Vitamin C

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

This page features 301 unique references to scientific papers.


All Essential Benefits/Effects/Facts & Information

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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Things To Know

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. Medical Disclaimer

How to Take

Recommended dosage, active amounts, other details

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.

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Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects vitamin c has on your body, and how strong these effects are.

Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Plasma Vitamin C Strong Very High See all 3 studies
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).
Blood Flow Minor Very High See all 4 studies
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 thereof); this is a phenomena general to antioxidants and not unique to Vitamin C
Low See all 6 studies
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 or antioxidant (respectively). There is no influence on resting cortisol concentrations.
General Oxidation Minor Moderate See all 6 studies
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 an increase being possible)
Heart Rate Minor Low See all 3 studies
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) seems unlikely.
Lipid Peroxidation Minor Low See all 6 studies
Mixed and weak influences on lipid peroxidation, but a possible reduction exists
Muscle Damage Minor Moderate See all 4 studies
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
Aerobic Exercise - Very High See all 4 studies
No significant influence on aerobic exercise performance
Exercise-Induced Immune Suppression - Very High See all 6 studies
More evidence suggests no significant effect than a possible protective effect, although the latter is possible
Inflammation - Very High See all 4 studies
No significant alterations seen in inflammatory cytokines associated with Vitamin C supplementation
Protection from Smoking - High See all 3 studies
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 in blood flow may be attenuated somewhat with antioxidants and this applies to Vitamin C
Adaptations to Exercise Minor Moderate See 2 studies
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 is seems possible with antioxidants
Anti-Oxidant Enzyme Profile Minor Very High See study
An increase in antioxidant enzymes have been noted in elderly persons
Bone Mineral Density Minor Very High See 2 studies
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 effect is not remarkably large
C-Reactive Protein Minor Very High See study
A possible reduction in C-Reactive Protein exists with Vitamin C supplementation
Fatigue Minor Very High See study
A decrease in fatigue has been noted in obese adults given Vitamin C in conjunction with exercise
Frequency of Intercourse Minor Very High See study
Supplementation of 3,000mg Vitamin C appears to increase sexual frequency from 4 times monthly to 14 times. No influence on masturbation frequency
Microcirculation Minor Very High See study
An increase in microcirculation has been noted secondary to increased blood flow, thought to be a general property of antioxidants
Muscle Soreness Minor Very High See study
A possible reduction in muscle soreness the day after exercise may result when preloading exercise with Vitamin C
Rate of Perceived Exertion Minor Moderate See 2 studies
The rate of percieved exertion in obese adults appears to be attenuated with Vitamin C supplementation
Subjective Well-Being Minor Very High See study
An improvement in mood has been noted in hospitalized persons
Symptoms of Bacterial Vaginosis Minor Very High See study
Vaginal bacterial infections are somewhat treatable with directly applied (via silicon coated tablets), as Vitamin C exerts some antioxidant effects against those bacterial strains
DNA Damage - Very High See 2 studies
No significant influences on DNA damage
Depression Low See study
Exercise-Induced Oxidation - Low See 2 studies
Highly mixed interactions with the exercise:oxidation axis with Vitamin C, with both increases and decreases being noted. Unlikely to have a reliable role
Fat Mass - Very High See study
Does not appear to significantly influence fat mass
Fat Oxidation - Very High See study
No significant influence on fat oxidation
Glycemic Control - Very High See study
No significant influence on glycemic control in diabetics with Vitamin C supplementation
HDL-C - Very High See study
No significant influence on HDL cholesterol
HbA1c - Very High See study
No significant influence of Vitamin C supplementation on HbA1c levels
Heart Palpitations - Very High See study
No significant influence on heart palpitations
Insulin Sensitivity - Very High See study
No significant influence on insulin sensitivity
LDL-C - Very High See study
No significant alterations in LDL cholesterol seen with Vitamin C supplementation
Length of Sickness - Moderate See 2 studies
Mixed influences on the length one is sick for, with possibly no effect
Mineral Bioaccumulation Low See study
Oxidation of LDL - Very High See 2 studies
No significant influence on the oxidation rates of LDL cholesterol
Oxygenation Cost of Exercise Low See study
Pre-Eclampsia Risk - Very High See study
No significant influence on pre-eclampsia risk
Risk of Cataracts - Very High See study
No significant influence on the risk of cataracts
Seminal Motility Low See study
Sperm Quality Low See study
Spontaneous Birth Risk - Very High See study
No significant influence on spontaneous birthing
Symptoms of Charcot-Marie-Tooth Disease - Very High See study
Insufficient evidence to support a role
Total Cholesterol - Very High See 2 studies
No significant influence on total cholesterol seems apparent with vitamin C supplementation
Triglycerides - Very High See 2 studies
No significant influence on fasting or postprandial triglycerides seems apparent with Vitamin C
Upper Respiratory Tract Infection Risk - Very High See 2 studies
No significant influence on the rate of acquiring sickness
VO2 Max - Very High See study
Does not appear to have a role in altering VO2 max
Weight - Very High See 2 studies
Vitamin C does not appear to have a weight reducing effect
Interleukin 6 - Low See study
Symptoms of Osteoarthritis - Very High See study
No significant influence on the symptoms of osteoarthritis

