decline);[198] this appears to extend to human infants.[200] Lower cerebral ascorbic acid concentrations during development appear to be biomarkers of increased oxidative stress,[201][202] and the importance of vitamin C in neural development is further demonstrated in studies that block vitamin C transport to the brain and causes perinatal death.[61][203]

Dietary requirements (FDA numbers) appear to be increased from 75mg up to 85mg (pregnancy) and 120mg (lactation)[14] and a maternal deficiency of Vitamin C (rodent studies, mostly guinea pigs) appears to deletiriously affect offspring with effects such as; reduced hippocampal neurogenesis and memory formation.[204][205]

Vitamin C is outright vital for cognitive development of infants during pregnancy, and there are higher dietary requirements of Vitamin C during pregnancy and lactation; these increased needs are still wholly feasible through dietary intake of Vitamin C, and a deficiency (however impractical in human life) may result in cognitive impairment to the child


Edit14. Various other Clinical Usages

14.1. Mineral Accumulation and Chelation

In animal studies, vitamin C has been found to reduce cadmium toxicity[206][207][208][209][210] and is implicated in aiding elimination of both lead[211][177] and mercury (although there is mixed evidence on mercury, with a reduction of bioaccumulation,[211] exacerbation of accumulation,[212][213] and no effects on bioaccumulation (despite some protective effects)[214] being reported in animals).

Lead, in particular, appears to be chelated by vitamin C with a potency lesser than EDTA despite requiring a higher dose to match carboxylic acid groups (40mg/kg injections of EDTA being equivalent to 1,750-2,333mg/kg vitamin C per rat).[215] EDTA and vitamin C are, however, additive.[215]

In animal research, supplementation of vitamin C appears to reduce the accumulation of toxic heavy metals and partially normalize the adverse changes. The protection does not appear to be absolute, although statistically significant

In humans not subject to lead toxicity (non-concernable serum and hair concentrations) given 500-1000mg vitamin C for three months, there was no significant influence of Vitamin C on lead accumulation.[216]

One study in psychiatric outpatients noted that combination therapy with vitamin C (2,000mg) and Zinc (30mg as gluconate) was found to reduce serum lead concentrations, but copper was also reduced.[3] Industrial workers exposed to lead have also noted a beneficial trend in sperm parameters with 1,000mg for 3 months[182] (lead is known to be adverse to testicular function at concentrations in industrial work utilizing lead[217][218]).

There is mixed evidence for oral supplementation of Vitamin C at doses exceeding 500mg for the removal of lead from the body, with suggestions that this may only affect persons already in a state of lead toxicity and not inherently to otherwise normal persons

14.2. Gout

In patients with gout given vitamin C supplementation (500mg) either in isolation or in addition to allopurinol for 8 weeks, supplementation has failed to significantly reduce plasma urate in either condition.[219]


Edit15. Nutrient-Nutrient Interactions

15.1. Vitamin E

Vitamin E is a very common addition to Vitamin C supplements, and the combination is marketed as an antioxidant blend. Vitamin C appears to have an ability to recycle and/or spare the oxidation of Vitamin E (in reference to α-tocopherol) in lipid membranes,[220][221] and this preservation of Vitamin E has been noted to probably be the reason lipid peroxidation (a type of oxidation to cellular membranes that Vitamin C does not effectively counter, but Vitamin E does) is reduced with cellular incubation of Vitamin C[222][223] and is synergistic with coincubation with α-tocopherol.[224][225]

In cellular cultures, Vitamin C appears to preserve Vitamin E (since Vitamin C is oxidized, Vitamin E is not and it can do other things) which results in a reduction in lipid peroxidation; incubations of Vitamin C with Vitamin E synergistically reduces lipid peroxidation

15.2. Dietary Minerals

Vitamin C has been found to increase the absorption of both iron and Zinc (only iron that is not bound in heme, so that from non-meat products[226][227]) and has been noted to reduce the inhibitory effects of phytic acid[228] but not tannins.[229]

May increase the absorption rates of zinc and iron, which would be of interest to those with anemia

15.3. Nitrates

Nitrate is a small molecule found in leafy green vegetables and most popularly in Beet Root, and is able to convert into Nitric Oxide independent of the NOS enzyme system (the enzyme system that Arginine is subject to). Nitrate's reduced form (nitrite) can convert amines in the body into nitrosamines via a process known as nitrosylation (which is donating a nitric oxide group to the structure of the amines, this is usually conducted by N2O3 or N2O4), and some of these nitrosamines are known to be carcinogenic.

Vitamin C interacts with nitrite to block nitrosamine formation as the products that conduct the nitrosylation, usually N2O3 or N2O4, react with vitamin C more readily than they do with many amines; the potency of blocking nitrosamine formation is dependent on the amine.[230][231] It has been noted that while a 2:1 ratio (ascorbate:nitrite) is sufficient to block a majority of some nitrosylation, even 20-fold higher dosages do not fully abolish nitrosamine formation.[231] This inhibition appears to occur at a pH of 3-4,[230] and although vitamin C is most well researched for this role some other antioxidant compounds are also implicated (Vitamin E[232] and both ferulic and caffeic acid[233]).

There are some instances where vitamin C has been implicated in augmenting nitrosamine production, such as coingestion with lipids[233] and at pH values below 2.[234][230]

Nitrates can form nitric oxide via nitrite, and nitric oxide that reacts with amines may cause the production of nitrosamines which are known carcinogens. This is mostly a concern with meat products (due to heme causing an increase in the reaction rate), and not too much of a concern with vegetables or water inherently

A few epidemiological studies note significant interactions between vitamin C intake and nitroso compound dietary intake and their influence on cancer.[235]

Oral ingestion of high doses vitamin C (23g/kg in mice) is able to reduce nitroso compound formation from nitrate by 42-56% as assessed by fecal analysis[236] (with no influence on nitroso increases in feces from hot dog ingestion, as the nitroso compounds were premade in the hotdog).


