- What is Vitamin C
- What Does Vitamin C Do
- Vitamin C Supplements
- Liposomal Vitamin C
- What are some of the Benefits of Vitamin C on Health
- Vitamin C and Cancer Prevention
- Vitamin C and Cancer Treatment
- High-Dose Intravenous Vitamin C for Cancer Treatment 1)
- Adverse Effects of High Dose Intravenous Vitamin C
- High Dose Intravenous Vitamin C Drug Interactions
- Human/Clinical Studies of High Dose Intravenous Vitamin C in Cancer Treatment
- How much vitamin C do you need ?
- What foods provide vitamin C ?
- Foods High in Vitamin C
- Are you getting enough vitamin C ?
- Vitamin C Deficiency – What happens if you don’t get enough vitamin C
- Groups at Risk of Vitamin C Deficiency
- Vitamin C Overdose – Effects of too much Vitamin C
What is Vitamin C
Even before its discovery in 1932, nutrition experts recognized that something in citrus fruits could prevent scurvy, a disease that killed as many as two million sailors between 1500 and 1800 2). Scurvy is a disease caused by a deficiency of vitamin C, characterized by swollen bleeding gums, malaise, lethargy, easy bruising, and spontaneous bleeding and the opening of previously healed wounds 3), which particularly affected poorly nourished sailors until the end of the 18th century 4). High-dose vitamin C has been studied as a treatment for patients with cancer since the 1970s. A Scottish surgeon named Ewan Cameron worked with Nobel Prize-winning chemist Linus Pauling to study the possible benefits of vitamin C therapy in clinical trials of cancer patients in the late 1970s and early 1980’s 5). In the 1970s, Linus Pauling promoted daily megadoses of vitamin C (the amount in 12 to 24 oranges) as a way to prevent colds and some chronic diseases 6). In the mid-20th century, a study hypothesized that cancer may be related to changes in connective tissue, which may be a consequence of vitamin C deficiency 7). A review of evidence published in 1974 suggested that high-dose ascorbic acid may increase host resistance and be a potential cancer therapy 8).
Vitamin C, also known as L-ascorbic acid or ascorbate, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Vitamin C is synthesized from D-glucose or D-galactose by many plants and animals. However, humans lack the enzyme L-gulonolactone oxidase required for ascorbic acid synthesis and must obtain vitamin C through food or supplements 9), 10). In the body, it acts as an antioxidant, helping to protect cells from the damage caused by free radicals. Free radicals are compounds formed when our bodies convert the food we eat into energy. People are also exposed to free radicals in the environment from cigarette smoke, air pollution, and ultraviolet light from the sun.
The intestinal absorption of vitamin C is regulated by at least one specific dose-dependent, active transporter 11). Cells accumulate vitamin C via a second specific transport protein. In vitro studies have found that oxidized vitamin C, or dehydroascorbic acid, enters cells via some facilitated glucose transporters and is then reduced internally to ascorbic acid. The physiologic importance of dehydroascorbic acid uptake and its contribution to overall vitamin C economy is unknown.
Oral vitamin C produces tissue and plasma concentrations that the body tightly controls. Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1 g/day, absorption falls to less than 50% and absorbed, unmetabolized ascorbic acid is excreted in the urine 12). Results from pharmacokinetic studies indicate that oral doses of 1.25 g/day ascorbic acid produce mean peak plasma vitamin C concentrations of 135 micromol/L, which are about two times higher than those produced by consuming 200–300 mg/day ascorbic acid from vitamin C-rich foods 13). Pharmacokinetic modeling predicts that even doses as high as 3 g ascorbic acid taken every 4 hours would produce peak plasma concentrations of only 220 micromol/L 14).
The total body content of vitamin C ranges from 300 mg (at near scurvy) to about 2 g 15). High levels of vitamin C (millimolar concentrations) are maintained in cells and tissues, and are highest in leukocytes (white blood cells), eyes, adrenal glands, pituitary gland, and brain. Relatively low levels of vitamin C (micromolar concentrations) are found in extracellular fluids, such as plasma, red blood cells, and saliva 16).
What Does Vitamin C Do
Vitamin C plays a role in collagen, carnitine, hormone, and amino acid formation. It is essential for wound healing and facilitates recovery from burns. Vitamin C is also an antioxidant, supports immune function, and facilitates the absorption of iron 17). High-Dose vitamin C, when taken by intravenous (IV) infusion, vitamin C can reach much higher levels in the blood than when it is taken by mouth. Studies suggest that these higher levels of vitamin C may cause the death of cancer cells in the laboratory. Surveys of healthcare practitioners at United States complementary and alternative medicine conferences in recent years have shown that high-dose IV vitamin C is frequently given to patients as a treatment for infections, fatigue, and cancers, including breast cancer 18).
Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism 19), 20). Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant 21) and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E) 22). Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role. In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function 23) and improves the absorption of nonheme iron 24), the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility 25), 26), 27), 28), 29), 30), 31).
Vitamin C Supplements
Supplements typically contain vitamin C in the form of ascorbic acid, which has equivalent bioavailability to that of naturally occurring ascorbic acid in foods, such as orange juice and broccoli 32), 33), 34). Other forms of vitamin C supplements include sodium ascorbate; calcium ascorbate; other mineral ascorbates; ascorbic acid with bioflavonoids; and combination products, such as Ester-C®, which contains calcium ascorbate, dehydroascorbate, calcium threonate, xylonate and lyxonate 35).
