Vitamin C twice a day enhances health

doi:10.4236/health.2010.28123

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Vol.2, No.8, 819-823 (2010)

doi:10.4236/health.2010.28123

HEALTH

Vitamin C twice a day enhances health

Alfred Roc Ordman

Biochemistry Program, Beloit College, Beloit, USA; Ordman@beloit.edu

Received 15 October 2009; revised 30 November 2009; accepted 3 December 2009.

ABSTRACT

This review provides information determining

how much vitamin C to take, including analysis

of the recent findings, which demonstrate ad-

vantages and problems with higher daily doses.

The Daily Value for vitamin C was raised to 90

mg for men in 2000, and Upper Limit of 2,000 mg

per day was established as being safe. This

followed a study of urinary excretion of vitamin

C (AA) that demonstrated 500 mg twice a day

provides levels sufficient to cause continuous

urinary excretion in humans. That is the lowest

oral dosage evaluated that significantly satu-

rates blood plasma. A later study endorsed 200

mg from dietary sources for the RDA. Even

though plasma concentration of AA is then sig-

nificantly lower, at 200 mg daily certain white

blood cells are saturated with AA. Recently

many studies have indicated the benefit of high

levels of AA to maintain the brain, bones, and

heart, reduce damage from stroke, brain trauma,

and cataracts, and lower the risk of cancer me-

tastasis and colds. Pro-oxidant activity has

been found only for i.v. adminstration, where

high concentrations appear effective destroying

tumor cells while not harming normal cells. This

review evaluates recent research and finds it

consistent with the hypothesis that people, es-

pecially older people and soldiers in combat

environments, are likely to benefit if they main-

tain the saturating level of AA by taking 500mg

supplements twice a day.

Keywords: Antioxidant; Vitamin C; Ascorbic

Acid; Stroke; Alzheimer’s; Oxidative Stress;

Cardiovascular Disease; Cataracts;

Osteoporosis; Mortality

1. INTRODUCTION

In 1956, Denham Harman, founder of AGE, proposed

the free radical (ROS) theory of aging [1]. Linus Pauling

proposed megadoses of the water-soluble antioxidant

vitamin C (ascorbic acid, AA) to trap free radicals, re-

commending dosages up to 16 g per day [2]. Harman

and Pauling’s efforts moved the nutrition standards from

levels that merely prevent short-term deficiency diseases

to higher levels that reduce the risk for chronic disease

associated with aging. For nutrition studies to identify

risk for chronic disease, it is helpful to identify bio-

markers that reflect disease-generating processes. For

instance, oxidized DNA resulting from free radical

damage may be a biomarker for future cancer.

2. BACKGROUND

Pauling based his recommendation for megadoses on the

evolutionary development of an AA requirement in peo-

ple. The first biomarker for long-term optimal dosage

was published in 1994. King et al. [3] discovered that

500 mg of AA taken orally every 12 hr are sufficient to

provide continuous excretion of excess AA into the urine.

In 1996, a similar study by Levine M et al. [4] confirmed

those results, showing that that dosage provides the

highest statistically significant concentration in plasma

for protection from free radical damage. But they chose

a different biomarker, based on the plasma AA level

necessary to saturate certain white blood cells. The

choice of that biomarker led to their recommendation of

only 200 mg AA. That is also a level that does not re-

quire supplements for people whose food selections are

rich in AA. However, neither of these studies evaluated

tissue concentrations, particularly in the brain and eyes,

where high levels are likely to have substantial benefits,

as described below. If the higher level Pauling advocated

is useful, then 500 mg twice a day provides the highest

statistically significant level possible by oral dosing.

SAFETY: There are periodic reports in the media that

taking large amounts of AA over long periods of time

may be harmful. A potential AA hazard was widely re-

ported after a paper in Nature claimed that elevated AA

acted as a pro-oxidant, causing DNA mutations [5]. The

popular press gave much less publicity to articles re-

porting that that study was seriously flawed because it

A. R. Ordman / HEALTH 2 (2010) 819-823

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used obsolete methods [6], and that AA prevents DNA

damage [7]. It had already been reported that AA pre-

vents damage to DNA in sperm [8].

