Health Care Professional Information

Scientific Name
Ascorbic Acid, C6H8O6
Common Name

Ascorbate, sodium ascorbate

Clinical Summary

Vitamin C, also known as ascorbic acid, is a water-soluble vitamin that is found in many fresh fruits and vegetables. It is essential for a variety of physiologic functions that include formation of collagen, catecholamines, and carnitine and peptide synthesis (1) . It is not synthesized in the human body, and deficiency can cause scurvy. Oral vitamin C is consumed as an antioxidant supplement for immune protection against cold and flu, for wound healing, cardiovascular health, and cancer prevention. High-dose of intravenous vitamin C has also been used as an alternative cancer treatment.

The purported effects of vitamin C have been examined in many clinical and epidemiologic studies. Regular intake of vitamin C supplements may reduce the duration and severity of common cold. However, the effect is minimal except in people exposed to acute severe physical stress (2). Vitamin C is believed to promote cardiovascular health but findings are inconsistent. Previous studies suggest that intake of dietary vitamin C, not supplements, may reduce the risk of coronary heart diseases (3). However, two large scale randomized trials did not find any benefits (4) (5). Furthermore, supplementation with vitamins C and E increased risk of mortality and nonfatal myocardial infarction in patients with coronary artery disease (6). Data on vitamin C’s effect in reducing blood pressure are also conflicting (7) (8).

Vitamin C supplementation may reduce blood glucose and lipids in type 2 diabetes patients (9). It also decreases urinary infection rates in pregnant women (10); lowers the incidence of organ failure and shortens ICU stay after surgery (11); and protects against Alzheimer's disease (12) (13). Vitamin C can help eradicate H. pylori infection when added to standard medication regimen (14). However, antioxidants including vitamin C do not prevent or slow the progression of age-related cataract (15) or macular degeneration (16).Vitamin C may also reduce endurance training efficiency (17).

The role of vitamin C in cancer prevention is unclear. Studies indicate that vitamin C reduces oxidative stress (18). High plasma level of vitamin C is associated with lower gastrointestinal cancer incidence probably due to its protective effects against dietary carcinogenic nitroso compounds (19). Intake of vitamins A, C, or E reduced risk of cervical cancer (20), but they do not prevent gastrointestinal (21), prostate (22), lung cancers (23) and other cancer incidence or affect cancer mortality (24). Further, vitamin C supplementation is associated with increased risk of liver cancer, although this effect is not observed with vitamin C from dietary sources (25).

High-dose vitamin C has been long been used as an alternative cancer treatment (26) based on the hypothesis that the formation of new collagen resists malignant infiltration (27). Early reports using parenteral plus oral ascorbic acid showed promising results (28). But subsequent randomized, placebo-controlled trials in advanced cancer patients using 10g per day of oral vitamin C did not demonstrate any significant benefits (29) (30). This lack of effect is explained by the finding of pharmacokinetic study that ascorbic acid can only reach a limited plasma concentration through oral administration (31). A higher pharmacologic concentration, achieved only via intravenous injection, had selective cytotoxic effects on cancer cell lines (32) (33). Ascorbic acid is postulated to act as a carrier of hydrogen peroxide to the extracelluar fluid (32) where it generates free radicals against tumor cells (33). High-dose IV ascorbic acid up to 1.5g /kg/day appears to be well-tolerated (34), may improve the quality of life of terminal cancer patients (35), and reduce chemotherapy-associated toxicity in patients with ovarian cancer (67).  This led to a renewed interest in studying high-dose IV vitamin C as an anticancer treatment (34) (36). However, it should be regarded as an investigational drug and used only in a clinical trial setting.

Interestingly, there is contradicting evidence against the use of vitamin C supplements during chemotherapy. In vitro and animal studies found that cancer cells preferentially uptake vitamin C (37) and render some chemotherapy drugs less effective (38). Also, a major concern surrounding use of antioxidants, such as vitamin C, is that they can interfere with the actions of chemotherapy and radiation therapy that rely on the production of reactive oxygen species for their cytotoxic activities (39). However, a clinical study showed that ascorbic acid does not reduce the therapeutic effects of paclitaxel and carboplatin (40). Another study found an increase in chemo-associated adverse effects with inadequate intake of vitamin C in children with acute lymphoblastic leukemia (41).