A few studies in humans have examined whether bioavailability differs among the various forms of vitamin C. In one study, Ester-C® and ascorbic acid produced the same vitamin C plasma concentrations, but Ester-C® produced significantly higher vitamin C concentrations in leukocytes 24 hours after ingestion 36). Another study found no differences in plasma vitamin C levels or urinary excretion of vitamin C among three different vitamin C sources: ascorbic acid, Ester-C®, and ascorbic acid with bioflavonoids. These findings, coupled with the relatively low cost of ascorbic acid, led the authors to conclude that simple ascorbic acid is the preferred source of supplemental vitamin C 37).
Liposomal Vitamin C
Intravenous administration of vitamin C has been shown to decrease oxidative stress and, in some instances, improve physiological function in adult humans. Compared with vitamin C infusion, oral vitamin C administration is typically less effective, in part due to inferior vitamin C bioavailability 38), 39).
Liposomes are manufactured microscopic, hollow spherical vesicles composed of a lipid bilayer. When loaded with pharmaceuticals and/or dietary supplements, liposomes are a very effective method of drug/supplement delivery 40). The majority of those clinically approved have diameters of 50-300 nm. At present, about 600 clinical trials involve lipid particle (liposomes) drug delivery systems. Greater understanding of pharmacokinetics, biodistribution, and disposition of liposomes facilitated particle surface hydration technology (with polyethylene glycol) to reduce rapid clearance and provide sufficient blood circulation time for drug to reach target tissues and cells. Surface hydration enabled the liposome-encapsulated cancer drug doxorubicin (Doxil) to gain clinical approval in 1995. When ingested, the pharmacokinetic properties of liposome intestinal absorption override the usual absorption pattern of the encapsulated drug. That is, the delivery of a drug/supplement with a typically slow or regulated pattern of absorption, such as vitamin C, may be accelerated when encapsulated within a liposome 41), 42).
In a very small study involving 11 adults between the ages of 45–70 years who are overweight or obese as defined by body mass index (>25 kg/m2), to compare the effectiveness between 4 g of unencapsulated vitamin C administered orally with 4 g of liposomal vitamin C (vitamin C encapsulated in liposomes) or intravenous delivery. The findings of this investigation were that the oral delivery of vitamin C encapsulated in liposomes produced circulating concentrations of vitamin C greater than those elicited by oral delivery of unencapsulated vitamin C but less than those following intravenous vitamin C administration 43).
In another study using anticancer drug, epirubicin encapsulated in a liposome with vitamin C. Enhanced epirubicin antitumor activity was a result of the synergistic antineoplastic activity of anthracyclines together with ascorbic acid. The coencapsulation increases its anticancer activity through a possibly synergistic effect previously reported by other groups for a free nonencapsulated drug/vitamin C cocktail 44).
Liposomes have also been intensively investigated as carriers for different applications in dermatology and cosmetics. This research showed ascorbate phosphatidylcholine liposomes formulation could penetrate through the epidermis and allow nonstable hydrophilic active ingredients reach epidermis and dermis preventing skin photodamage 45).
What are some of the Benefits of Vitamin C on Health
Due to its function as an antioxidant and its role in immune function, vitamin C has been promoted as a means to help prevent and/or treat numerous health conditions. Scientists are studying vitamin C to understand how it affects health. Here are several examples of what this research has shown.
Vitamin C and Cancer Prevention
Epidemiologic evidence suggests that people with high intakes of vitamin C from fruits and vegetables might have a lower risk of getting many types of cancer, such as lung, breast, and colon cancer, perhaps, in part, due to their high vitamin C content 46), 47). Vitamin C can limit the formation of carcinogens, such as nitrosamines 48), 49), in vivo; modulate immune response 50), 51); and through its antioxidant function, possibly attenuate oxidative damage that can lead to cancer 52).
Most case-control studies have found an inverse association between dietary vitamin C intake and cancers of the lung, breast, colon or rectum, stomach, oral cavity, larynx or pharynx, and esophagus 53), 54). Plasma concentrations of vitamin C are also lower in people with cancer than controls 55).
However, evidence from prospective cohort studies is inconsistent, possibly due to varying intakes of vitamin C among studies. In a cohort of 82,234 women aged 33–60 years from the Nurses’ Health Study, consumption of an average of 205 mg/day of vitamin C from food (highest quintile of intake) compared with an average of 70 mg/day (lowest quintile of intake) was associated with a 63% lower risk of breast cancer among premenopausal women with a family history of breast cancer 56). Conversely, Kushi and colleagues did not observe a significantly lower risk of breast cancer among postmenopausal women consuming at least 198 mg/day (highest quintile of intake) of vitamin C from food compared with those consuming less than 87 mg/day (lowest quintile of intake) 57). A review by Carr and Frei concluded that in the majority of prospective cohort studies not reporting a significantly lower cancer risk, most participants had relatively high vitamin C intakes, with intakes higher than 86 mg/day in the lowest quintiles 58). Studies reporting significantly lower cancer risk found these associations in individuals with vitamin C intakes of at least 80–110 mg/day, a range associated with close to vitamin C tissue saturation 59), 60), 61).