Edit16. Safety and Toxicology

16.1. General

Vitamin C is generally thought to be safe, although at higher doses (2,000-6,000mg) may cause diarrhea;[237][238] this is due to Vitamin C being near completely absorbed at low dietary levels (100mg or so) and progressively experiencing less absorption at doses exceeding 500mg.[239]

16.2. Case studies

There appears to be a rare possibility of nephrotoxicity (kidney toxicity) associated with oral Vitamin C supplementation, which has sometimes been reported to be fatal (72 year old man reported to take 'several grams a day'; exact dose not stated[240]). In other instances, clinical usage of intravenous Vitamin C has resulted in renal oxalate nephropathy when very large boluses (45-60g) are given[241][242][243][244][245] which results in development of reversible tubulointerstitial nephritis and possible renal failure.[246][247] This is a fairly treatable condition carrying a good prognosis if readily treated,[248] but again it can be fatal if left untreated or if treatment is refused.[240]

The above observations are thought to be due to the metabolism of Vitamin C into oxalate (known to occur with superloading),[249] which the (admittedly unreliable) production of excess oxalate and then deposition into kidney tissues is a known cause of renal failure.[250][251] It has been noted to be a bit more reliably occurring in calcium-kidney stone forming patients.[251]

At least one case study has linked 'several grams of vitamin C' daily towards oxalate nephrotoxicity (a toxic kidney condition due to excessive oxalate concentrations in the kidneys), and it is reasonable to assume that Vitamin C plays a significant role here since it is well established to be able to cause oxalate nephrotoxicity in clinical settings with injections of Vitamin C

Due to the lack of information in the lone oral case study and the long history of safe usage, it is reasonable to assume that oral supplementation does not carry a significant risk. However, intravenous usage of Vitamin C appears to carry more risk and unless supervised by a medical professional should be avoided