Adverse effects from vitamin C are rare but there are reports of gastrointestinal upset, kidney stone formation (42) , and hemolytic anemia in patients with G6PDH deficiency (43) (44) Patients with history of oxalate kidney stones, renal insufficiency, hematochromatosis, or those undergoing chemotherapy should consult their physicians before taking vitamin C supplements.

Food Sources

Citrus fruits, fresh vegetables, berries, melons

Purported Uses
  • Bronchitis
  • Cancer prevention
  • Cancer treatment
  • Cardiovascular disease
  • Cataracts
  • Common cold
  • Glaucoma
  • Hypertension
  • Immunostimulation
  • Infections
  • Parkinson's disease
  • Strength and stamina
  • Wound healing
Mechanism of Action

Ascorbic acid is essential for the formation and polymerization of collagen; therefore deficiency results in scurvy and poor wound healing (1). Vitamin C also inhibits hyaluronidase leading to the hypothesis that it can prevent cancer metastasis by strengthening the buildup and preventing the breakdown of collagen (45).
Ascorbic acid acts as an antioxidant to protect against oxidative damage from free radicals (46). It inactivates nitric oxide and improves endothelium-dependent vasodilation (47).
Ascorbic acid acts via different mechanisms depending on its plasma concentration. Physiological plasma concentration of less than 0.1mM is achieved through oral intake of dietary or supplemental forms. At pharmacologic plasma concentration of 0.3 - 20mM, achieved via intravenous injection, ascorbic acid is oxidized to an ascorbate radical which acts as prodrug for hydrogen peroxide formation within interstitial fluids (33). This induces DNA damage and adenosine triphosphate (ATP) depletion, and triggers ataxia telangiectasia mutated (ATM)/adenosine monophosphate–activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin mTOR in ovarian cancer cells (67).
Ascorbate decreases colon cancer cell proliferation by downregulating specificity proteins (Sp) (48). It depletes ATP and induces autophagy and cell death in prostate cancer cells (49).
Preferential oxidative cytotoxic effects on cancer cells may be due to the presence of intracellular iron (50), copper (51); an increase in p53 activity (52) and over expression of sodium-dependent vitamin C transporter 2 (SVCT-2) (53).
Dehydroascorbic acid, the oxidized form of vitamin C, may have cytoprotective effects by preserving mitochondrial membrane potential (38).

Pharmacokinetics

Absorption:
Sodium-dependent vitamin C transporters regulate the intestinal absorption, tissue accumulation and renal reabsorption to maintain a tightly controlled plasma concentration of vitamin C when taken orally (54). Intake of around 125mg from fruits and vegetables will result in plasma concentration of 50 micromol/l, a level needed to reduce the risk of free radical associated diseases (55).  A single dose of 1.25g orally will produce a peak concentration of 187 micromol/L. When given at the maximum tolerated dose of 3g orally, peak plasma concentration is 206 micromol/L. Based on data extrapolated from clinical studies, a pharmacokinetic model predicts that continued administration of 3g orally every 4 hours can only achieve plasma concentration of 220 micromol/L. In all doses, plasma concentrations return to steady-state of 70 - 85 micromol/L after 24 hours. However, intravenous vitamin C can reach a plasma concentration up to 70 times higher than the maximum tolerated oral doses of 3g (31).
Distribution:
Dehydroascorbic acid is the primary form that crosses the cell membrane, after which it is reduced intracellularly to ascorbate acid (31). High levels of the vitamin are maintained in the pituitary and adrenal glands, leukocytes, eye tissue and humors, and the brain, while relatively low levels are found in plasma and saliva.
Metabolism / Excretion:
Due to homeostatic regulation, the biological half-life varies widely from 8 to 40 days and is inversely related to body pools. Ascorbic acid is also metabolized into oxalic acid and is excreted in small amount in urine (56). Renal excretion increases proportionally with higher intake. With large intake of the vitamin, unabsorbed ascorbate is degraded in the intestine, a process that may account for the diarrhea and intestinal discomfort occasionally reported by people ingesting large doses (57).