Evidence from most randomized clinical trials suggests that vitamin C supplementation, usually in combination with other micronutrients, does not affect cancer risk. In the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) study, a randomized, double-blind, placebo-controlled clinical trial,13,017 healthy French adults received antioxidant supplementation with 120 mg ascorbic acid, 30 mg vitamin E, 6 mg beta-carotene, 100 mcg selenium, and 20 mg zinc, or placebo 62). After a median follow-up time of 7.5 years, antioxidant supplementation lowered total cancer incidence in men, but not in women. In addition, baseline antioxidant status was related to cancer risk in men, but not in women 63). Supplements of 500 mg/day vitamin C plus 400 IU vitamin E every other day for a mean follow-up period of 8 years failed to reduce the risk of prostate or total cancer compared with placebo in middle-aged and older men participating in the Physicians’ Health Study II 64). Similar findings were reported in women participating in the Women’s Antioxidant Cardiovascular Study 65). Compared with placebo, supplementation with vitamin C (500 mg/day) for an average of 9.4 years had no significant effect on total cancer incidence or cancer mortality. In a large intervention trial conducted in Linxian, China, daily supplements of vitamin C (120 mg) plus molybdenum (30 mcg) for 5–6 years did not significantly affect the risk of developing esophageal or gastric cancer 66). Moreover, during 10 years of follow-up, this supplementation regimen failed to significantly affect total morbidity or mortality from esophageal, gastric, or other cancers 67). A 2008 review of vitamin C and other antioxidant supplements for the prevention of gastrointestinal cancers found no convincing evidence that vitamin C (or beta-carotene, vitamin A, or vitamin E) prevents gastrointestinal cancers 68). A similar review by Coulter and colleagues found that vitamin C supplementation, in combination with vitamin E, had no significant effect on death risk due to cancer in healthy individuals 69).
At this time, the evidence is inconsistent on whether dietary vitamin C intake affects cancer risk. Results from most clinical trials suggest that modest vitamin C supplementation alone or with other nutrients offers no benefit in the prevention of cancer.
A substantial limitation in interpreting many of these studies is that investigators did not measure vitamin C concentrations before or after supplementation. Plasma and tissue concentrations of vitamin C are tightly controlled in humans. At daily intakes of 100 mg or higher, cells appear to be saturated and at intakes of at least 200 mg, plasma concentrations increase only marginally 70), 71), 72), 73), 74). If subjects’ vitamin C levels were already close to saturation at study entry, supplementation would be expected to have made little or no difference on measured outcomes 75), 76), 77), 78).
Vitamin C and Cancer Treatment
More than fifty years ago, a study suggested that cancer was a disease of changes in connective tissue caused by a lack of vitamin C. In the 1970’s, it was proposed that high-dose ascorbic acid could help build resistance to disease or infection and possibly treat cancer 79).
During the 1970s, studies by Cameron, Campbell, and Pauling suggested that high-dose vitamin C has beneficial effects on quality of life and survival time in patients with terminal cancer 80), 81). However, some subsequent studies—including a randomized, double-blind, placebo-controlled clinical trial by Moertel and colleagues at the Mayo Clinic 82) did not support these findings. In the Moertel study, patients with advanced colorectal cancer who received 10 g/day vitamin C fared no better than those receiving a placebo. The authors of a 2003 review assessing the effects of vitamin C in patients with advanced cancer concluded that vitamin C confers no significant mortality benefit 83).
Emerging research suggests that the route of vitamin C administration (intravenous vs. oral) could explain the conflicting findings 84), 85), 86). Most intervention trials, including the one conducted by Moertel and colleagues, used only oral administration, whereas Cameron and colleagues used a combination of oral and intravenous (IV) administration. Oral administration of vitamin C, even of very large doses, can raise plasma vitamin C concentrations to a maximum of only 220 micromol/L, whereas IV administration can produce plasma concentrations as high as 26,000 micromol/L [46,47]. Concentrations of this magnitude are selectively cytotoxic to tumor cells in vitro 87), 88). Research in mice suggests that pharmacologic doses of IV vitamin C might show promise in treating otherwise difficult-to-treat tumors 89). A high concentration of vitamin C may act as a pro-oxidant and generate hydrogen peroxide that has selective toxicity toward cancer cells 90), 91), 92). Based on these findings and a few case reports of patients with advanced cancers who had remarkably long survival times following administration of high-dose IV vitamin C, some researchers support reassessment of the use of high-dose IV vitamin C as a drug to treat cancer 93), 94), 95), 96), 97). Surveys of healthcare practitioners at United States complementary and alternative medicine conferences in recent years have shown that high-dose IV vitamin C is frequently given to patients as a treatment for infections, fatigue, and cancers, including breast cancer 98).
It is uncertain whether supplemental vitamin C and other antioxidants might interact with chemotherapy and/or radiation 99). Therefore, individuals undergoing these procedures should consult with their oncologist prior to taking vitamin C or other antioxidant supplements, especially in high doses 100), 101).
High-Dose Intravenous Vitamin C for Cancer Treatment 102)
This cancer information summary provides an overview of the use of high-dose vitamin C (also known as ascorbate or L-ascorbic acid) as a treatment for people with cancer. This summary includes a brief history of early clinical trials of high-dose vitamin C; reviews of laboratory, animal, and human studies; and current clinical trials.
- Vitamin C is an essential nutrient with redox functions at normal physiologic concentrations.
- High-dose vitamin C has been studied as a treatment for cancer patients since the 1970s.
- Laboratory studies have reported that high-dose vitamin C has redox properties and decreased cell proliferation in prostate, pancreatic, hepatocellular, colon, mesothelioma, and neuroblastoma cell lines.
- Two studies of high-dose vitamin C in cancer patients reported improved quality of life and decreases in cancer-related side effects.
- Studies of vitamin C combined with other drugs in animal models have shown mixed results.
- Intravenous vitamin C has been generally well tolerated in clinical trials.
The earliest experience of using high-dose vitamin C (intravenous [IV] and oral) for cancer treatment was by a Scottish surgeon, Ewan Cameron, and his colleague, Allan Campbell, in the 1970s 103). This work led to a collaboration between Cameron and the Nobel Prize–winning chemist Linus Pauling, further promoting the potential of vitamin C therapy in cancer management 104), 105). As a result, two clinical trials of oral vitamin C were conducted in the late 1970s and early 1980s 106), 107).