References

  1. Bailey DM, et al. Oxidative stress, inflammation and recovery of muscle function after damaging exercise: effect of 6-week mixed antioxidant supplementation. Eur J Appl Physiol. (2011)
  2. Yfanti C, et al. Role of vitamin C and E supplementation on IL-6 in response to training. J Appl Physiol. (2012)
  3. Sohler A, Kruesi M, Pfeiffer CC. Blood Lead Levels in Psychiatric Outpatients Reduced by Zinc and Vitamin C. J Orthomol Psychiatry. (1977)
  4. Svirbely JL, Szent-Györgyi A. The chemical nature of vitamin C. Biochem J. (1932)
  5. Zilva SS. The isolation and identification of vitamin C. Arch Dis Child. (1935)
  6. Kyle RA, Shampo MA. Walter Haworth--synthesis of vitamin C. Mayo Clin Proc. (2002)
  7. Hemilä H. Vitamin C supplementation and the common cold--was Linus Pauling right or wrong. Int J Vitam Nutr Res. (1997)
  8. Deni L. Dr. Linus Pauling and vitamin C. J Nurs Care. (1979)
  9. Kodama M, Kodama T. Is Linus Pauling, a vitamin C advocate, just making much ado about nothing? (Review). In Vivo. (1994)
  10. Naidu KA. Vitamin C in human health and disease is still a mystery? An overview. Nutr J. (2003)
  11. Karlowski TR, et al. Ascorbic acid for the common cold. A prophylactic and therapeutic trial. JAMA. (1975)
  12. Cameron E, Pauling L, Leibovitz B. Ascorbic acid and cancer: a review. Cancer Res. (1979)
  13. Maughan RJ, Depiesse F, Geyer H; International Association of Athletics Federations. The use of dietary supplements by athletes. J Sports Sci. (2007)
  14. Dietary supplement fact sheet Vitamin C
  15. García-Closas R, et al. Dietary sources of vitamin C, vitamin E and specific carotenoids in Spain. Br J Nutr. (2004)
  16. Nishiyama I, et al. Varietal difference in vitamin C content in the fruit of kiwifruit and other actinidia species. J Agric Food Chem. (2004)
  17. Agudo A, et al. Dietary intake of vegetables and fruits among adults in five regions of Spain. EPIC Group of Spain. European Prospective Investigation into Cancer and Nutrition. Eur J Clin Nutr. (1999)
  18. Subar AF, et al. Dietary sources of nutrients among US adults, 1989 to 1991. J Am Diet Assoc. (1998)
  19. Cotton PA, et al. Dietary sources of nutrients among US adults, 1994 to 1996. J Am Diet Assoc. (2004)
  20. Furusawa H, et al. Vitamin C is not essential for carnitine biosynthesis in vivo: verification in vitamin C-depleted senescence marker protein-30/gluconolactonase knockout mice. Biol Pharm Bull. (2008)
  21. HELLMAN L, BURNS JJ. Metabolism of L-ascorbic acid-1-C14 in man. J Biol Chem. (1958)
  22. Seib PA, Tolbert BM. Ascorbic Acid: Chemistry, Metabolism, and Uses. Adv Chem. (1982)
  23. Dhariwal KR, Hartzell WO, Levine M. Ascorbic acid and dehydroascorbic acid measurements in human plasma and serum. Am J Clin Nutr. (1991)
  24. Okamura M. Uptake of L-ascorbic acid and L-dehydroascorbic acid by human erythrocytes and HeLa cells. J Nutr Sci Vitaminol (Tokyo). (1979)
  25. Hulse JD, Ellis SR, Henderson LM. Carnitine biosynthesis. beta-Hydroxylation of trimethyllysine by an alpha-ketoglutarate-dependent mitochondrial dioxygenase. J Biol Chem. (1978)
  26. Rush RA, Geffen LB. Dopamine beta-hydroxylase in health and disease. Crit Rev Clin Lab Sci. (1980)
  27. Cameron E, Pauling L. Ascorbic acid and the glycosaminoglycans. An orthomolecular approach to cancer and other diseases. Oncology. (1973)
  28. Nishikimi M, Yagi K. Molecular basis for the deficiency in humans of gulonolactone oxidase, a key enzyme for ascorbic acid biosynthesis. Am J Clin Nutr. (1991)
  29. Kasa RM. Vitamin C: from scurvy to the common cold. Am J Med Technol. (1983)
  30. Touyz LZ. Vitamin C, oral scurvy and periodontal disease. S Afr Med J. (1984)
  31. Wilson LG. The clinical definition of scurvy and the discovery of vitamin C. J Hist Med Allied Sci. (1975)
  32. Ayaori M, et al. Plasma levels and redox status of ascorbic acid and levels of lipid peroxidation products in active and passive smokers. Environ Health Perspect. (2000)
  33. Schectman G. Estimating ascorbic acid requirements for cigarette smokers. Ann N Y Acad Sci. (1993)
  34. Will JC, Byers T. Does diabetes mellitus increase the requirement for vitamin C. Nutr Rev. (1996)
  35. Stankova L, et al. Plasma ascorbate concentrations and blood cell dehydroascorbate transport in patients with diabetes mellitus. Metabolism. (1984)
  36. Sinclair AJ, et al. Low plasma ascorbate levels in patients with type 2 diabetes mellitus consuming adequate dietary vitamin C. Diabet Med. (1994)
  37. Hume R, et al. Leucocyte ascorbic acid levels after acute myocardial infarction. Br Heart J. (1972)
  38. Riemersma RA, et al. Vitamin C and the risk of acute myocardial infarction. Am J Clin Nutr. (2000)
  39. Scott P, et al. Vitamin C status in patients with acute pancreatitis. Br J Surg. (1993)
  40. Bonham MJ, et al. Early ascorbic acid depletion is related to the severity of acute pancreatitis. Br J Surg. (1999)
  41. Padayatty SJ1, et al. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr. (2003)
  42. Dallongeville J, et al. Cigarette smoking is associated with unhealthy patterns of nutrient intake: a meta-analysis. J Nutr. (1998)
  43. Hori M, Nishida K. Oxidative stress and left ventricular remodelling after myocardial infarction. Cardiovasc Res. (2009)
  44. Pereda J, et al. Interaction between cytokines and oxidative stress in acute pancreatitis. Curr Med Chem. (2006)
  45. Stadler K. Oxidative stress in diabetes. Adv Exp Med Biol. (2012)
  46. Directive 2002/46/EC
  47. Bergström T, Bergman J, Möller L. Vitamin A and C compounds permitted in supplements differ in their abilities to affect cell viability, DNA and the DNA nucleoside deoxyguanosine. Mutagenesis. (2011)
  48. Gruenwald J, et al. Safety and tolerance of ester-C compared with regular ascorbic acid. Adv Ther. (2006)
  49. Verlangieri AJ, Fay MJ, Bannon AW. Comparison of the anti-scorbutic activity of L-ascorbic acid and Ester C in the non-ascorbate synthesizing Osteogenic Disorder Shionogi (ODS) rat. Life Sci. (1991)
  50. Moyad MA, et al. Vitamin C with metabolites reduce oxalate levels compared to ascorbic acid: a preliminary and novel clinical urologic finding. Urol Nurs. (2009)
  51. Moyad MA, et al. Vitamin C with metabolites: additional analysis suggests favorable changes in oxalate. Urol Nurs. (2009)
  52. Van Straten M, Josling P. Preventing the common cold with a vitamin C supplement: a double-blind, placebo-controlled survey. Adv Ther. (2002)
  53. Koshiishi I, et al. Degradation of dehydroascorbate to 2,3-diketogulonate in blood circulation. Biochim Biophys Acta. (1998)