Contraindications
  • Recurrent kidney stone formation
  • Renal impairment or on chronic hemodialysis
  • Hematochromatosis
  • Known G6PDH deficiency
  • Large doses of vitamin C may induce copper deficiency
Adverse Reactions

Common: Nausea, diarrhea and stomach cramps
Reported (oral): In patients with a history of kidney stones, increased oxalate kidney stone formation occurs with possible nephrolithiasis, acute renal failure, or renal insufficiency (42)(58)(59).
Reported (oral): In patients with G6PDH deficiency, hemolytic anemia may occur at high doses (43)(44).
Reported (oral): Severe cyanide poisoning following ingestion of 3 grams of amygdalin with concurrent use of 4800 mg of vitamin C per day (60).
Reported (oral): Excessive use of chewable tablets may break down tooth enamel, increasing the risk of dental caries (61).

Herb-Drug Interactions

Iron: Ascorbic acid increases iron absorption and modulates transport and storage in the body. Significant in patients with hematochromatosis (61).
Chemotherapy Drugs: Vitamin C can reduce the effectiveness of many antineoplastic agents, including vincristine, doxorubicin, methotrexate, cisplatin, and imatinib (38).
Bortezomib: Ascorbic acid intake reduces the activity of bortezomib (62). In a clinical trial using these agents together, the interaction is minimized by administrating bortezomib in the morning and ascorbic acid in the evening (63).
Glutathione: Glutathione, as an antioxidant, reduces the prooxidant cytotoxic effects of ascorbic acid (64).
Beta-blockers: Ascorbic acid can enhance the cardioprotective effects of beta-blockers in post-bypass patients (65).

Herb Lab Interactions

High dose ascorbic acid supplementation may alter results of urine glucose testing strips, and may cause a false negative guaiac (occult blood) test (66).

Literature Summary and Critique

Kim J, et al. Intakes of vitamin A, C, and E, and beta-carotene are associated with risk of cervical cancer: a case-control study in Korea. Nutr Cancer. 2010;62(2):181-9.
This study investigated the influence of antioxidant supplements in 144 cervical cancer patients and 288 age-matched, hospital-based controls. All subjects filled out a questionnaire regarding lifestyle and dietary and supplement intake. Study results indicated that patients with cervical cancer reported a statistically lower mean dietary intake for beta-carotene (p=0.004), vitamin A (p = 0.002), and vitamin C (p<0.001), than control subjects. Total dietary and supplement intake of Vitamin A (p=0.003) and E (p=0.001) were also found to be significantly lower in the cancer patients. Subjects in the highest quartiles were also found to have a statistically significant lower risk for cervical cancer compared to those in the lower quartiles for vitamin A (p<0.001), beta-carotene (p = 0.006), and vitamin C (p=0.001) intake. The authors concluded that total intakes of, vitamins A, C, or E were strongly correlated with a reduced risk for cervical cancer However, they advised that these correlations should be studied in large prospective studies with long- term follow-ups.

Muralikrishnan G, et al. Effects of vitamin C on lipid peroxidation and antioxidant status in tamoxifen-treated breast cancer patients. Chemotherapy. 2010;56(4):298-302.
This study enrolled 60 post-menopausal women with resectable breast cancer to determine the antioxidant effects of Vitamin C. Fifteen normal, healthy women were also enrolled as a control group. The women with breast cancer were divided into 4 groups of 15 who were: not treated with tamoxifen; treated with tamoxifen; treated with vitamin C after 45 days of tamoxifen treatment; or treated with vitamin C after 90 days of tamoxifen treatment. Levels of thiobarbituric acid (TBA) substances (an indicator of lipid peroxidation and oxidative stress) and antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase) were determined in plasma and red blood cell hemolysates. The level of TBA reacting substances was significantly elevated and the levels of antioxidant enzyme were significantly reduced in the untreated and tamoxifen-treated breast cancer patients. However, the authors found that in the groups receiving vitamin C supplementation with tamoxifen, the antioxidant enzyme levels had normalized. The authors concluded that the added antioxidant effect observed with coadministration of Vitamin C may benefit in breast cancer patients receiving tamoxifen treatment.

