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.
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
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.
[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.-
[3] Cheraskin, E. Antioxidants in health and disease: the big picture. J. Orthomolecular
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:
[5] Hoffer, A. Vitamin B3 schizophrenia: Discovery recovery controversy. Kingston,
[6] Foster, H.D. What really causes AIDS. Victoria, British Columbia: Trafford Publishing,
[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,
[9] Hoffer, A. Negative and positive side effects of vitamin B-3. J. Orthomolecular Med
[10] Horrobin, D.F. Niacin flushing, prostaglandin E and evening primrose oil: a possible
objective test for monitoring therapy in schizophrenia. Orthomolecular Psychiatry
[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
[14] Rajakumar, K. Pellagra in the United States: A historical perspective. South Med. J.
[15] Hoffer, A. Hong Kong veterans study. J. Orthomolecular Psychiatry 1974; 3: 34-36.
[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
[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.
[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):
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):
[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
[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,
[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:
[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
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.
FOLIC ACID AND HEALTH: AN OVERVIEW
Brookfield Health Sciences Complex,
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
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
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.
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
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.
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
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 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.
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