Pharmacokinetic studies later revealed substantial differences in the maximum achieved blood concentrations of vitamin C based on the route of administration. When vitamin C is taken orally, plasma concentrations of the vitamin are tightly controlled, with a peak achievable concentration less than 300 µM. However, this tight control is bypassed with IV administration of the vitamin, resulting in very high levels of vitamin C plasma concentration (i.e., levels up to 20 mM) 108), 109). Further research suggests that pharmacologic concentrations of ascorbate, such as those achieved with IV administration, may result in cell death in many cancer cell lines 110).
Adverse Effects of High Dose Intravenous Vitamin C
Intravenous (IV) high-dose ascorbic acid has been generally well tolerated in clinical trials 111), 112), 113), 114), 115), 116), 117), 118). Renal failure following ascorbic acid treatment has been reported in patients with preexisting renal disorders 119).
Case reports have indicated that patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency should not receive high doses of vitamin C because of the risk of developing hemolysis 120), 121), 122).
Vitamin C may increase bioavailability of iron, and high doses of the vitamin are not recommended for patients with hemochromatosis (a hereditary disorder in which iron salts are deposited in the tissues, leading to liver damage, diabetes mellitus, and bronze discoloration of the skin) 123).
High Dose Intravenous Vitamin C Drug Interactions
When administered in high doses, vitamin C may result in adverse interactions with some anticancer agents. These interactions have primarily been detected in preclinical studies. A 2013 phase I clinical study evaluated the safety of combining high-dose IV ascorbate with gemcitabine in stage IV pancreatic cancer patients. The combination therapy was well tolerated by patients, and no significant adverse events were reported 124).
In vitro and in vivo animal studies have suggested that combining oral vitamin C with bortezomib interferes with the drug’s ability to act as a proteasome inhibitor and blocks bortezomib-initiated apoptosis 125), 126), 127). This interference occurred even with the oral administration of vitamin C (40 mg /kg /day) to animals. Studies in cell culture and performed by adding blood plasma from healthy volunteers given oral vitamin C (1 g /day) also showed a significant decrease in bortezomib’s growth inhibitory effect on multiple myeloma cells. Another study found similar results. Plasma from healthy volunteers who took 1 g of oral vitamin C per day was shown to decrease bortezomib growth inhibition in multiple myeloma cells and to block its inhibitory effect on 20S proteasome activity 128). However, a study that utilized mice harboring human prostate cancer cell xenografts failed to find any significant effect of oral vitamin C (40 mg/kg/day or 500 mg/kg/day) on the tumor growth inhibitory action of bortezomib 129).
Several studies have been performed to assess the potential synergistic or inhibitory action of vitamin C on certain chemotherapy drugs, with variable results. A series of studies in cell culture and in animals bearing tumors has shown that when given at high concentrations or dosages, dehydroascorbic acid (an oxidized form of vitamin C) can interfere with the cytotoxic effects of several chemotherapy drugs 130). However, dehydroascorbic acid is generally present only at low concentrations in dietary supplements and fresh foods.
Human/Clinical Studies of High Dose Intravenous Vitamin C in Cancer Treatment
- Early Ascorbate-Only Trials
In the early 1970s, a consecutive case series was conducted in which 50 advanced-cancer patients were treated with large doses of ascorbic acid 131). These patients began ascorbic acid treatment after conventional therapies were deemed unlikely to be effective. Patients received intravenous (IV) ascorbic acid (10 g /day for 10 consecutive days; some patients received higher doses), oral ascorbic acid (10 g/day), or both. The subjects exhibited a wide variety of responses to treatment, including no or minimal response, tumor regression, and tumor hemorrhage. However, the authors noted that lack of controls prevented definitive assignment of any beneficial responses to the ascorbic acid treatment. A case report published in 1975 detailed one of the patients who had experienced tumor regression 132). Diagnosed with reticulum cell sarcoma, the patient exhibited improvement in well-being and resolution of lung masses after being treated with ascorbic acid. When the patient’s daily dose of ascorbic acid was reduced, some of signs of the disease returned; however, remission was achieved again after the patient reverted to the higher initial dose.
A larger case series of terminal cancer patients treated with ascorbate was reported in 1976. In this study, 100 terminal cancer patients (50 of whom were reported on previously) 133) were treated with ascorbate (10 g/day for 10 days IV, then orally) and compared with 1,000 matched controls from the same hospital. The mean survival time for ascorbate-treated patients was 300 days longer than that of the matched controls 134), 135).
Two studies tried to reproduce earlier results. These studies were randomized, placebo-controlled trials in which cancer patients received either 10 g oral vitamin C or placebo daily until signs of cancer progression. At the end of each study, no significant differences were noted between the two ascorbate-treated and placebo-treated groups for symptoms, performance status, or survival 136), 137).
- Recent Ascorbate-Only Trials
One study reported three case reports of cancer patients who received IV vitamin C as their main therapy. During vitamin C therapy, the patients used additional treatments, including vitamins, minerals, and botanicals. According to the authors, the cases were reviewed in accordance with the NCI Best Case Series guidelines. Histopathologic examination suggested poor prognoses for these patients, but they had long survival times after being treated with IV vitamin C 138). Vitamin C was given at doses ranging from 15 g to 65 g, initially once or twice a week for several months; two patients then received it less frequently for 1 to 4 years.
Two studies demonstrated that IV vitamin C treatment resulted in improved quality of life and decreases in cancer-related side effects in cancer patients 139), 140).
Studies have shown that vitamin C can be safely administered to healthy volunteers or cancer patients at doses up to 1.5 g/kg and with screening to eliminate treating individuals with risk factors for toxicity (e.g., glucose-6-phosphate dehydrogenase deficiency, renal diseases, or urolithiasis). These studies have also found that plasma concentrations of vitamin C are higher with IV administration than with oral administration and are maintained for more than 4 hours 141), 142).