Sesso, HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men. The Physicians' health study II Randomized Controlled Trial. JAMA. 2008;300(18):2123-2133.
This long-term study sought to evaluate the role of vitamin C or E supplementation in reducing the risk of cardiovascular disease, and involved over 14,000 men aged 50 or older. The participants were randomized to 400 IU of vitamin E every other day or its placebo and 500 mg of vitamin C daily or its placebo. The primary outcome of the study was onset of major cardiovascular events including, nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular disease.
At the 8-year follow-up, researchers observed the same number of cases in both the vitamin and the placebo groups, with increased risk of hemorrhagic stroke in the vitamin E group. These findings suggest no significant effects of vitamins in lowering the risk of cardiovascular disease as widely believed.
It should be noted that both the vitamins used in the study were synthetic and at much higher levels than those achieved via dietary intake, which may have led to the effects observed. More studies at different doses and involving other populations are warranted to fully assess the role of vitamin supplementation for cardiovascular health.
 
Slatore CG, Littman AJ, Au DH, et al. Long-term use of supplemental multivitamins, vitamin C, vitamin E, and folate does not reduce the risk of lung cancer. Am J Respir Crit Care Med. 2008;177(5):524-30.
A prospective study of 77,221 men and women (50-76 years) was conducted to determine the association between vitamin use and lung cancer. A total of 521 cases of lung cancer were identified. The findings were based on 10-year average daily use of supplemental multivitamins, vitamin C, vitamin E, and folate. Researchers conclude that vitamin supplementation does not decrease risk of lung cancer. Furthermore, vitamin E use was associated with a slight increase in risk of lung cancer.

Engelhart MJ, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002;287:3223-9.
A population-based, prospective cohort study evaluating antioxidant intake and risk of developing Alzheimer disease. Subjects (n=5393) were at least 55 years old, free of dementia, noninstitutionalized, and had reliable dietary assessment at baseline. Dietary intake was assessed by self-reported checklist and interview with dietitian using the semiquantitative food-frequency questionnaire (SFFQ). After mean follow-up of 6 years, 146 patients developed Alzheimer disease. After adjustments for age, sex, baseline Mini-Mental State Examination score, alcohol intake, education, smoking habits, pack-years of smoking, body mass index, total energy intake, presence of carotid plaques, and use of supplements, high intake of vitamin C and vitamin E were correlated with lower risk of Alzheimer disease. However, the apparent association may be caused by the influence of a preclinical illness on diet or diet recall/reporting, since the SFFQ itself may indirectly assess cognitive functioning. Furthermore, the multiple comparisons made suggest that some associations may be due to chance and that the critical P value should be set lower than .05.

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References
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Consumer Information

How It Works

Bottom Line: Vitamin C is important for maintaining general health, but vitamin C supplementation may not help lower the risk of cancer.

Vitamin C is a known antioxidant that protects the body against oxidative stress. This means that it reacts with and neutralizes free radicals in the body that can cause cellular and DNA damage. It is also important for the production of many essential molecules in the body, including proteins. Vitamin C plays an important role in the formation of collagen, which is the main structural protein in the skin. Therefore, vitamin C helps promote wound healing. Since the body cannot synthesize vitamin C, it must be gained from outside sources. In addition, scientists think that vitamin C might help reduce inflammation. However, vitamin C can make many chemotherapy drugs less effective. Patients should speak with their doctor before using vitamin C.

Purported Uses
  • To prevent and treat the common cold and upper respiratory infections
    Numerous clinical trials have shown that high-dose vitamin C (around 3 grams per day) does not prevent the common cold and other upper respiratory infections, but that it can slightly reduce the duration and severity of symptoms.
  • To prevent cancer
    Some studies suggest vitamin C from dietary sources can reduce risk of certain cancers. However, most large scale trials did not find vitamin C and other antioxidants useful in preventing cancers.
  • To treat cancer
    High doses of oral and injectable vitamin C have been used as alternative cancer treatment. Clinical studies concluded oral vitamin C is not effective probably due to limited absorption. High-dose of intravenous vitamin C is currently under investigation as a cancer treatment.
  • To treat heart disease
    High dietary intake and blood levels of vitamin C have been associated with lower risk of heart disease.
  • To treat cataracts
    Long-term clinical trials show that antioxidant intake has no effect on development of cataracts or age-related visual loss.
  • To improve wound healing
    Clinical trials indicate that intravenous vitamin C benefits severely burned patients. Other clinical trials show conflicting results regarding the use of vitamin C for pressure sores or other wounds. Deficiencies in vitamin C are known to impair wound healing.
Research Evidence