  54. Hickey DS, Roberts HJ, Cathcart RF. Dynamic Flow: A New Model for Ascorbate. J Orthomol Med. (2005)
  55. Wang Y, et al. Human vitamin C (L-ascorbic acid) transporter SVCT1. Biochem Biophys Res Commun. (2000)
  56. Hickey S, Roberts H. Misleading information on the properties of vitamin C. PLoS Med. (2005)
  57. Padayatty SJ, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. (2004)
  58. Frei B, et al. Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma. Protective effects of ascorbic acid. Biochem J. (1991)
  59. Panda K, et al. Vitamin C prevents cigarette smoke-induced oxidative damage in vivo. Free Radic Biol Med. (2000)
  60. Harrison FE1, May JM. Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free Radic Biol Med. (2009)
  61. Sotiriou S, et al. Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival. Nat Med. (2002)
  62. Lam DK, Daniel PM. The influx of ascorbic acid into the rat's brain. Q J Exp Physiol. (1986)
  63. Agus DB, et al. Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J Clin Invest. (1997)
  64. García Mde L, et al. Sodium vitamin C cotransporter SVCT2 is expressed in hypothalamic glial cells. Glia. (2005)
  65. Angelow S, Haselbach M, Galla HJ. Functional characterisation of the active ascorbic acid transport into cerebrospinal fluid using primary cultured choroid plexus cells. Brain Res. (2003)
  66. Hakvoort A, Haselbach M, Galla HJ. Active transport properties of porcine choroid plexus cells in culture. Brain Res. (1998)
  67. Spector R. Vitamin homeostasis in the central nervous system. N Engl J Med. (1977)
  68. Spector R, Lorenzo AV. Ascorbic acid homeostasis in the central nervous system. Am J Physiol. (1973)
  69. Miele M, Fillenz M. In vivo determination of extracellular brain ascorbate. J Neurosci Methods. (1996)
  70. Schenk JO, et al. Homeostatic control of ascorbate concentration in CNS extracellular fluid. Brain Res. (1982)
  71. Lönnrot K, et al. The effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity. Free Radic Biol Med. (1996)
  72. Reiber H, Ruff M, Uhr M. Ascorbate concentration in human cerebrospinal fluid (CSF) and serum. Intrathecal accumulation and CSF flow rate. Clin Chim Acta. (1993)
  73. Harrison FE, et al. Vitamin C distribution and retention in the mouse brain. Brain Res. (2010)
  74. Milby K, Oke A, Adams RN. Detailed mapping of ascorbate distribution in rat brain. Neurosci Lett. (1982)
  75. Mefford IN, Oke AF, Adams RN. Regional distribution of ascorbate in human brain. Brain Res. (1981)
  76. Odumosu A, Wilson CW. Regional brain ascorbic acid distribution: its functional relationship to appetite and leptazol-induced convulsions in guinea-pigs. Int J Vitam Nutr Res. (1980)
  77. Tsukaguchi H, et al. A family of mammalian Na+-dependent L-ascorbic acid transporters. Nature. (1999)
  78. Mun GH, et al. Immunohistochemical study of the distribution of sodium-dependent vitamin C transporters in adult rat brain. J Neurosci Res. (2006)
  79. Diliberto EJ Jr, Allen PL. Semidehydroascorbate as a product of the enzymic conversion of dopamine to norepinephrine. Coupling of semidehydroascorbate reductase to dopamine-beta-hydroxylase. Mol Pharmacol. (1980)
  80. Diliberto EJ Jr, Allen PL. Mechanism of dopamine-beta-hydroxylation. Semidehydroascorbate as the enzyme oxidation product of ascorbate. J Biol Chem. (1981)
  81. Chatterjee IB, et al. Synthesis and some major functions of vitamin C in animals. Ann N Y Acad Sci. (1975)
  82. Semenza GL. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell. (2001)
  83. Kuo CH, et al. Effect of ascorbic acid on release of acetylcholine from synaptic vesicles prepared from different species of animals and release of noradrenaline from synaptic vesicles of rat brain. Life Sci. (1979)
  84. Dhingra D, Parle M, Kulkarni SK. Comparative brain cholinesterase-inhibiting activity of Glycyrrhiza glabra, Myristica fragrans, ascorbic acid, and metrifonate in mice. J Med Food. (2006)
  85. Ciani E, et al. Inhibition of free radical production or free radical scavenging protects from the excitotoxic cell death mediated by glutamate in cultures of cerebellar granule neurons. Brain Res. (1996)
  86. Atlante A, et al. Glutamate neurotoxicity in rat cerebellar granule cells: a major role for xanthine oxidase in oxygen radical formation. J Neurochem. (1997)
  87. Majewska MD, Bell JA, London ED. Regulation of the NMDA receptor by redox phenomena: inhibitory role of ascorbate. Brain Res. (1990)
  88. Majewska MD, Bell JA. Ascorbic acid protects neurons from injury induced by glutamate and NMDA. Neuroreport. (1990)
  89. Radak Z, et al. Adaptation to exercise-induced oxidative stress: from muscle to brain. Exerc Immunol Rev. (2001)
  90. Kovacheva-Ivanova S, Bakalova R, Ribavov SR. Immobilization stress enhances lipid peroxidation in the rat lungs. Materials and methods. Gen Physiol Biophys. (1994)
  91. Oishi K, et al. Oxidative stress and haematological changes in immobilized rats. Acta Physiol Scand. (1999)
  92. Moretti M, et al. Protective effects of ascorbic acid on behavior and oxidative status of restraint-stressed mice. J Mol Neurosci. (2013)
  93. Moretti M, et al. Involvement of different types of potassium channels in the antidepressant-like effect of ascorbic acid in the mouse tail suspension test. Eur J Pharmacol. (2012)
  94. Galeotti N, et al. Effect of potassium channel modulators in mouse forced swimming test. Br J Pharmacol. (1999)
  95. Bortolatto CF, et al. Involvement of potassium channels in the antidepressant-like effect of venlafaxine in mice. Life Sci. (2010)
  96. Binfaré RW, et al. Ascorbic acid administration produces an antidepressant-like effect: evidence for the involvement of monoaminergic neurotransmission. Prog Neuropsychopharmacol Biol Psychiatry. (2009)
  97. Moretti M, et al. Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress. J Psychiatr Res. (2012)
  98. Cocchi P, et al. Antidepressant Effect of Vitamin C. Pediatrics. (1980)
  99. Brody S. High-dose ascorbic acid increases intercourse frequency and improves mood: a randomized controlled clinical trial. Biol Psychiatry. (2002)
  100. von Arnim CAF, et al. Dietary Antioxidants and Dementia in a Population-Based Case-Control Study among Older People in South Germany. J Alzheimers Dis. (2012)
  101. Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr. (2000)
  102. Pappolla MA, et al. Immunohistochemical evidence of oxidative (corrected) stress in Alzheimer's disease. Am J Pathol. (1992)
  103. Schipper HM, Cissé S, Stopa EG. Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain. Ann Neurol. (1995)
