Cell replication Folate transfers single carbon atoms in reactions essential to the

synthesis of purines and pyrimidines and hence to the production of deoxyribonucleic acid

(DNA). Unlike the methylation cycle, the DNA cycle does not depend on vitamin B12. Folic

acid can thus maintain the supply of intracellular folate required for DNA synthesis. DNA

synthesis, and hence cell replication, can therefore take place in people with vitamin B12

deficiency, provided that folic acid is available as a source of folate.

42 Rossana Salerno-Kennedy

A number of drugs interfere with the biosynthesis of folic acid and tetrahydrofolate.

Among these are the dihydrofolate reductase inhibitors (such as trimethoprim and

pyrimethamine), the sulfonamides (competitive inhibitors of para-aminobenzoic acid in the

reactions of dihydropteroate synthetase), and the anticancer drug methotrexate (inhibits both

folate reductase and dihydrofolate reductase).

DIETARY SOURCES

Naturally occurring folate is found in a wide variety of foods, including green leafy

vegetables, liver, kidneys, grains, bread and nuts. Folates are extremely unstable. Sensitive to

light, heat and oxygen, they rapidly lose activity in foods during harvesting, storage,

preparation and processing.

By contrast, synthetic folic acid, which is added to various foods during fortification (as

well as dietary supplements), is stable for months or even years. It is also more than 90 per

cent bioavailable, compared with folates in foods which are only about 45 % bioavailable.

RDI

The Reference Daily Intake (RDI) is the average daily dietary intake level that is

sufficient to meet the nutrient requirements of nearly all (97% to 98% of) healthy individuals

in each life-stage and gender group. The 1998 RDIs for folate are expressed in a term called

the "dietary folate equivalent" (DFE). This was developed to help account for the differences

in absorption of naturally-occurring dietary folate and the more bioavailable synthetic folic

acid [19]. The 1998 RDAs for folate expressed in micrograms (µg) of DFE for adults are:

1998 RDAs for Folate

Men Women

(19+) (19+) Pregnancy Breast feeding

400 µg 400 µg 600 µg 500 µg

1 µg of food folate = 0.6 µg folic acid from supplements and fortified foods

CLINICAL DEFICIENCY

The main causes of folate deficiency are:

• Decreased dietary intake - This occurs in people eating inadequate diets, such as

some elderly people, some people on low incomes, and alcoholics who substitute

alcoholic drinks for good sources of nutrition

• Decreased intestinal absorption - Patients with disorders of malabsorption (e.g.,

coeliac disease) may suffer folate deficiency

Folic Acid and Health: An Overview 43

• Increased requirements - Increased requirement for folate, and hence an increased

risk of deficiency, can occur in pregnancy, during lactation, in haemolytic anaemia

and in leukaemia

• Alcoholism - Chronic alcoholism is a common cause of folate deficiency. This may

occur as a result of poor dietary intake or through reduced absorption or increased

excretion by the kidney. The presence of alcoholic liver disease increases the

likelihood of folate deficiency

• Drugs - Long term use of certain drugs (e.g., phenytoin, sulphasalazine) is associated

with folate deficiency.

Folate deficiency has also been associated with neural tube defects [1], cardiovascular

disease [2], cancer of various sites [3], depression [4], dementia [5], and osteoporosis [6,7].

FOLIC ACID AND PREGNANCY

The traditional view that the only concern in relation to folate status was clinical

deficiency was challenged when it became clear that the risk of congenital malformations,

including neural tube defects (NTDs), could be reduced by increased folic acid intake during

the periconceptional period [13]. Neural tube defects result in malformations of the spine

(spina bifida), skull, and brain (anencephaly) [9]. Since the discovery of the link between

insufficient folic acid and neural tube defects (NTDs), governments and health organisations

worldwide have made recommendations concerning folic acid supplementation for women

intending to become pregnant [20]. It was suggested to take 400 micrograms of synthetic

folic acid daily from fortified foods and/or supplements [21]. This has also led to the

introduction in many countries of fortification, where folic acid is added to flour with the

intention of everyone benefiting from the associated rise in blood folate levels [20]. In

countries where mandatory fortification of flour was introduced, folate and homocysteine

status improved notably and neural tube defect rates fell by up to nearly 80% [20]. Despite

public-health campaigns, knowledge about the proper periconceptional time to use folic acid

supplements for the prevention of neural tube defects is not widespread in women and only a

maximum of half of them are following the recommendations [20]. Vulnerable groups are

people of low educational status, young people, immigrants, and women with unplanned

pregnancies. A substantial percentage of women still choose not to take the supplements even

though they are aware of the beneficial effects [20].

Why folic acid should influence the incidence of neural tube defects remains unclear.

Neural tube defects almost certainly occur as a result of complex genetic, nutritional and

environmental interactions, and some interesting clues have emerged in the area of genetics.

A defect in the methylene-tetrahydrofolate-reductase (MTHFR) gene, which occurs in about

5 to 15 per cent of white populations, has been identified [22]. This genetic defect appears to

result in an increased requirement for folates and an increased risk of recurrent early

pregnancy loss and NTDs [23]. In addition, elevated levels of plasma homocysteine have

been observed in mothers producing offspring with NTDs [24]. The possibility that this factor

could have toxic effects on the foetus at the time of neural tube closure is currently under

44 Rossana Salerno-Kennedy

further investigation. Although folic acid does reduce the risk of birth defects, it is only one

part of the picture and should not be considered a cure. Even women taking daily folic acid

supplements at the reccomended dose have been known to have children with neural tube

defects [20].

