University (Osaka, Japan), human pol κ by Dr. H. Ohmori and Dr. E. Ohashi of Kyoto
University (Kyoto, Japan), and human pol λ by Dr. O. Koiwai and Dr. N. Shimazaki of
Tokyo University of Science (Chiba, Japan).
This work was supported by Grant-in-aids (17380079 and 15658044) for Scientific
Research, MEXT (Ministry of Education, Culture, Sports, Science and Technology, Japan)
Universities: matching fund subsidy from MEXT, 2006-2010, (Y. M. and H. Y.). Y. M.
acknowledges Grants-in-aid from the Nakashima Foundation (Japan).
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In: Vitamin B: New Research ISBN 978-1-60021-782-1
Editor: Charlyn M. Elliot, pp. 21-38 © 2008 Nova Science Publishers, Inc.
THE CAUSES AND CONSEQUENCES OF
INSIGHTS FROM FIVE THOUSAND CASES
Department of Geography, University of Victoria, Canada;
Orthomolecular Vitamin Information Centre, Inc., Victoria, British Columbia, Canada.
Inadequacies of vitamin B-3 (niacin) can occur in at least six distinct, but
overlapping ways. Even when diet contains adequate niacin and there are no absorption
or storage problems, intake may be inadequate. This is because some individuals, for
genetic reasons, have abnormally high vitamin B-3 requirements that cannot be met by
the typical diet. As many as one-third of gene mutations result in the corresponding
enzyme having a decreased binding affinity for its coenzyme, producing a lower rate of
reaction. About fifty human genetic illnesses, caused by such defective enzymes,
therefore, can best be treated by very high doses of their corresponding coenzyme.
Several such genetic disorders have been linked to enzymes that have vitamin B-3 as
their coenzyme. These include elevated alcoholism and cancer risk, caused by defective
binding in aldehyde dehydrogenase and phenylketonuria II and hyperpharylalaninemia
that are associated with inadequate binding in dihydropteridine reductase.
There are two recently discovered types of niacin-responsive receptors, HM74A and
HM74B. HM74A is a high affinity receptor that mediates the stimulation of the synthesis
of prostaglandin by niacin. In parts of schizophrenics' brains, the protein for HM74A is
significantly decreased, confirming a niacin-related abnormality that results in very
elevated vitamin B-3 requirements. The simplest cases of niacin deficiency is caused by
diets that contain little or no vitamin B-3. Pellagra, for example, has traditionally been
diagnosed in patients who have been eating excessive quantities of maize, a food that
lacks easily available niacin. Vitamin B-3 deficiencies are also present in patients with
absorption and storage problems. Excessive consumption of sugars and starches, for
example, will deplete the body's supply of this vitamin, as will some antibiotics.
22 Harold D. Foster and Abram Hoffer
Addiction typically leads to niacin deficiency and can often be treated by taking high
doses of this vitamin. The breakdown of alcohol, for example, is vitamin B-3 dependent
because niacin is required as a coenzyme for one of the main enzymes involved,
aldehyde dehydrogenase. Since niacin is chemically similar to nicotine, the latter may
occupy niacin receptor sites. Certainly, high dose vitamin B-3 has helped many people
shed their addiction to nicotine.
Niacin deficiency also may be the result of excess oxidative stress, which causes an
abnormally high biochemical demand for this nutrient. It appears that multiple sclerosis,
amyotrophic lateral sclerosis, and Parkinson's disease involve the excessive breakdown
of dopamine, generating neurotoxins such as dopachrome. Vitamin B-3 can mitigate this
process but body stores are typically depleted by it. Similarly schizophrenics
overproduce adrenaline and its neurotoxic byproduct adrenochrome and other chrome
indoles. As a consequence, they become niacin depleted, a characteristic that is now
being used as a diagnostic symptom of this illness.
The ability to absorb nutrients typically declines with age. As a result, many vitamin
deficiencies, including niacin, are commonest in the elderly. These inadequacies are
reflected in cholesterol imbalances, cardiovascular disorders, stroke and arthritis, all of
which respond well to high dose niacin.
While optimum dosages vary, the literature, and Dr. Abram Hoffer's experience with
over 5,000 patients, suggest that required daily therapeutic intervention range from 10
mg in newly diagnosed cases of pellagra to 6 to 10 grams for cholesterol normalization,
and the treatment of cardiovascular disease and stroke.