Even doses of 10 g/day in adults have not been re-

ported to cause harm in confirmed scientific studies. The

Food and Nutrition Board [9] of the Institute of Medi-

cine raised the RDA for AA for men and women to 90

and 75 mg resp., with an Upper Limit (UL) for safety

established at 2 g per day. The UL was based on osmotic

diarrhea and gastrointestinal disturbances. The Panel on

dietary antioxidants and related compounds stated that

the in vivo data do not clearly show a relationship be-

tween excess ascorbic acid intake and kidney stone for-

mation, pro-oxidant effects, or excess iron absorption

[10].

Another concern is that a high dose of AA distorts re-

sults of tests commonly used to measure the amount of

glucose in urine and blood. Combining oral anticoagu-

lant drugs and excessive amounts of AA can produce

abnormal results in blood-clotting tests (e.g., lowering

prothrombin time).

However, while media reports periodically raise con-

cerns about taking AA and vitamin E supplements, those

reports are based on misinterpretations of peer-reviewed

studies. In response, a major review by numerous au-

thorities, John N. Hathcock, Angelo Azzi, Jeffrey Blum-

berg, Tammy Bray, Annette Dickinson, Balz Frei, Ish-

warlal Jialal, Carol S. Johnston, Frank J. Kelly, Klaus

Kraemer, Lester Packer, Sampath Parthasarathy, Helmut

Sies and Maret G. Traber [11], was titled “Vitamins E

and C are safe across a broad range of intakes”. They

provided numerous human studies justifying the toler-

able upper limit (UL) established by the Food and Nutri-

tion Board, which is 1,000 mg for vitamin E and 2,000

mg for AA.

This review describes recent studies relevant to the

selection of a daily intake of AA for health maintenance.

3. HOW CONCENTRATIONS IN

DIFFERENT TISSUES AFFECT

FUNCTION

In addition to serum and white blood cell concentrations

of vitamin C, there are many other tissues in which

maintaining high AA concentrations are important. Some

studies below reflect the metabolic and antioxidant func-

tions of AA in controlling cell differentiation through

nutrition signaling. In a process called nutrient signaling,

described only in the past decade, nutrients can trans-

form metabolic processes as hormones do [12,13]. AA

signals cell differentiation of brain and heart stem cells

described below.

BRAIN: Taking 500 mg of vitamin C twice daily may

lessen Alzheimer’s, stroke, and head trauma damage.

Stroke is the leading cause of disability worldwide [14],

and head trauma is common in war veterans. Several

studies reveal the value of elevated levels of AA for pro-

tecting brain function. First, in humans with Alzheimer’s

and mild cognitive impairment, tissues and biofluids

show evidence of oxidative stress [15]. Cognitive de-

cline in aging dogs is lessened simply by adding anti-

oxidants to the diet. The deposition of amyloid-beta is

decreased [16]. A review of 300 articles by Frank and

Gupta [17] concludes that the value of AA is often am-

biguous, but can be recommended based upon 1) epide-

miological evidence, 2) known benefits for prevention of

other maladies, and 3) benign nature of the substance.

AA is a water-soluble antioxidant that crosses the

blood-brain barrier. AA is produced in the liver of most

mammals. Hibernating animals naturally store high

concentrations of AA in the brain for protection from the

metabolic stress that accompanies arousal [18]. In hu-

mans, brain stroke damage continues when blood flow

resumes. AA substantially prevented this reperfusion

injury [19]. Polidori et al. [20] show that AA is much

lower in plasma for those with head trauma or intracran-

ial hemorrhage compared to healthy subjects, while

other antioxidants such as vitamin E are unaffected.

Even at a dose of 200 mg AA/day, ischemic stroke-

related lipid peroxidation decreased significantly in hu-

mans [21].