- Ascorbate-Combination Trials
A phase I study published in 2012 examined the safety and efficacy of combining IV ascorbate with gemcitabine and erlotinib in stage IV pancreatic cancer patients. Fourteen subjects entered the study and planned to receive IV gemcitabine (1,000 mg /m2 over 30 minutes, once a week for 7 weeks), oral erlotinib (100 mg daily for 8 weeks), and IV ascorbate (50 g/infusion, 75 g/infusion, or 100 g/infusion 3 times per week for 8 weeks). Minimal adverse effects were reported for ascorbic acid treatment. Five subjects received fewer than 18 of the planned 24 ascorbate infusions and thus did not have follow-up imaging to assess response. Three of those patients had clinically determined progressive disease. All of the other nine patients had repeat imaging to assess tumor size, and each met the criteria for having stable disease 143).
A 2013 phase I clinical study evaluated the safety of combining pharmacological ascorbate with gemcitabine in treating stage IV pancreatic cancer patients. During each 4-week cycle, patients received gemcitabine weekly for 3 weeks (1,000 mg/m2 over 30 minutes) and twice weekly ascorbate infusions for 4 weeks (15 g over 30 minutes during the first week, followed by weekly escalations in dose until plasma levels reached at least 350 mg/dL [20 mM]). Among nine patients, mean progression-free survival was 26 weeks and overall survival was 12 months. The combination treatment was well tolerated, and no significant adverse events were reported 144).
In 2014, a phase I/IIA clinical trial evaluated the toxicities of combining IV ascorbate with carboplatin and paclitaxel in stage III /IV ovarian cancer. Twenty-seven patients were randomly assigned to receive either chemotherapy alone or chemotherapy and IV vitamin C concurrently. Chemotherapy was given for 6 months, and IV vitamin C was given for 12 months. The addition of IV vitamin C was associated with reduced chemotherapy-related toxicities 145).
Trials of high-dose IV vitamin C with other drugs are ongoing 146), 147). A number of studies have included IV ascorbic acid treatment (1,000 mg) with arsenic trioxide regimens, with mixed results. The combination therapies were well tolerated and suggested beneficial effects in multiple myeloma patients, although the specific contribution of vitamin C could not be determined 148), 149), 150), 151). However, similar combination regimens resulted in severe side effects, disease progression, and no anticancer effect in patients with refractory metastatic colorectal cancer 152) and metastatic melanoma 153). Because these were not placebo-controlled trials, the extent that ascorbate contributed to the toxicity demonstrated in these studies is unclear.
- Current Clinical Trials
Check the list of National Cancer Institute supported cancer clinical trials for integrative, alternative, and complementary therapies clinical trials on ascorbic acid that are actively enrolling patients 154).
- Cardiovascular disease
People who eat lots of fruits and vegetables seem to have a lower risk of cardiovascular disease. Researchers believe that the antioxidant content of these foods might be partly responsible for this association because oxidative damage is a major cause of cardiovascular disease. However, scientists aren’t sure whether vitamin C itself, either from food or supplements, helps protect people from cardiovascular disease. It is also not clear whether vitamin C helps prevent cardiovascular disease from getting worse in people who already have it.
Evidence from many epidemiological studies suggests that high intakes of fruits and vegetables are associated with a reduced risk of cardiovascular disease 155), 156), 157). This association might be partly attributable to the antioxidant content of these foods because oxidative damage, including oxidative modification of low-density lipoproteins, is a major cause of cardiovascular disease 158), 159), 160). In addition to its antioxidant properties, vitamin C has been shown to reduce monocyte adherence to the endothelium, improve endothelium-dependent nitric oxide production and vasodilation, and reduce vascular smooth-muscle-cell apoptosis, which prevents plaque instability in atherosclerosis 161), 162).
Results from prospective studies examining associations between vitamin C intake and cardiovascular disease risk are conflicting 163). In the Nurses’ Health Study, a 16-year prospective study involving 85,118 female nurses, total intake of vitamin C from both dietary and supplemental sources was inversely associated with coronary heart disease risk 164). However, intake of vitamin C from diet alone showed no significant associations, suggesting that vitamin C supplement users might be at lower risk of coronary heart disease. A much smaller study indicated that postmenopausal women with diabetes who took at least 300 mg/day vitamin C supplements had increased cardiovascular disease mortality 165).
A prospective study in 20,649 British adults found that those in the top quartile of baseline plasma vitamin C concentrations had a 42% lower risk of stroke than those in the bottom quartile 166). In male physicians participating in the Physicians’ Health Study, use of vitamin C supplements for a mean of 5.5 years was not associated with a significant decrease in total cardiovascular disease mortality or coronary heart disease mortality 167). A pooled analysis of nine prospective studies that included 293,172 subjects free of coronary heart disease at baseline found that people who took ≥700 mg/day of supplemental vitamin C had a 25% lower risk of coronary heart disease incidence than those who took no supplemental vitamin C 168). The authors of a 2008 meta-analysis of prospective cohort studies, including 14 studies reporting on vitamin C for a median follow-up of 10 years, concluded that dietary, but not supplemental, intake of vitamin C is inversely associated with coronary heart disease risk 169).
Results from most clinical intervention trials have failed to show a beneficial effect of vitamin C supplementation on the primary or secondary prevention of cardiovascular disease. In the Women’s Antioxidant Cardiovascular Study, a secondary prevention trial involving 8,171 women aged 40 years or older with a history of cardiovascular disease, supplementation with 500 mg/day vitamin C for a mean of 9.4 years showed no overall effect on cardiovascular events 170). Similarly, vitamin C supplementation (500 mg/day) for a mean follow-up of 8 years had no effect on major cardiovascular events in male physicians enrolled in the Physicians’ Health Study II 171).