Cancer
A study of 144 cervical cancer patients and 288 age-matched control subjects was done to find out the effects of antioxidant supplements. All subjects filled out a questionnaire regarding lifestyle and dietary and supplement intake. The results showed that patients with cervical cancer reported lower dietary intake for beta-carotene, vitamin A, and vitamin C compared to control subjects. The association should however be studied in larger trials.

Another study included 60 post-menopausal women with resectable breast cancer (can be removed with surgery) to find out the effects of Vitamin C. Fifteen normal, healthy women were enrolled as a control group. The women with breast cancer were divided into 4 groups of 15: treated with tamoxifen; treated with tamoxifen; treated with vitamin C after 45 days of tamoxifen treatment; or treated with vitamin C after 90 days of tamoxifen treatment. The level of TBA reacting substances (an indicator of lipid peroxidation and oxidative stress) was much higher and the levels of antioxidant enzyme were greatly reduced in the untreated and tamoxifen-treated breast cancer patients. Women who received vitamin C with tamoxifen had normalized levels of antioxidant enzyme.

A study of 77,221 men and women (50-76 years) was done to find out the association between vitamin use and lung cancer. A total of 521 cases of lung cancer were identified. The findings were based on 10-year average daily use of supplemental multivitamins, vitamin C, vitamin E, and folate. Vitamin supplementation may not decrease risk of lung cancer. In addition, those who took vitamin E had a slight increase in risk of lung cancer.

A review of 14 clinical trials showed that supplementation with antioxidants B-carotene, vitamins A, C, and E does not seem to prevent gastrointestinal cancer and may increase overall mortality.

Cardiovascular disease
A long-term study involving over 14,000 men aged 50 or older was done to determine the role of vitamin C or E supplementation in reducing the risk of cardiovascular disease. The participants were randomized to receive 400 IU of vitamin E every other day or placebo and 500 mg of vitamin C daily or placebo. At the 8-year follow-up, the number of cases of cardiovascular disease in both vitamin and placebo groups were the same. Those in the vitamin E group also had an increased risk of hemorrhagic stroke. Vitamin supplements may not lower risk of cardiovascular disease.

Do Not Take If
  • You suffer from recurrent kidney stones.
  • You have kidney impairment or are on chronic hemodialysis.
  • You have hemochromatosis (Vitamin C increases iron absorption, transport, and storage in the body).
  • You have known G6PDH (glucose-6-dehydrogenase) deficiency.
  • You are a cancer patient undergoing radiation therapy or chemotherapy (These therapies use free radicals to kill cancer cells. Vitamin C or other antioxidants may neutralize these free radicals and lessen their effect).
  • You are using bortezomib (Vitamin C may reduce the effect of this drug).
Side Effects
  • Nausea
  • Diarrhea
  • Stomach cramps
  • Low blood sugar and low blood pressure are possible with doses greater than 1 gram.
  • In patients with a history of kidney stones, increased kidney stone formation can occur. This can lead to acute kidney failure damage.
  • In patients with G6PDH deficiency, hemolytic anemia (rupture of red blood cells) may occur at high doses.
  • Excessive use of chewable tablets may break down tooth enamel, increasing the risk of tooth erosion and decay.
Special Point

Recent laboratory experiments and animals studies suggest that cancer cells preferentially uptake vitamin C. This raises the possibility that high-dose vitamin C may be detrimental to cancer patients undergoing radiation or chemotherapy.

It is controversial whether antioxidants like vitamin C can lessen or negate the effects of chemotherapy and radiation therapy. Because these therapies work by creating free radicals that kill cancer cells, some physicians have suggested that high levels of antioxidants can neutralize these free radicals and thereby protect cancer cells from these therapies. So what protects healthy cells may protect cancer cells as well. This question is still not fully understood and patients who are interested in taking more than the RDA of any antioxidant should consult with their doctor.

E-mail your questions and comments to aboutherbs@mskcc.org.