FOLIC ACID AND CARDIOVASCULAR DISEASE

Low concentrations of folate, vitamin B12, or vitamin B6 may increase the plasma level of

the aminoacid Homocysteine (Hcy). As explained previously, homocysteine is derived from

dietary methionine, and is removed by conversion to cystathionine, cysteine and pyruvate, or

by remethylation to methionine.

There is evidence that an elevated homocysteine level is an independent risk factor for

cardiovascular disease (CVD) mortality [25-27]. Mechanisms by which plasma Hcy may be

associated with an increased risk of CVD have not been clearly established, but possibilities

include [28]:

• Oxidative damage to the vascular endothelium

• Inhibition of endothelial anticoagulant factors, resulting in increased clot formation

• Increased platelet aggregation

• Proliferation of smooth muscle cells, resulting in increased vulnerability of the

arteries to obstruction

An increased level of plasma Hcy may be caused by rare inborn errors of its metabolism.

An example is homocystinuria, which occurs as a result of a genetic defect in the enzyme

cystathione synthase. Genetic changes in the enzymes involved in the remethylation pathway,

including methylene tetrahydrofolate reductase and methionine synthase, are also associated

with an increase in plasma homocysteine concentrations. All such cases are associated with

premature vascular disease, thrombosis and early death. Such genetic disorders are rare and

cannot account for the raised homocysteine levels observed in many patients with

cardiovascular disease. However, attention is now being given to the possibility that

deficiency of the various vitamins which act as co-factors for the enzymes involved in

homocysteine metabolism could result in increased Hcy concentrations. In particular, folate is

required for the normal function of methylene-tetrahydrofolate-reductase, vitamin B12 for

methionine-synthase and vitamin B6 for cystathione-synthase.

In theory, lack of any one of these three vitamins could cause hyperhomocysteinaemia,

and could therefore increase the risk of cardiovascular disease [28]. In the Framingham Heart

Study [29], the longest observed cohort study on vascular disease, it was shown that folic

acid, vitamin B6 and vitamin B12 are determinants of plasma homocysteine levels, with folic

acid showing the strongest association.

The question whether increased vitamin intake can reduce cardiovascular disease risk

was examined in the Nurse's Health Study [30]. The results showed that those with the

highest intake of folate had a 31 % lower incidence of heart disease than those with the

lowest intake. Those with the highest intake of vitamin B6 had a 33 % lower risk of heart

Folic Acid and Health: An Overview 45

disease, while in those with the highest intake of both vitamin B6 and folate, the risk of heart

disease was reduced by 45 %. The risk of heart disease was reduced by 24 % in those who

regularly used multivitamins.

Another question is whether homocysteine levels can be lowered with folate and other B

vitamins. Studies have shown that folic acid (250μg daily), in addition to usual dietary

intakes of folate, significantly decreased plasma homocysteine concentrations in healthy

young women [31]. Breakfast cereal fortified with folic acid reduced plasma homocysteine in

men and women with coronary artery disease [32].

Another study has demonstrated that the addition of vitamin B12 to either folic acid

supplements or enriched foods (400μg folic acid daily) maximizes the reduction of

homocysteine [33]. Furthermore, two meta-analyses [34, 35] suggest that the administration

of folic acid reduces plasma homocysteine concentrations and that vitamin B12, but not

vitamin B6, may have an additional effect [35].

On the other hand, the NORVIT trial [36] has suggested that folic acid supplementation

may do more harm than good. As of 2006, studies have shown that giving folic acid to reduce

levels of homocysteine does not result in clinical benefit and have suggested that in

combination with B12 it may even increase some cardiovascular risks [36,37].

Unfortunately, a definitive answer to the most important question of whether or not

reducing homocysteine can reduce cardiovascular disease does not yet exist due to the lack of

published data. However, there is currently no evidence available to suggest that lowering

homocysteine with vitamins will reduce the risk of heart disease. Clinical intervention trials

are needed to determine whether supplementation with folic acid, vitamin B12 or vitamin B6

can lower the risk of developing coronary heart disease.

FOLIC ACID AND MENTAL DISORDERS

There is an apparent increase in mental disorders associated with reduced folate status

[38]. However, whether this reduced vitamin status is a cause of the disease, or occurs as a

result of having the disease, is unknown.

Studies have found that Alzheimer's disease (AD) is associated with low blood levels of

folate and vitamin B12 and elevated homocysteine (Hcy) levels [39, 40]. In particular, the

long-running Framingham Study, has shown that people with hyperhomocysteinemia (Hcy

>14 μmol/l) had nearly double the risk of developing AD [41]. This study was the first to

associate Hcy levels, measured several years earlier, with later diagnosis of AD and other

dementias. Furthermore, the association between Hcy and AD was found to be strong and

independent of other factors, such as age, gender, APOE genotype, and other known or

suspected risk factors for dementia and AD. Clarke et al. [42] have also shown that low

serum folate and consequently elevated concentrations of serum Hcy, was associated with

progressive atrophy of the medial temporal lobe in subjects with AD. The serum folate

seemed to have a strong negative association with the severity of atrophy of the neocortex in

the “Nun Study”, suggesting that atrophy may be specific to relatively low folate

concentrations [43]. Therefore, the relationship between Hcy and dementia is of particular

46 Rossana Salerno-Kennedy

interest because blood levels of Hcy might be reduced by increasing the intake of folic acid

and vitamins B6 and B12.

The recent Baltimore Longitudinal Study of Aging on 579 older individuals without

dementia (follow-up of 9.3 years) has suggested that consuming levels of folate at or above

RDA (400 micrograms) is associated with a reduced risk of AD [44]. It has also been

suggested that a fortification policy based on folic acid and vitamin B12, rather than folic acid

alone, is likely to be much more effective at lowering Hcy concentrations, with potential

benefits for reducing the risk of AD and vascular disease [44].