Studies Excluded from Consideration

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Scientific Research

Table of Contents:

  1. 1 Sources and Structure
    1. 1.1 Sources
    2. 1.2 Biological Significance
    3. 1.3 Structure and Properties
    4. 1.4 Supplement Variants and Specifications
  2. 2 Pharmacology
    1. 2.1 Serum
    2. 2.2 Distribution
    3. 2.3 Metabolism
  3. 3 Neurology
    1. 3.1 Kinetics and Distribution
    2. 3.2 Mechanisms
    3. 3.3 Acetylcholine
    4. 3.4 Neuroprotection
    5. 3.5 Stress
    6. 3.6 Depression
    7. 3.7 Dementia
    8. 3.8 Alzheimer's
  4. 4 Cardiovascular Health
    1. 4.1 Blood Flow
    2. 4.2 Artherosclerosis
  5. 5 Interactions with Glucose Metabolism
    1. 5.1 Pancreas
    2. 5.2 Cancer
  6. 6 039;Fallon JR, Schutt AJ, O&
  7. 7 Exercise and Physical Performance
    1. 7.1 Mechanisms
    2. 7.2 Exercise Immunology
    3. 7.3 Delayed Onset Muscle Soreness (DOMS)
    4. 7.4 Power Output
    5. 7.5 Endurance Performance
  8. 8 Skeletal and Bone Metabolism
    1. 8.1 Bone Mass
  9. 9 Inflammation and Immunology
    1. 9.1 Cold and Flu
    2. 9.2 Bacterial Interactions
  10. 10 Interactions with Oxidation
    1. 10.1 Mechanisms
    2. 10.2 Antioxidant Enzymes
  11. 11 Interactions with Hormones
    1. 11.1 Cortisol
    2. 11.2 Testosterone
  12. 12 Interactions with Lungs
    1. 12.1 Smoking
  13. 13 Interactions with other Organ Systems
    1. 13.1 Kidneys
    2. 13.2 Adrenal Glands
    3. 13.3 Testicles
  14. 14 Pregnancy and Infancy
    1. 14.1 Requirements
  15. 15 Various other Clinical Usages
    1. 15.1 Mineral Accumulation and Chelation
    2. 15.2 Gout
  16. 16 Nutrient-Nutrient Interactions
    1. 16.1 Vitamin E
    2. 16.2 Dietary Minerals
    3. 16.3 Nitrates
  17. 17 Safety and Toxicology
    1. 17.1 General
    2. 17.2 Case studies

1Sources 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 or Mineral, first structurally identified by Szent-Gyorgyi, Waugh, and King in 1932-1935[5][6] and first synthesized by Haworth and Hirst in 1933.[7] It has been popularized mostly by Linus Pauling for prevention of the common cold[8][9][10] and has since been said to be the most popular supplement in the world.[11]

Vitamin C is most commonly supplemented because of its potential protection against the common cold,[12] and purported anticancer effects.[13] Athletes report using vitamin C for both the antioxidant properties and potential immune support.[14]