Via nutrient signaling, AA may exert effects on brain

maintenance and recovery. How neural progenitor cells

(NPCs) differentiate is determined by the redox state of

the brain [22]. In the reducing environment produced by

AA, NPCs become neurons. Under oxidizing conditions,

astrocytes are formed. Prozorovski et al. [23] conclude

that nontoxic manipulation of redox conditions in the

brain influences NPC fate to produce neurons. People

are able to generate new neurons throughout their entire

lives [24]. High AA concentrations in the brain maintain

the potential to generate new neurons.

HEART: The benefits of AA for the circulatory system

include improved circulation and heart health. AA re-

verses the endothelial dysfunction caused by oxidative

stress [25]. As with brain stem cells mentioned above,

sufficient AA causes embryonic stem cells to differenti-

ate into cardiac myocytes [26].

PLASMA: Heinz bodies reflect ROS damage to red

blood cells (RBCs). Johnston and Cox [27] measured

Heinz bodies in RBCs [28] in college students. They

concluded that the antioxidant protection afforded by

short-term vitamin C supplementation is maximal at the

500-1000 mg dosage. When taken in conjunction with

400 IU of vitamin E, a fat-soluble antioxidant, Moser

et al. [29] concluded that 500 mg of AA taken twice

A. R. Ordman / HEALTH 2 (2010) 819-823

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daily was superior to 200 mg in reducing Heinz bodies,

while vitamin E with minimal AA prevented protein

carbonyl and TBARS damage.

CATARACTS: A major study in Europe shows that

blood levels of AA above 49 µmol/L were associated

with a 64% reduced odds for cataract [30]. US daily

value for AA provides only about 20 µmol/L, while 500

mg twice daily provides about 75 µmol/L.

BONES: Sahni et al. [31] have shown a correlation

between AA intake and 4 yr change in bone mineral

density among 334 men of mean age 75 in the Framing-

ham Osteoporosis Study. They indicate results had only

borderline significance that may relate to other factors in

fruits and vegetables.

COLDS: Evidence for any benefit of AA for prevent-

ing or treating colds remains controversial. Hemilä [32]

completed a meta-analysis showing that the most influ-

ential reviews contain serious inaccuracies and short-

comings, and suggests this may be a remnant of hostility

to Linus Pauling’s opposition to nuclear weapons. He

found consistent evidence that studies using more than 1

g/d had physiologic effects on colds. However, a later

meta-analysis by Douglas and Hemilä [33] evaluated 55

comparative studies treating colds with oral doses of 200

mg of AA per day, and found at most limited evidence

for any benefit in prevention or treatment of colds. The

inconsistency may relate to the AA dosage. Although

twice-a-day dosing is necessary to maintain elevated

serum AA, I have not been able to locate any studies

conducted with this protocol. Recently Saszuki et al. [34]

reported that the risk of getting a cold decreased in re-

sponse to single doses of AA. In a study over the range

from 50 to 500 mg AA daily, the risk of contracting three

or more colds during a 5 yr period was decreased 66%

by daily intake of 500 mg.

CANCER: Research has demonstrated that mutations

of mitochondria accumulate with age [35]. Each mito-

chondrion generates about 4,000 free radicals per second

[36,37]. In human tumors, mitochondrial DNA muta-

tions occur at high frequency. Ishikawa et al. [38] dem-

onstrated that pretreatment of tumor cells in mice with

free radical scavengers prevents those cells from meta-

stasizing. By prevention of mitochondrial DNA muta-

tions, a mechanism to maintain a high concentration of

antioxidants in mitochondria could reduce the risk of

metastatic tumors.

But at higher plasma levels achieved by intravenous

(iv) doses, AA becomes a pro-oxidant that may be toxic

to cancer cells. In vitro AA killed cancer cells at ex-

tracellular concentrations above 1 mM [39]. Chen et al.