Several epidemiological studies also provide evidence that an elevated total plasma level

of Homocysteine (tHcy) is associated with an increased risk of psychiatric disorders such as

depression [45-48]. Most of these studies suggest that a significant association is observed for

tHcy levels above 12-15 μmol/L [45, 46]. For instance, the Hordaland Homocysteine Study

(HHS-II) has shown that subjects with tHcy > 15umol/L had a two-fold higher risk of having

depression compared with those with tHcy < 9 umol/L. In addition, it was observed that those

with Methyltetrahydrofolate Reductase (MTHFR) 677 TT genotype had a 70% higher risk of

depression compared with the CC genotype [45-48]. This effect is exacerbated in the

presence of low folate status, indicating a strong gene-nutrient interaction [45]. These data

may suggest that some depressed patients are genetically vulnerable and that they may

benefit from folic acid supplementation in addition to their antidepressant treatment. There is

some limited evidence from randomised controlled trials that using folic acid in addition to

antidepressant medication may have benefits [49]. However, the evidence is probably too

limited at present for this to be a routine treatment recommendation. To date, the association

between tHcy, depression score and risk of depression needs to be fully evaluated.

FOLIC ACID AND CANCER

Several studies have recently implicated folate in modulating the risk of several cancers

[3], in particular, colorectal and breast cancer [50]. Folate is involved in the synthesis, repair,

and functioning of DNA and a deficiency of folate may result in damage to DNA that may

lead to cancer [51]. It is not clear whether folate itself has a direct link to the risk of cancer of

various sites, as other dietary factors (e.g. alcohol, methionine) as well as genetic

polymorphisms seem to modulate the risk. Polymorphism of a potentially wide range of other

enzymes involved in folate metabolism may also modulate the risk of cancer [50].

Although folate could prevent cancer in healthy people, it might also promote the

progression of pre-malignant and malignant lesions. Low folate status and antifolate

treatment, respectively, inhibit human tumor growth in these stages [52-56]. The results of

studies in animals suggest that the effect of folate on carcinogenesis is dependent on the stage

of the carcinogenic process and the dose of folate tested [56]; folate deficiency inhibits,

whereas folate supplementation promotes the progression of established tumors.

Concerning the association between folate and colon cancer, data from prospective

studies [57,58] and case-control studies [59-62], indicate that inadequate intake of folate may

increase the risk of this type of cancer.

Folic Acid and Health: An Overview 47

Recent epidemiological studies also support an inverse association between folate status

and the rate of colorectal adenomas and carcinomas. High dietary folate (including

supplements), but not folate from foods only, was inversely associated with the risk of

colorectal adenoma in women (RR= 0.66; 95% CI, 0.46-0.95) of the Nurses’ Health Study

[63], and in men (RR= 0.63; 95% CI, 0.41-0.98) of the Health Professional Follow-up Study

[64]. The relative risk of those with a high alcohol and low methionine and folate intake

compared with those with low alcohol and high folate and methionine consumption was 3.17

(95% CI, 1.69-5.95) (men and women combined). These findings suggest that maintaining

adequate folate levels may be important in reducing the risk of colon cancer. Animal trials

have also provided considerable support for the epidemiological findings [65], suggesting

that folate supplementation might decrease or increase cancer risk depending on timing and

dosage. Moreover, a recent cross-sectional study [66] has shown that high folate status in

smokers may confer increased or decreased risk for high risk adenoma, depending on the

MTHFR genotype.

Although not uniformly consistent, epidemiologic data also report an inverse association

between dietary intake and blood measurements of folate and the risk of breast cancer [67].

The risk of postmenopausal breast cancer may be increased among women with low intakes

of folate, especially those consuming alcohol-containing beverages [68]. Achieving adequate

circulating levels of folate may be particularly important in attenuating the risk of

postmenopausal breast cancer associated with family history, but only if alcohol use is

avoided or minimized [69]. More recent findings confirm the positive associations between

moderate alcohol consumption and breast cancer. However, they also suggest that a high

intake, generally attributable to supplemental folic acid, may increase the risk in

postmenopausal women. In particular, the Prostate, Lung, Colorectal, and Ovarian (PLCO)

Cancer Screening trial [70] has recently reported for the first time a potentially harmful effect

of high folate intake on breast cancer risk. In this study, the risk of developing breast cancer

was significantly increased by 20% in women taking supplemental folic acid intake ≥ 400

μg/d compared with those with no supplemental intake. Furthermore, although food folate

intake was not significantly related to breast cancer risk, total folate intake, mainly from folic

acid supplementation, significantly increased breast cancer risk by 32%. The data from the

PLCO trial also support prior observations made in epidemiologic, clinical, and animal

studies [50] suggesting that folate possesses dual modulatory effects on the development and

progression of cancer, depending on the timing and dose of folate intervention. Based on the

lack of compelling supportive evidence, routine folic acid supplementation should not be

recommended as a chemopreventive measure against breast cancer at present.

Data concerning the relationship between folate and other types of cancer are sparse and

controversial. A recent population-based prospective study [71] of 81,922 cancer free

Swedish women and men, has suggested that increased inatake of folate from food sources,

but not from supplements, may be associated with a reduced risk of pancreatic cancer. In the

same study, 61,084 women, aged 38-76 years, were also assessed for ovarian cancer risk and

the results have suggested that a high dietary folate intake may play a role in reducing the risk

of ovarian cancer, especially among women who consume alcohol [72]. The effect of folate

on carcinogenesis in the cervix remains uncertain. Two trials have shown no significant

48 Rossana Salerno-Kennedy

effect of folic acid on the rates of cervical intraepithelial neoplasia regression or progression

[50].