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.[15] 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.[15]

Average dietary intakes have been reported to be 152+/-83.7mg in spain,[16]

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[17])

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

  • Citrus Fruits (29.6% in spain,[16] usually oranges[18]) and 9% in the US (all fruits inclusive[19])

  • Noncitrus fruits (21.5% in spain,[16] usually apples[18])

  • Juices (6.3% in spain[16] and 25-34% in the US[20][19])

  • Fruiting vegetables (usually peppers and sweet peppers) at 20% in spain[16] and 23% in the US (all vegetables inclusive[19])

  • Potatoes (3.9% in spain[16])

  • Leafy green vegetables (6.7% in spain[16])

  • Cruciferous vegetables (2.9% in spain[16])

  • Fortified cereals (4% in US[19])

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[21]), and some neurotransmitters (particularly catecholamines).[11] 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.[11] 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[22][23] (50μM is right in the middle of the 40-60μM range found in humans[24][25]).

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).[26] 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.[27] 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.[28]

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.[11] 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.[11][29]

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,[30][31] and the ability of a molecule to prevent scurvy (of which Vitamin C is the reference drug) is known as being anti-scorbutic.[32]

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,[11] smoking,[33][34] type II diabetes[35][36] despite consuming adequate vitamin C,[37] and in persons who have very recently suffered a myocardial infarction[38][39] or acute pancreatitis (these last two normalizing after some time).[40][41]

It has been noted[42] 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[43]); at least in myocardial infarction[44] and acute pancreatitis,[45] there is a drastic increase in oxidation rapidly and both diabetes[46] and smoking[33] 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[11]

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.[47] 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.[48] Due to this, it appears that Ascorbyl-6-Palmitate is used often in antioxidant supplements,[11] 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.[49]

Beyond this, Ester-C appears to be more effective at treating scurvy (Vitamin C deficiency)[50] and at decreasing oxalate levels (a metabolite of Vitamin C),[51][52] Ester-C has been reported to reduce the common cold, but was not compared to basic Vitamin C and has not been replicated.[53]

Studies conducted using Ester-C that have been funded by Zila Nutraceuticals are cited following this sentence.[49]

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


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;[24][25] the difference is possibly due to a short half-life of dehydroasorbate of 2-6 minutes.[54] 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.[55]

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[56]) and have a prolonged half-life of 8-40 days.[57] 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).[58]

2.2. Distribution

Supplementation of 500mg Vitamin C twice daily appears to increase expression of the transporter that mediates uptake of vitamin C in skeletal muscle (SVCT2) and subsequently Vitamin C concentrations after one week, maintaining over 42 days of supplementation, despite no alterations in oxidative balance.[59]

2.3. 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.[11][54]

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[60][61] 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


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.[62][63] Due to this, it is known to be transported across the blood brain barrier.[64][65] While from systemic circulation (through the blood brain barrier) the oxidized form of dehydroascorbate appears to be required to be transported through GLUT transporters,[65] the choroid plexus epithelium (connection of cerebrospinal fluid to the brain) expresses SVCT2[66][67] and this appears to be the majority route of entry.[67][68][69]

There appears to be a 4-fold higher cerebrospinal fluid concentration of ascorbate relative to plasma in rats,[70][69] resulting in a cerebrospinal concentration of around 200-400μM when plasma are 60μM or less[71][72] although human measurements are more modest at 160μM relative to the same plasma level of 40-60μM.[73][74]

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[75][76][77] with slightly lower concentrations in the frontal cortex, thalamic nuclei, olfactoy bulb, and striatum with lowest detected in the spinal cord and pons (lowest).[75][78] 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[79] and frontal cortex[80]), although this does not fully explain the distribution as the parietal cortex does not possess SVCT2.[80]

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[27][81][82]) and other neurohormones such as oxytocin, vasopressin, and α-Melanocyte-stimulating hormone.[28][83] 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.[62][84] 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.[85]

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).[86]