[40] found pharmacologic concentrations of AA caused

prooxidant cytotoxicity toward a variety of tumor cells

in vitro, without adversely affecting normal cells. Ovar-

ian, pancreatic, and glioblastoma tumors established in

mice significantly decreased growth rates in vivo in re-

sponse to parenteral AA administration.

Padayatty et al. [41] demonstrate using hospital vol-

unteers that this concentration can be achieved in vivo,

reaching 13 mM for a 50-g iv dose, 140-fold greater than

can be achieved by oral dosing. A review by Frei and

Lawson [6] also shows many recent studies demonstrat-

ing that millimolar AA by iv infusion will kill cancer

cells but not normal cells.

DEATH: Despite the evidence for mechanisms by

which AA may benefit, there remains doubt about the

benefits of antioxidants in general. A review in JAMA in

2007 by Bjelakovic et al. [42] reviewed all randomized

trials of adults taking antioxidants for the prevention of

several diseases, finally including 68 randomized trials

with 232,606 participants. They found beta-carotene,

vitamin A and vitamin E significantly increased mortal-

ity. Vitamin C had no significant effect on mortality.

DISCUSSION: One goal for a review is to elucidate

pros and cons. However, except for the flawed Podmore

study, I have found no reason for not taking 500 mg of

AA twice a day except inconvenience. Since the UL was

established at 2 g/d, studies have at most questioned the

benefit of AA supplements, and have often demonstrated

both theoretical and practical benefit.

Physicians accept the role of AA as a vitamin for im-

mediate health benefits such as prevention of scurvy.

Ever since Harman’s free radical theory of aging and

anti-nuclear activist Linus Pauling’s proposal to take

megadoses of AA as an ROS scavenger to maintain

long-term health, people have found higher doses con-

troversial. The American Aging Association held a con-

sensus conference in 1996 that concluded a daily dose

from 200 to 1,000 mg per day in divided doses was war-

ranted [43].

The dosages still advocated actively in the literature

are three. They are: 90 mg, found in most diets, provid-

ing the Daily Value, sufficient to prevent scurvy; 200 mg,

the highest intake likely through a conscientious diet,

sufficient to saturate certain WBCs, but substantially

lower than was found necessary in many studies cited in

Table 1, and 500 mg twice a day, which can be obtained

only through oral supplements, the highest dosage nec-

essary and sufficient for oral dosage saturation of plasma

in vivo.

Given the safety of AA supplements, greater education

might help people to alleviate the expense and suffering

that may be caused by inadequate AA intake. However,

the media report erroneous findings, like those of Pod-

more et al. [5] that AA may cause DNA mutations, while

they fail to report the UL for safe consumption of AA.

A. R. Ordman / HEALTH 2 (2010) 819-823

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Openly accessible at

Table 1. Summary of potential damage by oxidative stress and

benefits of aa intakes of 500 mg twice a day to humans.

BRAIN

ROS contribute to Alzheimer’s [15]

AA reduces cognitive decline [16]

AA reduces reperfusion injury [19]

AA reduces damage from head trauma [20]

AA generates new neurons [23]

HEART

AA reverses endothelial dysfunction [25]

AA generates new cardiac myocytes [26]

AA (500 mg twice daily) protects plasma [29]

EYES AA reduced cataract odds 64% [30]

COLDS AA (500 mg) reduced frequency of colds by

66% [34]

BONES Highest tertile had less bone loss [31]

CANCER

AA reduced mutations causing metastases

[38]

iv AA reduced tumor growth in mice and did

not harm normal cells in vitro [40]

SAFETY Up to 2,000 mg AA daily is safe [11]

DEATH No significant effect on mortality [42]

4. CONCLUSIONS

As documented above, 500 mg of vitamin C taken every

12 hrs may reduce many major causes of chronic disease

and aging decline, not to mention colds. The safety and

benefit of vitamin C supplements is of critical impor-

tance, especially for those in war zones at risk for brain

trauma or of advancing years at risk for chronic disease

and stroke. People ought to be informed of the safety

and benefit of vitamin C supplements.

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