 

considered only modest changes, Kaufman noted that improvement among his patients

started after four to 12 weeks - the time at which Jonas' study stopped. He also found that

people might continue to improve for up to a year before they plateaued. Jonas' recent study

identified no significant side effects, but to be safe, those who opt for long-term niacinamide

therapy should have their liver enzymes periodically assessed.

CONCLUSIONS

The preceding discussion establishes that niacin deficiency is very common. It may

occur, for example, because of a polymorphism that causes an abnormal need for vitamin B-3

in some alcoholics and schizophrenics. Alternatively, poor quality diets, often maize

dominated, can result in pellagra and the extreme longterm deficiencies seen in former

prisoners-of-war. Addictions to alcohol, tobacco or LSD also increase the need for vitamin B3. Beyond this, natural methyl acceptors, such as niacin, appear to have a major, high dose

role to play in the treatment of Parkinson's disease, schizophrenia, multiple sclerosis and

amyotrophic lateral sclerosis. This is because vitamin B-3 helps prevent the cellular damage

of dopamine's and adrenaline's oxidative byproducts. Beyond this, vitamin B-3 deficiency

seems commonest amongst the elderly, where it is associated with excessive cholesterol,

coronary and cardiovascular disorders, stroke and arthritis.

While optimum dosages vary from individual to individual, the literature and Dr. Hoffer's

experience with over 5,000 patients allow some generalizations. The classic deficiency

disease pellagra, when recently developed, can typically be reversed with daily doses of

around 10 mg. of niacin. Long-term pellagrans, however, require much larger gram doses. A

long continuing deficiency appears to lead to vitamin B-3 dependency. This, of course, is

also the case in prisoners-of-war. Similar dependencies seem to occur in many psychiatric

conditions (including schizophrenia) and in arthritis where optimum daily doses of niacin are

typically in the one to four gram range. Beyond this, normalizing cholesterol and the

treatment of cardiovascular disease and stroke may require daily doses of 6 to 10 grams or

more. The optimum dosages required to slow or prevent the development of Parkinson's

disease, multiple sclerosis and amyotrophic lateral sclerosis are yet unclear but they are

almost certain to be in the several grams per day range. It is clear, however, that for the

majority of patients high doses of niacin are required, often one hundred times or more than

the Recommended Dietary Allowance advised in the United States. This, of course, implied

that the vitamins-as-drugs paradigm is valid for vitamin B-3.

REFERENCES

[1] Hoffer, A. Niacin Therapy in Psychiatry. Springfield, Illinois: CC Thomas, 1962.

[2] MedicineNet.com. Definition of Pellagra. http://www.medterms.com/script/main/art.-

asp?articlekey=4821

[3] Cheraskin, E. Antioxidants in health and disease: the big picture. J. Orthomolecular

Med., 1995; 10(2): 89-96.

36 Harold D. Foster and Abram Hoffer

[4] Pauling, L. Orthomolecular psychiatry: Varying the concentrations of substances

normally present in the human body may control mental disease. Science 1968; 160:

265-271.

[5] Hoffer, A. Vitamin B3 schizophrenia: Discovery recovery controversy. Kingston,

Ontario: Quarry Press, 1998.

[6] Foster, H.D. What really causes AIDS. Victoria, British Columbia: Trafford Publishing,

2002.

[7] Ames, B.N., Elson-Schwab, I., Silver, E.A. High-dose vitamin therapy stimulates

variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to

genetic disease and polymorphisms. Am J Clin Nutr 2002; 75: 616-658.

[8] Hoffer, A., Osmond, H. How to Live with Schizophrenia. New York: University Books,

1966.

[9] Hoffer, A. Negative and positive side effects of vitamin B-3. J. Orthomolecular Med

2003, 18: 146-160.

[10] Horrobin, D.F. Niacin flushing, prostaglandin E and evening primrose oil: a possible

objective test for monitoring therapy in schizophrenia. Orthomolecular Psychiatry

1980; 9: 33-34.

[11] Benyo, Z., Gille, A., Kero, J., Csiky, M., Suchankova, M.C., Nusing, R.M., Moers,

A.W. et al. GPR 109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J

Clin Invest 2005; 115(12): 3634-3640.

[12] Cheng, K., Wu, T.J., Wu, K.K., Sturino, C., Metters, K., Gottesdiener, K., Wright, S.D.

et al. Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid- induced

vasodilation in mice and humans. Proc. Natl. Acad Sci USA 2006; 103: 6682- 6687.

[13] Miller, C.L., Dulay, J.R. A molecular basis for decreased niacin receptor function in

schizophrenia. (In Review).

[14] Rajakumar, K. Pellagra in the United States: A historical perspective. South Med. J.

2000; 93(3): 272-277.

[15] Hoffer, A. Hong Kong veterans study. J. Orthomolecular Psychiatry 1974; 3: 34-36.

[16] Antoshechkin, A.G. Physiological model of stimulative effect of alcohol in low-tomoderate doses. Annals of the New York Academy of Sciences 2002; 957: 288-291.

[17] Smith, R.F. A five year field trial of massive nicotinic acid therapy of alcoholics in

Michigan. J. Orthomolecular Psychiatry 1974; 3: 327-331.

[18] Larsen, J.M. Seven Weeks to Sobriety. Westminster, Maryland: Fawcett Books, 1997.