3.4. Neuroprotection

Vitamin C has been found to, in vitro, protect cerebellar granule cells from glutamate induced excitotoxicity[87][88] which is thought to be related to how NDMA receptors can respond to REDOX modulation.[89][90] This is more of a general phenomena that applies to reducing agents (antioxidants), and is abolished by prooxidants.[90]

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[91] and mental[92][93]), 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.[94]

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).[95] In short, potassium channel blockers appear to have anti-depressant effects[96] while potassium channel openers have pro-depressive effects and inhibit the actions of potassium channel blockers[97][96] and vitamin C appears to be synergistically antidepressive with potassium channel blockers.[95]

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,[98][95] chronic unpredictable manageable stress,[99] and acute stress[94] 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[100] 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);[101] 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.[102]

3.8. Alzheimer's

In regards to Alzheimer's, oxidative stress is thought to play a major role in the pathogenesis of the disease[103] with byproducts of peroxidation being detected in higher than normal levels in neurofibrillary tangles[104][105][106] and lower serum vitamin C concentrations despite adequate dietary intake[107] although due to a higher cerebrospinal fluid to plasma ratio in alzheimer's (5.1 relative to 3.1 in controls[108]) it is thought the lower serum concentration reflects increased uptake by the brain to counter increaed oxidative stress;[109] 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)[110] 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).[111]

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

4Cardiovascular 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.[112]

The endothelial variant of the NOS enzyme (eNOS) appears to be susceptible to oxidative damage, including both translation of the enzyme itself[113] and the required cofactor tetrahydrobiopterin is readily oxidized and rendered inactive.[114] 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[115] secondary to 'recycling' (preserving) tetrahydrobiopterin.[116][117] As this is an antioxidative effect and other studies in animals have noted comparable benefits with other antioxidants (such as Melatonin[118][119]) 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[120] which would otherwise reduce nitric oxide into peroxynitrate[121] and directly reducing nitrite (product of Nitrate) into nitric oxide[122] or producing nitric oxide from S-nitrosothiols.[123]

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.[11][124][125] This increase in cholesterol retention (by reducing its elimination rate) also appears to be a risk factor for cardiovascular diseases and particularly artherosclerosis.[126][127]

5Interactions with Glucose Metabolism

5.1. Pancreas

Ascorbate appears to be important to a pancreatic β-cell due in part to its antioxidant properties[128] (these cells tend to have low levels of antioxidant enzymes[129][130]) and its presence is required for proper secretion of insulin.[131] In rats that are able to synthesize vitamin C, it accumulates to high levels in these cells.[132] Furthermore, there is possible competitive inhibition of ascorbate acid metabolites (dehydroascorbate) with glucose as they use the same transporter.[133]

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),[134] 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

5.2. Cancer

Recent[135] research has shown that vitamin C interactions with glucose metabolism may make it useful as a potential anti-cancer agent.[136] Although Vitamin C anti-cancer effects were proposed as early as the 1970s by the Nobel prize winning chemist Dr. Linus Pauling,[137] later clinical trials failed to demonstrate any efficacy as a cancer treatment.[138][135]

This cast doubt on any anti-cancer properties for vitamin C, which was further reinforced by studies suggesting that antioxidants may actually give cancer cells an advantage by promoting, rather than inhibiting tumorigenesis.[139] It turns out that Linus Pauling may have been right after all about vitamin C and cancer, but not for the reasons he originally envisioned. At high doses vitamin C promotes, rather than reduces oxidative stress in cancer cells, leading to cytotoxic effects.[140]

The mechanism behind the selective toxicity of vitamin C against cancer cells was unknown until only recently, when a recent study found that vitamin C-induced oxidative stress inhibits GAPDH, an important metabolic enzyme in the glycolytic pathway.[136] Because cancer cells tend to rely on high rates of glycolysis for survival,[141] the ability of high-dose vitamin C to suppress glycolytic metabolism confer anti-tumorigenic activity in certain types of cancer cells.[136]

By suppressing an important enzyme in the glycolytic pathway, high dose vitamin C may have selectively kill certain types of cancer cells. Clinical trials are currently under way to evaluate the efficacy of vitamin C as a cancer treatment in humans.