  104. Smith MA, et al. Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease. J Neurosci. (1997)
  105. Rivière S, et al. Low plasma vitamin C in Alzheimer patients despite an adequate diet. Int J Geriatr Psychiatry. (1998)
  106. Quinn J, et al. Antioxidants in Alzheimer's disease-vitamin C delivery to a demanding brain. J Alzheimers Dis. (2003)
  107. Heo JH, Hyon-Lee, Lee KM. The possible role of antioxidant vitamin C in Alzheimer's disease treatment and prevention. Am J Alzheimers Dis Other Demen. (2013)
  108. Rosales-Corral S, et al. Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-beta peptide in rat brain: a comparative, in vivo study versus vitamin C and E. J Pineal Res. (2003)
  109. Harrison FE, et al. Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice. Pharmacol Biochem Behav. (2009)
  110. May JM, Harrison FE. Role of Vitamin C in the Function of the Vascular Endothelium. Antioxid Redox Signal. (2013)
  111. Peterson TE, et al. Opposing effects of reactive oxygen species and cholesterol on endothelial nitric oxide synthase and endothelial cell caveolae. Circ Res. (1999)
  112. Kuzkaya N, et al. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem. (2003)
  113. Heller R, et al. L-Ascorbic acid potentiates nitric oxide synthesis in endothelial cells. J Biol Chem. (1999)
  114. Heller R, et al. L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem. (2001)
  115. Huang A, et al. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. (2000)
  116. Sönmez MF, et al. Melatonin and vitamin C ameliorate alcohol-induced oxidative stress and eNOS expression in rat kidney. Ren Fail. (2012)
  117. Sönmez MF, et al. Effect of melatonin and vitamin C on expression of endothelial NOS in heart of chronic alcoholic rats. Toxicol Ind Health. (2009)
  118. Bendich A, Machlin LJ, Scandurra O. The antioxidant role of vitamin C. Adv Free Radical Biol Med. (1986)
  119. Ischiropoulos H. Biological tyrosine nitration: a pathophysiological function of nitric oxide and reactive oxygen species. Arch Biochem Biophys. (1998)
  120. Millar J. The nitric oxide/ascorbate cycle: how neurones may control their own oxygen supply. Med Hypotheses. (1995)
  121. Scorza G, Pietraforte D, Minetti M. Role of ascorbate and protein thiols in the release of nitric oxide from S-nitroso-albumin and S-nitroso-glutathione in human plasma. Free Radic Biol Med. (1997)
  122. Ginter E. Vitamin-C deficiency and gallstone formation. Lancet. (1971)
  123. [No authors listed. Ascorbic acid and the catabolism of cholesterol. Nutr Rev. (1973)
  124. Turley SD, West CE, Horton BJ. The role of ascorbic acid in the regulation of cholesterol metabolism and in the pathogenesis of artherosclerosis. Atherosclerosis. (1976)
  125. Ginter E. Marginal vitamin C deficiency, lipid metabolism, and atherogenesis. Adv Lipid Res. (1978)
  126. Steffner RJ, et al. Ascorbic acid recycling by cultured beta cells: effects of increased glucose metabolism. Free Radic Biol Med. (2004)
  127. Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med. (1996)
  128. Malaisse WJ, et al. Determinants of the selective toxicity of alloxan to the pancreatic B cell. Proc Natl Acad Sci U S A. (1982)
  129. Wells WW, et al. Ascorbic acid is essential for the release of insulin from scorbutic guinea pig pancreatic islets. Proc Natl Acad Sci U S A. (1995)
  130. Zhou A, Thorn NA. High ascorbic acid content in the rat endocrine pancreas. Diabetologia. (1991)
  131. Mooradian AD. Effect of ascorbate and dehydroascorbate on tissue uptake of glucose. Diabetes. (1987)
  132. Johnston CS, Yen MF. Megadose of vitamin C delays insulin response to a glucose challenge in normoglycemic adults. Am J Clin Nutr. (1994)
  133. Omaye ST, et al. Measurement of vitamin C in blood components by high-performance liquid chromatography. Implication in assessing vitamin C status. Ann N Y Acad Sci. (1987)
  134. Carr AC, et al. Human skeletal muscle ascorbate is highly responsive to changes in vitamin C intake and plasma concentrations. Am J Clin Nutr. (2013)
  135. Savini I, et al. SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids. (2008)
  136. Peternelj TT, Coombes JS. Antioxidant supplementation during exercise training: beneficial or detrimental. Sports Med. (2011)
  137. Cupps TR, Fauci AS. Corticosteroid-mediated immunoregulation in man. Immunol Rev. (1982)
  138. Davison G, Gleeson M. Influence of acute vitamin C and/or carbohydrate ingestion on hormonal, cytokine, and immune responses to prolonged exercise. Int J Sport Nutr Exerc Metab. (2005)
  139. Palmer FM, et al. Influence of vitamin C supplementation on oxidative and salivary IgA changes following an ultramarathon. Eur J Appl Physiol. (2003)
  140. Carrillo AE, Murphy RJ, Cheung SS. Vitamin C supplementation and salivary immune function following exercise-heat stress. Int J Sports Physiol Perform. (2008)
  141. Nakhostin-Roohi B, et al. Effect of vitamin C supplementation on lipid peroxidation, muscle damage and inflammation after 30-min exercise at 75% VO2max. J Sports Med Phys Fitness. (2008)
  142. Nieman DC, et al. Influence of vitamin C supplementation on oxidative and immune changes after an ultramarathon. J Appl Physiol. (2002)
  143. Fischer CP, et al. Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle. J Physiol. (2004)
  144. Douglas RM, et al. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. (2007)
  145. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. (2013)
  146. Ekkekakis P, Lind E. Exercise does not feel the same when you are overweight: the impact of self-selected and imposed intensity on affect and exertion. Int J Obes (Lond). (2006)
  147. Huck CJ, et al. Vitamin C status and perception of effort during exercise in obese adults adhering to a calorie-reduced diet. Nutrition. (2012)
  148. Zhu LL, et al. Vitamin C prevents hypogonadal bone loss. PLoS One. (2012)
  149. Anderson TW, Suranyi G, Beaton GH. The effect on winter illness of large doses of vitamin C. Can Med Assoc J. (1974)
  150. Douglas RM. Vitamin C for Preventing and Treating the Common Cold. PLoS One. (2005)
  151. Pauling L. The significance of the evidence about ascorbic acid and the common cold. Proc Natl Acad Sci U S A. (1971)
  152. Ritzel VG. Kritische Beurteilung des Vitamins C als Prophylacticum und Therapeuticum der Erkältungskrankheiten. Helv Med Acta. (1961)
  153. Vilchèze C, et al. Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction. Nature. (2013)
  154. Schulze HR, Gallenkamp H, Staudinger H. Microsomal NADH-dependent electron transport. Hoppe Seylers Z Physiol Chem. (1970)