[19] Bill, W. (editor). The Vitamin B-3 Therapy: A Third Communication to Alcoholics

Anonymous Physicians. 1971.

[20] Serdaru, M., Hauser-Hauw, C., Laplane, D., Buge, A., Castaigne, P., Goulon, M.,

Lhermitte, F., Hauw, J-J. The clinical spectrum of alcoholic pellagra encephalopathy.

Brain 1988; 111(4): 829-842.

[21] Ieraci, A., Herrera, D.G. Nicotinamide protects against ethanol-induced apoptotic

neurodegeneration in the developing mouse brain. PloS Med 2006; 3(4): 101.

[22] Clarkes, R. Niacin for nicotine? Lancet 1980; 1(8174): 936.

[23] Prousky, J.E. Vitamin B-3 for nicotine addiction. J. Orthomolecular Med. 2004; 19(1):

56-57.

The Causes and Consequences of Vitamin B-3 Deficiency… 37

[24] Foster, H.D., Hoffer, A. The two faces of L-DOPA: benefits and adverse side effects in

the treatment of Encephalitis lethargica, Parkinson's disease, multiple sclerosis and

amyotrophic lateral sclerosis. Med Hypotheses 2004; 62: 177-181.

[25] Johannsen, P., Velander, G., Mai, J., Thorling, E.B., Dupont, E. Glutathione peroxidase

in early and advanced Parkinson's disease. J Neurol Neurosurg Psychiatry 1991; 54(8):

679-682.

[26] Skukla, U.K., Jensen, G.E., Clausen, J. Erythrocyte glutathione peroxidase deficiency

in multiple sclerosis. Acta Neurol Scand 1997; 56(6): 542-550.

[27] Shults et al. Cited by Hoffer, A. 1998 op.cit.

[28] Hoffer, A., Walker, N. Putting it all together: the new orthomolecular nutrition. New

Canaan; Keats, 1996.

[29] Behonick, G.S., Novak, M.J., Nealley, E.W., Baskin, S.I. Toxicology update: the

cardiotoxicity of the oxidative stress metabolites of catecholamines (Aminochromes). J

Applied Toxicology 2001; 21: S21-S22.

[30] Rouleau, J.L., Pitt, B., Dhalla, N.S., Dhalla, K.S., Swedberg, K. et al. Prognostic

importance of the oxidized product of catecholamines, adrenolutin, in patients with

severe heart failure. Am Heart J 2003; 145(5): 926-932.

[31] Macarthur, H., Westfall, T.C., Riley, D.P., Misko, T.P., Salvemini, D. Inactivation of

catecholamines by superoxide gives new insights on the pathogenesis of septic shock.

Proc Natl Acad Sci USA 2000; 97: 9753-9758.

[32] Irvine cited by Pfeiffer, C.C., Mailloux, R., Forsythe, L. The schizophrenias: ours to

conquer. Wichita, Kansas: Bio-Communications Press, 1988.

[33] Irvine, D.G. Hydroxy-hemopyrrolenone not kryptopyrroles in the urine of

schizophrenics and phorphyrics. Clinical Chemistry 1978; 14: 1069-1070.

[34] O'Reilly and Hughes cited by Pfeiffer et al. op.cit.

[35] Hoffer A., Walker, M. Smart Nutrients. Prevent and Treat Alzheimer's and Senility,

Enhance Brain Function and Longevity. Ridgefield, CT: Vital Health Publishing.

[36] Canner, P.L., Berge, K.G., Wenger, N.K., Stamler, J., Friedman, L., Prineas, R.J.,

Friedewald, W. Fifteen year mortality in Coronary Drug Project patients: long-term

benefits of niacin. J Am Coll Cardiol 1986; 8(6): 1245-1255.

[37] Condorelli, L. Nicotinic acid in the therapy of the cardiovascular apparatus. In

Altschul, R. (editor) Niacin in Vascular Disorders and Hyperlipemia. Springfield,

Illinois: C.C. Thomas, 1964.

[38] Yang, J., Klaidman, L.K., Adams, J.D. Medicinal chemistry of nicotinamide in the

treatment of Ischemis and Reperfusion. Mini Reviews in Medicinal Chemistry 2002; 2:

125-134.

[39] Yang, J., Adams, J.D. Nicotinamide and its pharmacological properties for clinical

therapy. Drug Design Reviews 2004; 1: 43-52.

[40] Kaufman, W. Common forms of niacinamide deficiency disease: aniacin amidosis.

New Haven: Yale University Press, 1943.

[41] Kaufman, W. The common form of joint dysfunction: its incidence and treatment.

Brattleboro, Connecticut: E.L. Hildreth and Co.

[42] Hoffer, A. Treatment of arthritis by nicotinic acid and nicotinamide. Can Med Ass J

1959; 81: 235-238.

38 Harold D. Foster and Abram Hoffer

[43] Jonas, W.B., Rapoza, C.P., Blair, W.F. The effect of niacinamide on osteoarthritis: a

pilot study. Inflamm Res 1996; 45: 330-334.

In: Vitamin B: New Research ISBN 978-1-60021-782-1

Editor: Charlyn M. Elliot, pp. 39-56 © 2008 Nova Science Publishers, Inc.

Chapter III

FOLIC ACID AND HEALTH: AN OVERVIEW

Rossana Salerno-Kennedy∗

School of Medicine,

Brookfield Health Sciences Complex,

University College Cork,

Cork, Ireland.

ABSTRACT

The review summarizes current thinking on the relationship between folate and

health with an emphasis on the potential benefits and risks associated with folic acid

supplements and fortification of food.