7Exercise and Physical Performance

7.1. Mechanisms

Skeletal muscle is known to be a large store of bodily vitamin C (around two thirds[142]) 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[143]). Vitamin C is readily taken up via SVCT transporters in skeletal muscle tissue.[144]

The main mechanism of concern with Vitamin C supplementation and muscle metabolism would be the antioxidant properties of Vitamin C,[145] 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

7.2. 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.[146] Despite an interaction with cortisol following exercise with Vitamin C supplemenation (1,500mg for 7-12 days)[147][148][149][150] a few studies measuring IgA have failed to find any significant influence, with similar decreases in both placebo and Vitamin C.[148][149] One study has noted a significant increase in post-exercise lymphocyte counts associated with a decrease in cortisol,[150] whereas another has reported a relative suppression.[147]

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[151] nor any influence on IL-6 following short-term exercise.[150] 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).[152]

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.[149]

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.[151][148] 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.[153][154]

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

7.3. 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]

7.4. 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]

7.5. 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.[155] 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.[156]

In another study, 11 health men took 500 mg vitamin C twice daily along with 400 IU vitamin E once daily or placebo for four weeks. They were then subject to a strenuous 60 minute exercise routine on a stationary bicycle. The VO2peak of the vitamin group did not differ from placebo, nor did the rate of perceived exertion or maximal power output.[3]

8Skeletal and Bone Metabolism

8.1. 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.[157] 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.[157]

9Inflammation and Immunology

9.1. 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%);[158][154] 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[153])

It has been noted[159] 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[160] was in regards to children in a skiing school (German PDF[161]).

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

9.2. 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.[162] 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

10Interactions with Oxidation

10.1. 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.[163][164][165] 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.[166] Although conversion of the two AFR molecules into dehydroascorbic acid is also reversible (various antioxidant enzymes such as glutathione or thiol reductases[167]), it can possibly not occur due to a short half-life of around 2-6 minutes under physiological conditions[54] the dehydroascorbic molecule and spontaenous formation of 2,3-diketogulonic acid which is irreversible and cannot be converted back into L-ascorbic acid.[54] 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-)[168] and some reactive nitrogen species such as peroxynitrate either directly[169] or reducing an O2- induced conversion of Nitric Oxide into peroxynitrate.[168]

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.[170][171] Dietary minerals in vitro are able to oxidize ascorbate as ascorbate is oxidized in the presence of minerals such as iron or copper[172][173] while chelating the minerals prevents autooxidation;[174] this reduction of minerals via ascorbate produces reduced minerals that are better able to exert prooxidative effects. It has been noted[171] 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.

10.2. Antioxidant Enzymes

Exercise is known to reduce oxidation levels in serum[175][176] possibly associated with an increase in antioxidant enzymes,[177][178] 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]

In a study where 11 healthy men took 500 mg of vitamin C twice daily plus 400 IU vitamin E for 4 weeks before being subject to strenuous aerobic exercise, the vitamin group had lower superoxide dismutase activity in their muscles versus the placebo group measured through a muscle biopsy. However, markers of oxidative stress in the muscle biopsy was ultimately unaffected.[3]

11Interactions with Hormones

11.1. Cortisol

A deficiency of vitamin C in rodents tends to result in elevated plasma cortisol without influencing ACTH concentrations,[179][180] and ACTH stimulation appears to be somewhat hindered despite higher serum cortisol concentrations.[181]

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[182] and has been found to enhance ACTH-induced cortisol production.[183]

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[147][150] and up to 12 days supplementation[149] 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,[149] or a relative decrease.[150] These results are not unanimous as some studies note only a trend towards a reduction in cortisol that fails to reach significance,[184] 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).[151][148] These studies either fail to report an increase in oxidative damage[148] or actually note increases in some oxidative biomarkers such as F2-Isoprostane,[151] 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.[185]

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

11.2. 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,[186]Alcohol ingestion,[187] stressors such as noise or burns,[188][189] and various research toxins that act via pro-oxidative means.[190] These protective effects have been noted at oral doses as low as 20-40mg/kg in rats[190][186] and similar protective effects on the testicles has been noted in human males at 1,000mg vitamin C daily.[191]