Other clinical trials have generally examined the effects on cardiovascular disease of supplements combining vitamin C with other antioxidants, such as vitamin E and beta-carotene, making it more difficult to isolate the potential contribution of vitamin C. The SU.VI.MAX study examined the effects of a combination of vitamin C (120 mg/day), vitamin E (30 mg/day), beta-carotene (6 mg/day), selenium (100 mcg/day), and zinc (20 mg/day) in 13,017 French adults from the general population 172). After a median follow-up time of 7.5 years, the combined supplements had no effect on ischemic cardiovascular disease in either men or women. In the Women’s Angiographic Vitamin and Estrogen (WAVE) study, involving 423 postmenopausal women with at least one coronary stenosis of 15%–75%, supplements of 500 mg vitamin C plus 400 IU vitamin E twice per day not only provided no cardiovascular benefit, but significantly increased all-cause mortality compared with placebo 173).
The authors of a 2006 meta-analysis of randomized controlled trials concluded that antioxidant supplements (vitamins C and E and beta-carotene or selenium) do not affect the progression of atherosclerosis 174). Similarly, a systematic review of vitamin C’s effects on the prevention and treatment of cardiovascular disease found that vitamin C did not have favorable effects on cardiovascular disease prevention 175). Since then, researchers have published follow-up data from the Linxian trial, a population nutrition intervention trial conducted in China 176). In this trial, daily vitamin C supplements (120 mg) plus molybdenum (30 mcg) for 5–6 years significantly reduced the risk of cerebrovascular deaths by 8% during 10 years of follow-up after the end of the active intervention. Although the Linxian trial data suggest a possible benefit, overall, the findings from most intervention trials do not provide convincing evidence that vitamin C supplements provide protection against cardiovascular disease or reduce its morbidity or mortality. However, as discussed in the cancer prevention section, clinical trial data for vitamin C are limited by the fact that plasma and tissue concentrations of vitamin C are tightly controlled in humans. If subjects’ vitamin C levels were already close to saturation at study entry, supplementation would be expected to have made little or no difference on measured outcomes 177), 178), 179), 180).
- Age-related macular degeneration (AMD) and cataracts
AMD and cataracts are two of the leading causes of vision loss in older people. Researchers do not believe that vitamin C and other antioxidants affect the risk of getting AMD. However, research suggests that vitamin C combined with other nutrients might help slow AMD progression. In a large study among older people with AMD who were at high risk of developing advanced AMD, those who took a daily dietary supplement with 500 mg vitamin C, 80 mg zinc, 400 IU vitamin E, 15 mg beta-carotene, and 2 mg copper for about 6 years had a lower chance of developing advanced AMD. They also had less vision loss than those who did not take the dietary supplement. People who have or are developing the disease might want to talk with their doctor about taking dietary supplements.The relationship between vitamin C and cataract formation is unclear. Some studies show that people who get more vitamin C from foods have a lower risk of getting cataracts. But further research is needed to clarify this association and to determine whether vitamin C supplements affect the risk of getting cataracts.
A population-based cohort study in the Netherlands found that adults aged 55 years or older who had high dietary intakes of vitamin C as well as beta-carotene, zinc, and vitamin E had a reduced risk of AMD 181). However, most prospective studies do not support these findings 182). The authors of a 2007 systematic review and meta-analysis of prospective cohort studies and randomized clinical trials concluded that the current evidence does not support a role for vitamin C and other antioxidants, including antioxidant supplements, in the primary prevention of early AMD 183).
Although research has not shown that antioxidants play a role in AMD development, some evidence suggests that they might help slow AMD progression 184). The Age-Related Eye Disease Study (AREDS), a large, randomized, placebo-controlled clinical trial, evaluated the effect of high doses of selected antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene, 80 mg zinc, and 2 mg copper) on the development of advanced AMD in 3,597 older individuals with varying degrees of AMD 185). After an average follow-up period of 6.3 years, participants at high risk of developing advanced AMD (i.e., those with intermediate AMD or those with advanced AMD in one eye) who received the antioxidant supplements had a 28% lower risk of progression to advanced AMD than participants who received a placebo. A follow-up AREDS2 study confirmed the value of this and similar supplement formulations in reducing the progression of AMD over a median follow-up period of 5 years 186).
High dietary intakes of vitamin C and higher plasma ascorbate concentrations have been associated with a lower risk of cataract formation in some studies 187), 188). In a 5-year prospective cohort study conducted in Japan, higher dietary vitamin C intake was associated with a reduced risk of developing cataracts in a cohort of more than 30,000 adults aged 45–64 years 189). Results from two case-control studies indicate that vitamin C intakes greater than 300 mg/day reduce the risk of cataract formation by 70%–75% 190), 191). Use of vitamin C supplements, on the other hand, was associated with a 25% higher risk of age-related cataract extraction among a cohort of 24,593 Swedish women aged 49–83 years 192). These findings applied to study participants who took relatively high-dose vitamin C supplements (approximately 1,000 mg/day) and not to those who took multivitamins containing substantially less vitamin C (approximately 60 mg/day).
Data from clinical trials are limited. In one study, Chinese adults who took daily supplements of 120 mg vitamin C plus 30 mcg molybdenum for 5 years did not have a significantly lower cataract risk 193). However, adults aged 65–74 years who received 180 mg vitamin C plus 30 mcg molybdenum combined with other nutrients in a multivitamin/mineral supplement had a 43% significantly lower risk of developing nuclear cataracts than those who received a placebo 194). In the AREDS study, older individuals who received supplements of 500 mg vitamin C, 400 IU vitamin E, and 15 mg beta-carotene for an average of 6.3 years did not have a significantly lower risk of developing cataracts or of cataract progression than those who received a placebo 195). The AREDS2 study, which also tested formulations containing 500 mg vitamin C, confirmed these findings 196).