For decades, folate has been known to produce a form of anemia called

“megaloblastica”, there is now evidence that it is also essential to the development of the

central nervous system and that insufficient folate activity, at the time of conception and

early pregnancy, can result in congenital neural tube defects. More recently, degrees of

folate inadequacy have been found to be associated with high blood levels of the aminoacid homocysteine (Hcy). Hcy is a well known risk factor for cardiovascular and

neurodegerative diseases, dementia and Alzheimer’s disease, osteoporotic fractures and

complications during pregnancy. Moreover, folate has been implicated in modulating the

risk of several cancers. For instance, recent epidemiological studies support an inverse

association between folate status and the rate of colorectal adenomas and carcinomas,

suggesting that maintaining adequate folate levels may be important in reducing this risk.

On the other hand, several studies suggest that a high intake, generally attributable to

supplemental folic acid, may increase the risk of breast cancer in postmenopausal

women, particularly those with moderate alcohol consumption.

There is also the risk that widespread folate fortification, may mask B12 deficiency,

which in turn may lead to neurological damage. Vitamin B12 deficiency produces an

anemia that is identical to that of folate deficiency and also causes irreversible damage to

∗

 Correspondence concerning this article should be addressed to: Dr. R. Salerno-Kennedy, School of Medicine,

Brookfield Health Sciences Complex, University College Cork, Cork, Ireland; E-mail: r.kennedy@ucc.ie.

40 Rossana Salerno-Kennedy

the central and peripheral nervous systems. Folate fortification may also affect

antiepileptic drug seizure control, and influence the genetic selection of a potentially

deleterious genotype, albeit over a number of generations.

As folic acid is now under consideration worldwide as an important functional food

component, there is great interest in finding whether dietary supplements and food

fortification with folic acid can improve health or be harmful. These and other aspects of

this matter will be explored in this review.

Keywords: folic acid, pregnancy, cardiovascular disease, mental disorders, cancer.

INTRODUCTION

Folic acid and folate (the anion form) are forms of a water-soluble B vitamin.

Folate, which is the generic term, gets its name from the Latin word folium ("leaf"). Folic

acid is the most oxidised and stable form of folate, which is used in vitamin supplements and

in fortified food products.

Folic acid plays an important part in the prevention of neural tube defects and is

suspected to prevent some other congenital anomalies and low birth weight [1] as well as

chronic diseases such as cardiovascular disease [2], cancer of various sites [3], depression

[4], dementia [5] and osteoporosis [6,7]. There is therefore great interest in whether dietary

supplements of folic acid can improve health; hence it is under consideration as an important

functional food component. However, definite scientific evidence of a risk reduction in

clinical trials is only available for synthetic folic acid and neural tube defects This has led to

a general consensus in recommending daily supplementation of synthetic folic acid to reduce

the risk of neural tube defects [8-13]. Despite the noted beneficial effects of folic acid

fortification on folate status and neural tube defects in countries that implemented either

mandatory or voluntary fortification in addition to the promotion of supplement use, concern

continues that folic acid might also have adverse effects [14]. Although folate is safe and

almost free of toxicity [15], concerns that folic acid fortification could mask symptoms of

vitamin B12 deficiency and precipitate neurological complications have been raised [15].

Other examples of potential safety issues are interactions with drugs, hypersensitivity

reactions, cancer promotion, and an increase in the twinning rate [15-17].

Researchers are continuing to investigate the benefits and risks of enhanced folate intake

from foods or folic acid supplements in diseases.

This review summarizes the current thinking on this important issue.

BIOCHEMISTRY

Folate biochemistry [18] is complex and parts of it are still being researched. Folic acid

(pteroylmonoglutamic acid or PGA) (Figure 1) is a conjugated molecule consisting of a

pteridine ring structure linked to para-aminobenzoic acid (PABA) that forms pteroic acid.

Folic Acid and Health: An Overview 41

Folic acid itself is then generated through the conjugation of glutamic acid residues to pteroic

acid.

Dietary folates, which exist in several different forms, have to be hydrolysed to a

particular form - the monoglutamate - before absorption can occur. Following hydrolysis, the

monoglutamate form is reduced and methylated to produce 5-methyl-tetrahydrofolate (5-

methyl-H4 folate), which is the form of the vitamin found circulating in the plasma. To enter

the cells, where it performs various functions, 5-methyl-H4 folate must be converted

(principally in the liver where it is stored) to tetrahydrofolate (THF also H4 folate), while

donating its methyl group to produce methionine. This reaction is controlled by the enzyme

methionine synthase, an enzyme which is dependent on vitamin B12. Thus, for dietary folates

to enter cells, vitamin B12 is essential. By contrast, folic acid can enter cells by a process

which is not dependent on vitamin B12.

Figure 1. Folic Acid. Positions 7 & 8 carry hydrogens in dihydrofolate (DHF), positions 5-8 carry

hydrogens in tetrahydrofolate (THF).

In the cells, the function of folic acid is to carry one-carbon fragments to various

biochemical targets. The one-carbon piece can be in several different oxidation states but the

two important forms are methyl-tetrahydrofalate (methyl-THF) and methylene-THF. Thus,

folate functions can basically be divided into two categories:

• Methylation reactions

• Cell replication

Methylation reactions The methylation cycle depends on both folate and vitamin B12 to

produce methionine, which is an essential amino acid in human beings and is obtained

exclusively from the diet. Any excess methionine is degraded to produce homocysteine. At

this point, homocysteine can be either degraded to form pyruvate, which can then be used as

a source of energy, or it can be remethylated to form methionine.