  155. Lumper L, Schneider W, Staudinger H. Studies on the kinetics of microsomal NADH:semidehydroascorbate oxidoreductase. Hoppe Seylers Z Physiol Chem. (1967)
  156. Wakefield LM, Cass AE, Radda GK. Electron transfer across the chromaffin granule membrane. Use of EPR to demonstrate reduction of intravesicular ascorbate radical by the extravesicular mitochondrial NADH:ascorbate radical oxidoreductase. J Biol Chem. (1986)
  157. Bielski BHJ, Allen AO, Schwarz HA. Mechanism of the disproportionation of ascorbate radicals. J Am Chem Soc. (1981)
  158. Wells WW, Xu DP. Dehydroascorbate reduction. J Bioenerg Biomembr. (1994)
  159. Jackson TS, et al. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res. (1998)
  160. Landino LM, et al. Ascorbic acid reduction of microtubule protein disulfides and its relevance to protein S-nitrosylation assays. Biochem Biophys Res Commun. (2006)
  161. Buettner GR. The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch Biochem Biophys. (1993)
  162. Buettner GR, Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat Res. (1996)
  163. Buettner GR. Ascorbate oxidation: UV absorbance of ascorbate and ESR spectroscopy of the ascorbyl radical as assays for iron. Free Radic Res Commun. (1990)
  164. Buettner GR. Ascorbate autoxidation in the presence of iron and copper chelates. Free Radic Res Commun. (1986)
  165. Buettner GR. In the absence of catalytic metals ascorbate does not autoxidize at pH 7: ascorbate as a test for catalytic metals. J Biochem Biophys Methods. (1988)
  166. Alessio HM, Goldfarb AH. Lipid peroxidation and scavenger enzymes during exercise: adaptive response to training. J Appl Physiol. (1988)
  167. Heitkamp HC, et al. Effect of an 8-week endurance training program on markers of antioxidant capacity in women. J Sports Med Phys Fitness. (2008)
  168. Higuchi M, et al. Superoxide Dismutase and Catalase in Skeletal Muscle: Adaptive Response to Exercise. J Gerontol. (1985)
  169. Oh-ishi S, et al. Effects of endurance training on superoxide dismutase activity, content and mRNA expression in rat muscle. Clin Exp Pharmacol Physiol. (1997)
  170. Fordyce MK, Kassouny ME. Influence of vitamin C restriction on guinea pig adrenal calcium and plasma corticosteroids. J Nutr. (1977)
  171. Doulas NL, Constantopoulos A, Litsios B. Effect of ascorbic acid on guinea pig adrenal adenylate cyclase activity and plasma cortisol. J Nutr. (1987)
  172. Hodges JR, Hotston RT. Suppression of adrenocorticotrophic activity in the ascorbic acid deficient guinea-pig. Br J Pharmacol. (1971)
  173. Kodama M, et al. Intraperitoneal administration of ascorbic acid delays the turnover of 3H-labelled cortisol in the plasma of an ODS rat, but not in the Wistar rat. Evidence in support of the cardinal role of vitamin C in the progression of glucocorticoid synthesis. In Vivo. (1996)
  174. Kodama M, et al. Vitamin C infusion treatment enhances cortisol production of the adrenal via the pituitary ACTH route. In Vivo. (1994)
  175. Davison G, Gleeson M. The effect of 2 weeks vitamin C supplementation on immunoendocrine responses to 2.5 h cycling exercise in man. Eur J Appl Physiol. (2006)
  176. Kallner A. Influence of vitamin C status on the urinary excretion of catecholamines in stress. Hum Nutr Clin Nutr. (1983)
  177. Ayinde OC, Ogunnowo S, Ogedegbe RA. Influence of Vitamin C and Vitamin E on testicular zinc content and testicular toxicity in lead exposed albino rats. BMC Pharmacol Toxicol. (2012)
  178. Harikrishnan R, et al. Protective effect of ascorbic acid against ethanol-induced reproductive toxicity in male guinea pigs. Br J Nutr. (2013)
  179. Jewo PI, et al. The protective role of ascorbic acid in burn-induced testicular damage in rats. Burns. (2012)
  180. Saki G, et al. Effect of administration of vitamins C and E on fertilization capacity of rats exposed to noise stress. Noise Health. (2013)
  181. Takhshid MA, et al. Protective effect of vitamins e and C on endosulfan-induced reproductive toxicity in male rats. Iran J Med Sci. (2012)
  182. Vani K, et al. Clinical relevance of vitamin C among lead-exposed infertile men. Genet Test Mol Biomarkers. (2012)
  183. Thomas LD, et al. Ascorbic acid supplements and kidney stone incidence among men: a prospective study. JAMA Intern Med. (2013)
  184. Flatmark T, Terland O. Cytochrome b 561 of the bovine adrenal chromaffin granules. A high potential b-type cytochrome. Biochim Biophys Acta. (1971)
  185. Njus D, et al. Electron transfer across the chromaffin granule membrane. J Biol Chem. (1983)
  186. Levine M, et al. Ascorbic acid and catecholamine secretion from cultured chromaffin cells. J Biol Chem. (1983)
  187. Padayatty SJ, et al. Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone. Am J Clin Nutr. (2007)
  188. Stone KJ, Townsley BH. The effect of L-ascorbate on catecholamine biosynthesis. Biochem J. (1973)
  189. Kurtzman D, et al. Fatigue and lower-extremity ecchymosis in a 36-year-old woman. Scurvy. Arch Dermatol. (2012)
  190. Olmedo JM, et al. Scurvy: a disease almost forgotten. Int J Dermatol. (2006)
  191. Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol. (1999)
  192. Amano A, et al. Effect of ascorbic acid deficiency on catecholamine synthesis in adrenal glands of SMP30/GNL knockout mice. Eur J Nutr. (2013)
  193. Menniti FS, Knoth J, Diliberto EJ Jr. Role of ascorbic acid in dopamine beta-hydroxylation. The endogenous enzyme cofactor and putative electron donor for cofactor regeneration. J Biol Chem. (1986)
  194. Richards ML, Sadee W. Human neuroblastoma cell lines as models of catechol uptake. Brain Res. (1986)
  195. May JM, et al. Ascorbic acid efficiently enhances neuronal synthesis of norepinephrine from dopamine. Brain Res Bull. (2013)
  196. Bedwal RS, Bahuguna A. Zinc, copper and selenium in reproduction. Experientia. (1994)
  197. Tuncer I, et al. Histological effects of zinc and melatonin on rat testes. Bratisl Lek Listy. (2011)
  198. Kratzing CC, Kelly JD, Kratzing JE. Ascorbic acid in fetal rat brain. J Neurochem. (1985)
  199. Kratzing CC, Kelly JD. Tissue levels of ascorbic acid during rat gestation. Int J Vitam Nutr Res. (1982)
  200. Zalani S, Rajalakshmi R, Parekh LJ. Ascorbic acid concentration of human fetal tissues in relation to fetal size and gestational age. Br J Nutr. (1989)
  201. Lykkesfeldt J, et al. Vitamin C deficiency in weanling guinea pigs: differential expression of oxidative stress and DNA repair in liver and brain. Br J Nutr. (2007)
  202. Harrison FE, et al. Low ascorbic acid and increased oxidative stress in gulo(-/-) mice during development. Brain Res. (2010)