Overall, the currently available evidence does not indicate that vitamin C, taken alone or with other antioxidants, affects the risk of developing AMD, although some evidence indicates that the AREDS formulations might slow AMD progression in people at high risk of developing advanced AMD.
- The common cold
Although vitamin C has long been a popular remedy for the common cold, research shows that for most people, vitamin C supplements do not reduce the risk of getting the common cold. However, people who take vitamin C supplements regularly might have slightly shorter colds or somewhat milder symptoms when they do have a cold. Using vitamin C supplements after cold symptoms start does not appear to be helpful.
In the 1970s Linus Pauling suggested that vitamin C could successfully treat and/or prevent the common cold 197). Results of subsequent controlled studies have been inconsistent, resulting in confusion and controversy, although public interest in the subject remains high 198), 199).
A 2007 Cochrane review examined placebo-controlled trials involving the use of at least 200 mg/day vitamin C taken either continuously as a prophylactic treatment or after the onset of cold symptoms 200), 201). Prophylactic use of vitamin C did not significantly reduce the risk of developing a cold in the general population. However, in trials involving marathon runners, skiers, and soldiers exposed to extreme physical exercise and/or cold environments, prophylactic use of vitamin C in doses ranging from 250 mg/day to 1 g/day reduced cold incidence by 50%. In the general population, use of prophylactic vitamin C modestly reduced cold duration by 8% in adults and 14% in children. When taken after the onset of cold symptoms, vitamin C did not affect cold duration or symptom severity.
Overall, the evidence to date suggests that regular intakes of vitamin C at doses of at least 200 mg/day do not reduce the incidence of the common cold in the general population, but such intakes might be helpful in people exposed to extreme physical exercise or cold environments and those with marginal vitamin C status, such as the elderly and chronic smokers 202), 203), 204), 205). The use of vitamin C supplements might shorten the duration of the common cold and ameliorate symptom severity in the general population 206), 207), possibly due to the anti-histamine effect of high-dose vitamin C 208). However, taking vitamin C after the onset of cold symptoms does not appear to be beneficial 209).
How much vitamin C do you need ?
Intake recommendations for vitamin C and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Institute of Medicine 210). DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:
- Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals.
- Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
- Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects.
Table 1 lists the current RDAs for vitamin C 211). For infants from birth to 12 months, the Institute of Medicine Food and Nutritional Board established an AI for vitamin C that is equivalent to the mean intake of vitamin C in healthy, breastfed infants.
The amount of vitamin C you need each day depends on your age. Average daily recommended amounts for different ages are listed below in milligrams (mg).
Table 1: Recommended Dietary Allowances (RDAs) for Vitamin C 212)
|Life Stage||Recommended Amount|
|Birth to 6 months||40 mg|
|Infants 7–12 months||50 mg|
|Children 1–3 years||15 mg|
|Children 4–8 years||25 mg|
|Children 9–13 years||45 mg|
|Teens 14–18 years (boys)||75 mg|
|Teens 14–18 years (girls)||65 mg|
|Adults (men)||90 mg|
|Adults (women)||75 mg|
|Pregnant teens||80 mg|
|Pregnant women||85 mg|
|Breastfeeding teens||115 mg|
|Breastfeeding women||120 mg|
If you smoke, add 35 mg to the above values to calculate your total daily recommended amount.
Vitamin C status is typically assessed by measuring plasma vitamin C levels. Other measures, such as leukocyte vitamin C concentration, could be more accurate indicators of tissue vitamin C levels, but they are more difficult to assess and the results are not always reliable.
What foods provide vitamin C ?
Fruits and vegetables are the best sources of vitamin C. You can get recommended amounts of vitamin C by eating a variety of foods including the following:
- Citrus fruits (such as oranges and grapefruit) and their juices, as well as red and green pepper and kiwifruit, which have a lot of vitamin C.
- Other fruits and vegetables—such as broccoli, strawberries, cantaloupe, baked potatoes, and tomatoes—which also have vitamin C.
- Some foods and beverages that are fortified with vitamin C. To find out if vitamin C has been added to a food product, check the product labels.
The vitamin C content of food may be reduced by prolonged storage and by cooking. Steaming or microwaving may lessen cooking losses. Fortunately, many of the best food sources of vitamin C, such as fruits and vegetables, are usually eaten raw.
The U.S. Department of Agriculture’s (USDA’s) Nutrient Database website 213) lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin C arranged by nutrient content 214) and by food name 215).
Foods High in Vitamin C
|Food||Milligrams (mg) per serving||Percent (%) DV*|
|Red pepper, sweet, raw, ½ cup||95||158|
|Orange juice, ¾ cup||93||155|
|Orange, 1 medium||70||117|
|Grapefruit juice, ¾ cup||70||117|
|Kiwifruit, 1 medium||64||107|
|Green pepper, sweet, raw, ½ cup||60||100|
|Broccoli, cooked, ½ cup||51||85|
|Strawberries, fresh, sliced, ½ cup||49||82|
|Brussels sprouts, cooked, ½ cup||48||80|
|Grapefruit, ½ medium||39||65|
|Broccoli, raw, ½ cup||39||65|
|Tomato juice, ¾ cup||33||55|
|Cantaloupe, ½ cup||29||48|
|Cabbage, cooked, ½ cup||28||47|
|Cauliflower, raw, ½ cup||26||43|
|Potato, baked, 1 medium||17||28|
|Tomato, raw, 1 medium||17||28|
|Spinach, cooked, ½ cup||9||15|
|Green peas, frozen, cooked, ½ cup||8||13|
*DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin C is 60 mg for adults and children aged 4 and older. The FDA requires all food labels to list the percent DV for vitamin C. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.[Source 216)]
Are you getting enough vitamin C ?