 The relationship between oxidative stress and the catecholamines, seen, for example, in

Parkinson's disease and multiple sclerosis, is now apparent. This is largely because of the

research conducted in Winnipeg by Behonick and colleagues [29] who first developed a

method for measuring adrenolutin in blood. This is very significant because adrenochrome

rapidly is converted to adrenolutin in the body. Beyond this, Rouleau and colleagues [30]

have demonstrated that high levels of adrenolutin in patients with severe heart failure is

associated with a poor prognosis. Macarthur and colleagues [31] also have shown that, in

septic shock, excess oxidation occurs and adrenalin is very rapidly oxidized to adrenochrome

and noradrenalin to noradrenochrome. This process results in septic shock, in which blood

pressure no longer responds to injections of catecholamines. Inhibiting the oxidation helps to

restore the vasopressor properties of these catecholamines. Interestingly, vitamin B-12, in

large doses, seems very effective in the treatment of septic shock or in preventing the organ

failure seen too often during or after surgery.

In 1960, the hallucinogenic drug LSD was being used to treat alcoholics [5]. Hoffer

realized that this protocol was causing alcoholics to hallucinate in a manner similar to many

schizophrenics. This coincidence led him to believe that LSD use might be triggering

biochemical imbalances in alcoholics similar to those seen in schizophrenia. To test this

hypothesis, urine samples were collected from alcoholic patients before and after receiving

therapeutic doses of LSD. Urine from the first of these patients showed a mauve staining spot

on the paper chromatogram after development with Ehrlich's regeant. Such a mauve spot did

not appear in tests of the urine from alcoholics before they were given LSD, but it appeared

in tests of the urine of many, but not all of them, after taking this drug. Schizophrenic

patients' urine was then tested in the same way. The characteristic mauve stain also appeared

on the chromatogram paper for many, but again not all, of the samples from these patients.

The mauve factor was structurally identified in 1969 by Irvine, [32] and is now thought to be

2-hydroxy-hemopyrrolene-5-one [33]. As it circulates in the body it "forms a stable Schiff's

base with pyridoxal (the aldehyde form of pyridoxine or vitamin B-6) and subsequently

complexes with zinc, stripping the body of these two essential substances as it is excreted."

32 Harold D. Foster and Abram Hoffer

As a result of these reactions, schizophrenics producing large quantities of it are

simultaneously also very zinc and vitamin B-6 deficient.

Just how common is elevated "kryptopyrrole" in disorders involving excess oxidative

stress? In 1965, O'Reilly and Hughes [34] claimed that it was present in 11 percent of healthy

controls, 24 percent of disturbed children, 42 percent of psychiatric patients, and 52 percent

of schizophrenics. Hoffer's experience after testing a much larger sample consisting of

thousands of patients at our four research centers was somewhat different. Elevated

"kryptopyrrole" was found in the urine of 75 percent of acute schizophrenics, 25 percent of

all non-psychotic patients, and 5 percent of physically ill patients. It was absent from the

urine of normal subjects and most interestingly was never found in the urine of recovered

schizophrenics. The evidence suggests that although urinary "kryptopyrrole" (probably 2-

hydroxy-hemopyrrolene-5-one) is not an absolute sign of schizophrenia, it occurs with much

greater regularity in schizophrenics than in anyone else.

It does, however, seem to be a good indicator of excessive oxidative stress. It is found in

all classes of patients exposed to this problem, such as those suffering from schizophrenia

and autism. As previously discovered, the use of high dose vitamin B-3 as a methyl acceptor

can help prevent the cellular damage associated with derivatives of dopamine and

adrenochrome. As a result, niacin can play a key role in reducing the adverse effects of

oxidative stress identified by elevated urine "kryptopyrrole".

Malabsorption in the Elderly

The ability to absorb nutrients typically declines with age. As a result, vitamin

deficiencies are commonly seen in the elderly [35]. These are associated with a wide variety

of disorders. To illustrate the elevated blood levels seen in many patients are linked to an

inadequacy of niacins and related illnesses.

(1) Cholesterol Excess and Imbalance

The discovery that niacin lowered cholesterol levels arose from research conducted by

Professor Rudl Altschul, Chair, Department of Anatomy, University of Saskatchewan and

one of this chapter's authors, Dr. Abram Hoffer, then Director of Psychiatric Research in the

Department of Health. Professor Altschul had found that rabbits developed

hypercholesterolemia very rapidly, if they were fed cooked egg yolk in a specially baked

cake. Raw egg yolk did not have the same effect. He had also discovered that exposing

rabbits to ultraviolet light decreased their cholesterol levels. He wanted to try ultraviolet light

on people, but could not find any doctor in Saskatoon willing to work with him. Hoffer

agreed to provide subjects in one of the provincial mental hospitals. Since the treatment was

safe and patients could not be harmed by it, he considered that it would be good for them to

mix with healthy young people who would be conducting the research. At that time, Hoffer

had been suffering from bleeding gums, but found that large doses of vitamin C did not help.

After taking niacin for two weeks for other reasons, his gums were healed. From this Dr.

Hoffer concluded that the niacin had increased the rate of repair of gum tissues, which had

been under a lot of physical stress from maloccluded teeth.

The Causes and Consequences of Vitamin B-3 Deficiency… 33

Professor Altschul thought that the most important single pathological factor in coronary

disease was the inability of the intima (the inner wall of the blood vessel) to repair itself,

especially where the blood stream changed direction, causing the greatest stress to the

arteries. As Professor Altschul explained this hypothesis to Hoffer, the latter suddenly

recalled his bleeding gums and suggested that niacin might be able to heal the arterial wall's

intima. Hoffer then gave the professor one pound of crystalline niacin to test the effects on

experimental rabbits. A few months later, Altschul reported back that the niacin had lowered

rabbit cholesterol levels. On receiving this news, Hoffer organized a similar study using

humans [9]. The results were published in 1995 and were soon corroborated as a result of the

interest and enthusiasm of Dr. William Parsons Jr., than at the Mayo Clinic in Rochester,

Minnesota.