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

12Interactions with Lungs

12.1. Smoking

13Interactions with other Organ Systems

13.1. 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.[192]

13.2. 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)[165][193][194] where it is then secreted alongside catecholamines,[195] which has been detected in humans when stimulated by ACTH.[196] 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).[197]

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).[198][199][200] In rodent models where vitamin C deficiencies are induced, circulating catecholamines do appear to be reduced.[201]

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[202] but has been found to increase noradrenaline production from dopamine in SH-SY5Y neuroblastoma cells (50% increase with 1mM ascorbate over 6 hours,[203] with a later study noting 100-1000µM of ascorbate or 100-300µM dehydroascrobate also causing a similar increase but a plateau at around 500µM[204]). This reaction appeared to be unique to vitamin C (the other antioxidants trolox and N-acetylcysteine failed to mimic the results).[204]

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.[185]

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

13.3. 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[205][206]), vitamin C supplementation preserved testosterone concentrations that dropped with lead.[186]

14Pregnancy and Infancy

14.1. Requirements

In rat brains, Vitamin C concentrations in the brain approximately double during the last portion of pregnancy[207][208] which does not further increase after birth (slight decline);[207] this appears to extend to human infants.[209] Lower cerebral ascorbic acid concentrations during development appear to be biomarkers of increased oxidative stress,[210][211] 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.[63][212]

Dietary requirements (FDA numbers) appear to be increased from 75mg up to 85mg (pregnancy) and 120mg (lactation)[15] 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.[213][214]

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

15Various other Clinical Usages

15.1. Mineral Accumulation and Chelation

In animal studies, vitamin C has been found to reduce cadmium toxicity[215][216][217][218][219] and is implicated in aiding elimination of both lead[220][186] and mercury (although there is mixed evidence on mercury, with a reduction of bioaccumulation,[220] exacerbation of accumulation,[221][222] and no effects on bioaccumulation (despite some protective effects)[223] 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).[224] EDTA and vitamin C are, however, additive.[224]

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.[225]

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.[4] Industrial workers exposed to lead have also noted a beneficial trend in sperm parameters with 1,000mg for 3 months[191] (lead is known to be adverse to testicular function at concentrations in industrial work utilizing lead[226][227]).

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

15.2. 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.[228]

16Nutrient-Nutrient Interactions

16.1. 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,[229][230] 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[231][232] and is synergistic with coincubation with α-tocopherol.[233][234]

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

16.2. Dietary Minerals

Vitamin C has been found to increase the absorption of both iron not bound by heme (ie. not in meat products)[235][236]) and has been noted to reduce the inhibitory effects of phytic acid[237] but not tannins.[238]

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

16.3. 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.[239][240] 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.[240] This inhibition appears to occur at a pH of 3-4,[239] and although vitamin C is most well researched for this role some other antioxidant compounds are also implicated (Vitamin E[241] and both ferulic and caffeic acid[242]).

There are some instances where vitamin C has been implicated in augmenting nitrosamine production, such as coingestion with lipids[242] and at pH values below 2.[243][239]

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.[244]

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[245] (with no influence on nitroso increases in feces from hot dog ingestion, as the nitroso compounds were premade in the hotdog).

17Safety and Toxicology

17.1. General

Vitamin C is generally thought to be safe, although at higher doses (2,000-6,000mg) may cause diarrhea;[246][247] 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.[248]

17.2. 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[249]). In other instances, clinical usage of intravenous Vitamin C has resulted in renal oxalate nephropathy when very large boluses (45-60g) are given[250][251][252][253][254] which results in development of reversible tubulointerstitial nephritis and possible renal failure.[255][256] This is a fairly treatable condition carrying a good prognosis if readily treated,[257] but again it can be fatal if left untreated or if treatment is refused.[249]

The above observations are thought to be due to the metabolism of Vitamin C into oxalate (known to occur with superloading),[258] which the (admittedly unreliable) production of excess oxalate and then deposition into kidney tissues is a known cause of renal failure.[259][260] It has been noted to be a bit more reliably occurring in calcium-kidney stone forming patients.[260]

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

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