  203. Harrison FE, et al. Low vitamin C and increased oxidative stress and cell death in mice that lack the sodium-dependent vitamin C transporter SVCT2. Free Radic Biol Med. (2010)
  204. Tveden-Nyborg P, et al. Vitamin C deficiency in early postnatal life impairs spatial memory and reduces the number of hippocampal neurons in guinea pigs. Am J Clin Nutr. (2009)
  205. Tveden-Nyborg P, et al. Maternal vitamin C deficiency during pregnancy persistently impairs hippocampal neurogenesis in offspring of guinea pigs. PLoS One. (2012)
  206. Richardson ME, Fox MR, Fry BE Jr. Pathological changes produced in Japanese quail by ingestion of cadmium. J Nutr. (1974)
  207. Fox MR. Protective effects of ascorbic acid against toxicity of heavy metals. Ann N Y Acad Sci. (1975)
  208. Fox MRS, et al. EFFECTS OF VITAMIN C AND IRON ON CADMIUM METABOLISM. Ann NY Acad Sci. (1980)
  209. Fox MR, et al. Effect of ascorbic acid on cadmium toxicity in the young coturnix. J Nutr. (1971)
  210. Suzuki T, Yoshida A. Long-term effectiveness of dietary iron and ascorbic acid in the prevention and cure of cadmium toxicity in rats. Am J Clin Nutr. (1978)
  211. Hill CH. Interactions of vitamin C with lead and mercury. Ann N Y Acad Sci. (1980)
  212. Blackstone S, Hurley RJ, Hughes RE. Some inter-relationships between vitamin C (L-ascorbic acid) and mercury in the guinea-pig. Food Cosmet Toxicol. (1974)
  213. Murray DR, Hughes RE. The influence of dietary ascorbic acid on the concentration of mercury in guinea-pig tissues {proceedings}. Proc Nutr Soc. (1976)
  214. Chatterjee GC, Pal DR. Metabolism of L-ascorbic acid in rats under in vivo administration of mercury: effect of L-ascorbic acid supplementation. Int J Vitam Nutr Res. (1975)
  215. Goyer RA, Cherian MG. Ascorbic acid and EDTA treatment of lead toxicity in rats. Life Sci. (1979)
  216. Calabrese EJ, et al. The effects of vitamin C supplementation on blood and hair levels of cadmium, lead, and mercury. Ann N Y Acad Sci. (1987)
  217. Naha N, Manna B. Mechanism of lead induced effects on human spermatozoa after occupational exposure. Kathmandu Univ Med J (KUMJ). (2007)
  218. Naha N, Chowdhury AR. Inorganic lead exposure in battery and paint factory: effect on human sperm structure and functional activity. J UOEH. (2006)
  219. Stamp LK, et al. Clinically insignificant effect of supplemental vitamin C on serum urate in patients with gout; A pilot randomised controlled trial. Arthritis Rheum. (2013)
  220. May JM, Qu ZC, Mendiratta S. Protection and recycling of alpha-tocopherol in human erythrocytes by intracellular ascorbic acid. Arch Biochem Biophys. (1998)
  221. Niki E, et al. Interaction among vitamin C, vitamin E, and beta-carotene. Am J Clin Nutr. (1995)
  222. Seregi A, Schaefer A, Komlós M. Protective role of brain ascorbic acid content against lipid peroxidation. Experientia. (1978)
  223. Kovachich GB, Mishra OP. The effect of ascorbic acid on malonaldehyde formation, K+, Na+ and water content of brain slices. Exp Brain Res. (1983)
  224. Sato K, Saito H, Katsuki H. Synergism of tocopherol and ascorbate on the survival of cultured brain neurones. Neuroreport. (1993)
  225. Bano S, Parihar MS. Reduction of lipid peroxidation in different brain regions by a combination of alpha-tocopherol and ascorbic acid. J Neural Transm. (1997)
  226. Hazell T. Vitamin C has a key physiological role in facilitating the absorption of non-heme iron from the diet. Hum Nutr Appl Nutr. (1987)
  227. Kalgaonkar S, Lönnerdal B. Effects of dietary factors on iron uptake from ferritin by Caco-2 cells. J Nutr Biochem. (2008)
  228. Han O, et al. Ascorbate offsets the inhibitory effect of inositol phosphates on iron uptake and transport by Caco-2 cells. Proc Soc Exp Biol Med. (1995)
  229. Engle-Stone R, et al. Meat and ascorbic acid can promote Fe availability from Fe-phytate but not from Fe-tannic acid complexes. J Agric Food Chem. (2005)
  230. Mirvish SS, et al. Ascorbate-nitrite reaction: possible means of blocking the formation of carcinogenic N-nitroso compounds. Science. (1972)
  231. Tannenbaum SR, Wishnok JS, Leaf CD. Inhibition of nitrosamine formation by ascorbic acid. Am J Clin Nutr. (1991)
  232. Mirvish SS. Effects of vitamins C and E on N-nitroso compound formation, carcinogenesis, and cancer. Cancer. (1986)
  233. Combet E, et al. Dietary phenolic acids and ascorbic acid: Influence on acid-catalyzed nitrosative chemistry in the presence and absence of lipids. Free Radic Biol Med. (2010)
  234. Chang SK, et al. Accelerating effect of ascorbic acid on N-nitrosamine formation and nitrosation by oxyhyponitrite. Cancer Res. (1979)
  235. Loh YH, et al. N-Nitroso compounds and cancer incidence: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study. Am J Clin Nutr. (2011)
  236. Mirvish SS, et al. Effect of feeding nitrite, ascorbate, hemin, and omeprazole on excretion of fecal total apparent N-nitroso compounds in mice. Chem Res Toxicol. (2008)
  237. Johnston CS. Biomarkers for establishing a tolerable upper intake level for vitamin C. Nutr Rev. (1999)
  238. Hoyt CJ. Diarrhea from vitamin C. JAMA. (1980)
  239. Sauberlich HE. Bioavailability of vitamins. Prog Food Nutr Sci. (1985)
  240. McHugh GJ, Graber ML, Freebairn RC. Fatal vitamin C-associated acute renal failure. Anaesth Intensive Care. (2008)
  241. Nankivell BJ, Murali KM. Images in clinical medicine. Renal failure from vitamin C after transplantation. N Engl J Med. (2008)
  242. Lawton JM, et al. Acute oxalate nephropathy after massive ascorbic acid administration. Arch Intern Med. (1985)
  243. Swartz RD, et al. Hyperoxaluria and renal insufficiency due to ascorbic acid administration during total parenteral nutrition. Ann Intern Med. (1984)
  244. Wong K, et al. Acute oxalate nephropathy after a massive intravenous dose of vitamin C. Aust N Z J Med. (1994)
  245. Alkhunaizi AM, Chan L. Secondary oxalosis: a cause of delayed recovery of renal function in the setting of acute renal failure. J Am Soc Nephrol. (1996)
  246. Rathi S, Kern W, Lau K. Vitamin C-induced hyperoxaluria causing reversible tubulointerstitial nephritis and chronic renal failure: a case report. J Med Case Rep. (2007)
  247. Mashour S, Turner JF Jr, Merrell R. Acute renal failure, oxalosis, and vitamin C supplementation: a case report and review of the literature. Chest. (2000)
  248. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. (2003)
  249. Hatch M, et al. Effect of megadoses of ascorbic acid on serum and urinary oxalate. Eur Urol. (1980)
  250. Gabardi S, Munz K, Ulbricht C. A review of dietary supplement-induced renal dysfunction. Clin J Am Soc Nephrol. (2007)