In 1986, a study by Canner and colleagues [36] showed that men who experience a

coronary and who were then given niacin died less frequently than normal and lived longer.

Specifically, there was a ten percent decrease in death rate and a two-year increase in

longevity. Since that time niacin has become the gold standard for normalizing lipid levels,

even though this fact is rarely taught in medical school. Niacin also lowers triglycerides and

lipoprotein(a) and elevated HDL (the good cholesterol fraction) which is its most important

function.

(2) Cardiovascular System

Niacin has been shown to be valuable in the treatment of disorders of the cardiovascular

system. This is not news. Condorelli [37] began to study the therapeutic applications of

niacin in 1938, very soon after it was identified as the anti-pellagra factor and its vasodilator

properties were observed. He reported the following properties of niacin, given by

intravenous injection or by mouth (1) increase in the velocity of the circulation (2) increase in

cardiac output (3) increase in systolic stroke volume (4) decrease in total pulmonary pressure

(5) increase in peripheral circulation in the viscera, brain and muscles (6) increased

oxygenation (7) increase in pulmonary oxygen diffusion (8) decrease in EEG abnormalities

caused by hypoxia of the myocardium. In short, niacin improves the body's blood flow,

improves circulation of oxygen and restores organ function. It does not increase blood

pressure.

Condorelli also described niacin's therapeutic effect on the following conditions (1)

Angiospasms, includes headaches and other regional spasms as in the retina which may occur

with hypertensive spells, are relieved by niacin but it must be given intravenously. Spasm in

the limbs also responded to niacin but it did not benefit Raynaud's disease (2) Niacin also

helped in embolism by relaxing the spastic vessels around and in the embolus (3) Thrombotic

arteriopathies such as intermittent claudication (4) Angina (5) Coronary insufficiency (6)

Eclampsia and (7) Nephritis. Condorelli reported "The experience of twenty years has always

confirmed the efficacy of nicotinic acid in acute diffuse glomerulonephritis, and we also

established that in sub-acute or chronic forms and in other nephritis disorders this treatment

may be in some way beneficial".

34 Harold D. Foster and Abram Hoffer

(3) Stroke

Evidence is accumulating that niacin helps recovery of the damaged brain. Yang and

coworkers [38] for example, found that nicotinamide could rescue viable but injured nerve

cells, within the ischemic area, after experimental strokes in animals. Early injection of

nicotinamide reduced the number of necrotic and apoptotic neurons. Later injections were not

as effective. Yang and Adams [39] concluded "Early administration of nicotinamide may be

of therapeutic interest in preventing the development of stroke, by rescuing the still viable but

injured and partially preventing infarction". They also found that this vitamin decreased the

progression of neurodegenerative disease. It prevented learning and memory impairment

caused by cerebral oxidative stress. According to these studies nicotinamide works more

quickly than niacin but both are interconvertable and in our opinion niacin will have an

advantage because it dilates the capillaries.

(4) Arthritis

Kaufman [40-41] was the first to report that niacinamide in large doses, starting from 250

milligrams taken four times daily, was useful in reversing the changes normally associated

with old age. His primary interest was in reversing arthritic symptoms, but he observed

significant associated improvement in other functions. A few months after the first report by

Hoffer and colleagues was published on the therapeutic effect of vitamin B-3 on

schizophrenic patients, Dr. Kaufman wrote that they were wrong in claiming that they had

used larger doses of this vitamin than anyone else had, Kaufman pointed out that he had, in

fact, been using these doses since the early 1940's. Dr. Hoffer asked him for copies of his

books and promptly received two which he still cherishes. Dr. Kaufman wrote "Ever since

1943 I have tried to call my work on niacinamide to the attention of leading hematologists,

nutritionists and gerontologists through conversation with them, by sending them copies of

my monograph and paper on this subject and by two talks given on the usefulness of

niacinamide and other vitamins which I gave at International Gerontological Congresses in

1951 and 1954, I think two factors have made it difficult for doctors to accept the concept

that continuous therapy with large doses of niacinamide could cause improvement to joint

dysfunction and give other benefits; (a) the advent of cortisone and (b) the fact that my use of

the vitamins was such a departure from the recommended daily allowance for vitamins by the

National Research Council". Dr. Hoffer then prepared a brief report of his work supported by

the results of six cases [42]. One patient with osteoarthritis became normal, another with

rheumatoid arthritis became much better, two arthritis cases became normal, one patient with

both schizophrenia and arthritis became completely well, while the last, who suffered from

vascular nodulitis, was much improved. Since this time, Dr. Hoffer has beneficially treated

many more arthritis patients with niacin. Large numbers have significantly improved.

In November 1999, Nutrition Science by Dan Lukaczer, reported "A few years ago,

Wayne Jonas [43] from the NIH Office of Alternative Medicine in Bethesda, Md., conducted

a 12-week, double-blind, placebo-controlled study of 72 patients to assess the validity of

Kaufman's earlier observations that niacin was of great benefit to the elderly, reducing

arthritis. Jonas reported that niacinamide at 3 g/day reduced overall disease severity by 29

percent, inflammation by 22 percent and use of anti-inflammatory medication by 13 percent."

Patients in the placebo group either had no improvement or worsened. Although these may be

The Causes and Consequences of Vitamin B-3 Deficiency… 35