Most people in the United States get enough vitamin C from foods and beverages. However, certain groups of people are more likely than others to have trouble getting enough vitamin C:
- People who smoke and those who are exposed to secondhand smoke, in part because smoke increases the amount of vitamin C that the body needs to repair damage caused by free radicals. People who smoke need 35 mg more vitamin C per day than nonsmokers.
- Infants who are fed evaporated or boiled cow’s milk, because cow’s milk has very little vitamin C and heat can destroy vitamin C. Cow’s milk is not recommended for infants under 1 year of age. Breast milk and infant formula have adequate amounts of vitamin C.
- People who eat a very limited variety of food.
- People with certain medical conditions such as severe malabsorption, some types of cancer, and kidney disease requiring hemodialysis.
Vitamin C Deficiency – What happens if you don’t get enough vitamin C
Vitamin C deficiency is rare in the United States and Canada. People who get little or no vitamin C (below about 10 mg per day) for many weeks can get scurvy. Scurvy causes fatigue, inflammation of the gums, small red or purple spots on the skin, joint pain, poor wound healing, and corkscrew hairs. Additional signs of scurvy include depression as well as swollen, bleeding gums and loosening or loss of teeth. People with scurvy can also develop anemia. Scurvy is fatal if it is not treated.
Groups at Risk of Vitamin C Deficiency
Vitamin C inadequacy can occur with intakes that fall below the RDA but are above the amount required to prevent overt deficiency (approximately 10 mg/day). The following groups are more likely than others to be at risk of obtaining insufficient amounts of vitamin C.
- Smokers and passive “smokers”
Studies consistently show that smokers have lower plasma and leukocyte vitamin C levels than nonsmokers, due in part to increased oxidative stress . For this reason, the IOM concluded that smokers need 35 mg more vitamin C per day than nonsmokers 217). Exposure to secondhand smoke also decreases vitamin C levels. Although the IOM was unable to establish a specific vitamin C requirement for nonsmokers who are regularly exposed to secondhand smoke, these individuals should ensure that they meet the RDA for vitamin C 218), 219).
- Infants fed evaporated or boiled milk
Most infants in developed countries are fed breastmilk and/or infant formula, both of which supply adequate amounts of vitamin C 220), 221). For many reasons, feeding infants evaporated or boiled cow’s milk is not recommended. This practice can cause vitamin C deficiency because cow’s milk naturally has very little vitamin C and heat can destroy vitamin C 222), 223).
- Individuals with limited food variety
Although fruits and vegetables are the best sources of vitamin C, many other foods have small amounts of this nutrient 224). Thus, through a varied diet, most people should be able to meet the vitamin C RDA or at least obtain enough to prevent scurvy. People who have limited food variety—including some elderly, indigent individuals who prepare their own food; people who abuse alcohol or drugs; food faddists; people with mental illness; and, occasionally, children—might not obtain sufficient vitamin C 225).
- People with malabsorption and certain chronic diseases
Some medical conditions can reduce the absorption of vitamin C and/or increase the amount needed by the body. People with severe intestinal malabsorption or cachexia and some cancer patients might be at increased risk of vitamin C inadequacy 226). Low vitamin C concentrations can also occur in patients with end-stage renal disease on chronic hemodialysis 227).
Vitamin C Overdose – Effects of too much Vitamin C
Vitamin C has low toxicity and is not believed to cause serious adverse effects at high intakes 228). The most common complaints are diarrhea, nausea, abdominal cramps, and other gastrointestinal disturbances due to the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract 229), 230).
In postmenopausal women with diabetes who participated in the Iowa Women’s Health Study, supplemental (but not dietary) vitamin C intake (at least 300 mg/day) was significantly associated with an increased risk of cardiovascular disease mortality 231). The mechanism for this effect, if real, is not clear and this finding is from a subgroup of patients in an epidemiological study. No such association has been observed in any other epidemiological study, so the significance of this finding is uncertain. High vitamin C intakes also have the potential to increase urinary oxalate and uric acid excretion, which could contribute to the formation of kidney stones, especially in individuals with renal disorders 232). However, studies evaluating the effects on urinary oxalate excretion of vitamin C intakes ranging from 30 mg to 10 g/day have had conflicting results, so it is not clear whether vitamin C actually plays a role in the development of kidney stones 233), 234), 235), 236). The best evidence that vitamin C contributes to kidney stone formation is in patients with pre-existing hyperoxaluria 237).
Due to the enhancement of nonheme iron absorption by vitamin C, a theoretical concern is that high vitamin C intakes might cause excess iron absorption. In healthy individuals, this does not appear to be a concern. However, in individuals with hereditary hemochromatosis, chronic consumption of high doses of vitamin C could exacerbate iron overload and result in tissue damage.
Under certain conditions, vitamin C can act as a pro-oxidant, potentially contributing to oxidative damage. A few studies in vitro have suggested that by acting as a pro-oxidant, supplemental oral vitamin C could cause chromosomal and/or DNA damage and possibly contribute to the development of cancer 238), 239), 240). However, other studies have not shown increased oxidative damage or increased cancer risk with high intakes of vitamin C 241), 242).
Other reported effects of high intakes of vitamin C include reduced vitamin B12 and copper levels, accelerated metabolism or excretion of ascorbic acid, erosion of dental enamel, and allergic responses. However, at least some of these conclusions were a consequence of assay artifact, and additional studies have not confirmed these observations 243).
Can vitamin C be harmful ?
Taking too much vitamin C can cause diarrhea, nausea, and stomach cramps. In people with a condition called hemochromatosis, which causes the body to store too much iron, high doses of vitamin C could worsen iron overload and damage body tissues.
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