  251. Baxmann AC, De O G Mendonça C, Heilberg IP. Effect of vitamin C supplements on urinary oxalate and pH in calcium stone-forming patients. Kidney Int. (2003)
  252. Mazloom Z, et al. Effect of vitamin C supplementation on postprandial oxidative stress and lipid profile in type 2 diabetic patients. Pak J Biol Sci. (2011)
  253. De Marchi S, et al. Ascorbic acid prevents vascular dysfunction induced by oral glucose load in healthy subjects. Eur J Intern Med. (2012)
  254. Khemis A, et al. A randomized controlled study to evaluate the depigmenting activity of L-ascorbic acid plus phytic acid-serum vs. placebo on solar lentigines. J Cosmet Dermatol. (2011)
  255. Gomes ME, et al. High dose ascorbic acid does not reverse central sympathetic overactivity in chronic heart failure. J Clin Pharm Ther. (2011)
  256. Colby JA, et al. Effect of ascorbic acid on inflammatory markers after cardiothoracic surgery. Am J Health Syst Pharm. (2011)
  257. Talaulikar VS, Chambers T, Manyonda I. Exploiting the antioxidant potential of a common vitamin: could vitamin C prevent postmenopausal osteoporosis. J Obstet Gynaecol Res. (2012)
  258. Petersen EE, et al. Efficacy of vitamin C vaginal tablets in the treatment of bacterial vaginosis: a randomised, double blind, placebo controlled clinical trial. Arzneimittelforschung. (2011)
  259. Stewart JM, Ocon AJ, Medow MS. Ascorbate improves circulation in postural tachycardia syndrome. Am J Physiol Heart Circ Physiol. (2011)
  260. Knab AM, et al. Quercetin with vitamin C and niacin does not affect body mass or composition. Appl Physiol Nutr Metab. (2011)
  261. Fernandes PR, et al. Vitamin C restores blood pressure and vasodilator response during mental stress in obese children. Arq Bras Cardiol. (2011)
  262. Theodorou AA, et al. No effect of antioxidant supplementation on muscle performance and blood redox status adaptations to eccentric training. Am J Clin Nutr. (2011)
  263. Roberts LA, et al. Vitamin C consumption does not impair training-induced improvements in exercise performance. Int J Sports Physiol Perform. (2011)
  264. Knab AM, et al. Influence of quercetin supplementation on disease risk factors in community-dwelling adults. J Am Diet Assoc. (2011)
  265. Pareyson D, et al. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol. (2011)
  266. Yfanti C, et al. Effect of antioxidant supplementation on insulin sensitivity in response to endurance exercise training. Am J Physiol Endocrinol Metab. (2011)
  267. Kuiper HC, et al. Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans. Free Radic Biol Med. (2011)
  268. Kalpdev A, Saha SC, Dhawan V. Vitamin C and E supplementation does not reduce the risk of superimposed PE in pregnancy. Hypertens Pregnancy. (2011)
  269. Christen WG, et al. Age-related cataract in a randomized trial of vitamins E and C in men. Arch Ophthalmol. (2010)
  270. Lagowska-Lenard M, Stelmasiak Z, Bartosik-Psujek H. Influence of vitamin C on markers of oxidative stress in the earliest period of ischemic stroke. Pharmacol Rep. (2010)
  271. Hauth JC, et al. Vitamin C and E supplementation to prevent spontaneous preterm birth: a randomized controlled trial. Obstet Gynecol. (2010)
  272. Constantini NW, et al. The effect of vitamin C on upper respiratory infections in adolescent swimmers: a randomized trial. Eur J Pediatr. (2011)
  273. Zhang M, et al. Vitamin C provision improves mood in acutely hospitalized patients. Nutrition. (2011)
  274. Nazıroğlu M, et al. Vitamins C and E treatment combined with exercise modulates oxidative stress markers in blood of patients with fibromyalgia: a controlled clinical pilot study. Stress. (2010)
  275. Ruiz-Ramos M, et al. Supplementation of ascorbic acid and alpha-tocopherol is useful to preventing bone loss linked to oxidative stress in elderly. J Nutr Health Aging. (2010)
  276. Ristow M, et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. (2009)
  277. Chuin A, et al. Effect of antioxidants combined to resistance training on BMD in elderly women: a pilot study. Osteoporos Int. (2009)
  278. Block G, et al. Vitamin C treatment reduces elevated C-reactive protein. Free Radic Biol Med. (2009)
  279. Retana-Ugalde R, et al. High dosage of ascorbic acid and alpha-tocopherol is not useful for diminishing oxidative stress and DNA damage in healthy elderly adults. Ann Nutr Metab. (2008)
  280. Ataka S, et al. Effects of Applephenon and ascorbic acid on physical fatigue. Nutrition. (2007)
  281. Guarnieri S, Riso P, Porrini M. Orange juice vs vitamin C: effect on hydrogen peroxide-induced DNA damage in mononuclear blood cells. Br J Nutr. (2007)
  282. Bryer SC, Goldfarb AH. Effect of high dose vitamin C supplementation on muscle soreness, damage, function, and oxidative stress to eccentric exercise. Int J Sport Nutr Exerc Metab. (2006)
  283. Camargo JL, Stifft J, Gross JL. The effect of aspirin and vitamins C and E on HbA1c assays. Clin Chim Acta. (2006)
  284. Bryant RJ, et al. Effects of vitamin E and C supplementation either alone or in combination on exercise-induced lipid peroxidation in trained cyclists. J Strength Cond Res. (2003)
  285. Fuller CJ, May MA, Martin KJ. The effect of vitamin E and vitamin C supplementation on LDL oxidizability and neutrophil respiratory burst in young smokers. J Am Coll Nutr. (2000)
  286. Johnston CS, Dancho CL, Strong GM. Orange juice ingestion and supplemental vitamin C are equally effective at reducing plasma lipid peroxidation in healthy adult women. J Am Coll Nutr. (2003)
  287. Kim MK, et al. Long-term vitamin C supplementation has no markedly favourable effect on serum lipids in middle-aged Japanese subjects. Br J Nutr. (2004)
  288. Stamatelopoulos KS, et al. Oral administration of ascorbic acid attenuates endothelial dysfunction after short-term cigarette smoking. Int J Vitam Nutr Res. (2003)
  289. Thompson D, et al. Prolonged vitamin C supplementation and recovery from eccentric exercise. Eur J Appl Physiol. (2004)
  290. Kinlay S, et al. Long-term effect of combined vitamins E and C on coronary and peripheral endothelial function. J Am Coll Cardiol. (2004)
  291. Van Hoydonck PG, et al. Does vitamin C supplementation influence the levels of circulating oxidized LDL, sICAM-1, sVCAM-1 and vWF-antigen in healthy male smokers. Eur J Clin Nutr. (2004)
  292. Mastaloudis A, et al. Antioxidant supplementation prevents exercise-induced lipid peroxidation, but not inflammation, in ultramarathon runners. Free Radic Biol Med. (2004)

(Common misspellings for Vitamin C include ascorbat, ascorbc, askorbic, ascorbik, vitmin, vitamn)

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