Keywords: Binding affinity, HM74A, receptors, niacin, niacinamide, pellagra, alcoholism,
smoking, nicotinic acid, Parkinson's disease, multiple sclerosis, schizophrenia,
Identifying what constitutes a deficiency of vitamin B-3 is obviously an essential first
step in any discussion of its causes and consequences. So what represents an inadequacy of
this vitamin? Innocuous as this question may sound, it lies at the heart of a disagreement that
has divided medicine for over fifty years [1]. Many definitions of vitamins stress the very
small dosages that are required to maintain human and animal health. This is because
proponents of this viewpoint, referred to as the vitamins-as-prevention paradigm, believe that
vitamin deficiencies always cause obvious observable symptoms, such as the hemorrhaging
of scurvy seen in those with extreme vitamin C inadequacy, or the dementia occurring in
vitamin B-3 depleted patients with pellagra. It follows that if vitamins are needed only in
very small doses to prevent such deficiency diseases, large amounts are unnecessary, even
dangerous. This belief, that very small amounts of vitamins are all that are required to
maintain health, is enshrined in the concept of the recommended daily allowance (RDA),
established by law in many countries. Such dosages are typically the result of
recommendations by nutritionists, based on animal research. They do not rest on the results
from controlled studies, attempting to establish the vitamin intakes needed to establish
The Causes and Consequences of Vitamin B-3 Deficiency… 23
There is no conflict over the efficacy of small vitamin doses for the prevention of
classical deficiency diseases. To illustrate, in regions where maize formed an excessive part
of the diet, pellagra was often endemic. However, this was not true of Central America where
maize was typically treated with alkali before it was cooked. Such lime solutions released
niacin from the tight biochemical bonds found in maize, so preventing pellagra. Indeed, the
addition of small amounts of nicotinamide to flour, the standard practice since 1942, has
greatly reduced the global incidence of classic pellagra [2]. In a similar manner, small doses
of vitamin C now prevent most scurvy, while low dosage amounts of vitamin D-3 are
The history of medicine, indeed of science as a whole, is one of paradigm shifts.
Scientific theories resemble architectural wonders. They are interesting to visit and
prestigious to be associated with. All too often, however, while they may appear to casual
observation to be sound and unassailable, termites are feasting deep within their foundations.
Anomalies, factors that the ruling theory and its supporters cannot adequately explain, are the
termites of science. As they breed and multiply, the infected theory weakens until it
eventually collapses. This process is now well underway within the vitamins-as-prevention
paradigm. Cheraskin [3], for example, has pointed out that although according to the
Recommended Dietary Allowance advised for the United States, 60 mg of vitamin C was the
accepted requirement of this nutrient, many conditions benefited from much more. The
research literature, for example, showed that one to three grams a day of this vitamin, taken
for several months, could correct infertility, strengthen blood vessels in diabetics, reduce the
severity of bipolar disease, extend male life expectancy by approximately six years, reduce
periodontal disease, and protect against ischemic heart disease, macular degeneration,
hypertension and cataracts. High doses of vitamin A and E seem to be beneficial in the
treatment of a similar wide variety of disorders. Cheraskin, of course, was supporting the
vitamins-as-drugs paradigm. The proponents of this viewpoint, known as orthomolecular
medicine, believe that vitamins, and indeed many other nutrients, taken regularly at dosages
far above the Recommended Dietary Allowances, can prevent, and in many cases cure, a
wide range of diseases and disorders [4-6]. This chapter examines whether this generalization
CAUSES OF VITAMIN B-3 DEFICIENCIES
According to Ames and colleagues [7] "As many as one-third of mutations in a gene
result in the corresponding enzyme having an increased Michaelis constant, or Km (decreased
binding affinity) for a coenzyme, resulting in a lower rate of reaction". This means that there
are some 50 known human genetic diseases that occur because of defective, low binding
enzymes that can only be prevented or ameliorated by very high doses of their corresponding
coenzymes. Such elevated coenzyme doses may restore, or partially correct, depressed
enzymatic activity, so curing or mitigating these illnesses.
24 Harold D. Foster and Abram Hoffer
Several such polymorphisms result in lowered activity in enzymes that have a specific
vitamin as a cofactor. The resulting disorders can only be successfully treated by very high
doses of the appropriate vitamin, such as riboflavin, thiamine or folic acid. The mega-doses
of vitamins needed to treat such genetic diseases are levels that are a hundred to a thousand
or more fold higher than those as dietary reference intakes. To illustrate, if the enzyme
pyruvate decarboxylase is defective, causing Leigh disease and lactate and pyruvate buildup
in the serum, high dose thiamine is likely to be an effective treatment. Similarly, binding
defects in the enzyme protoporphyrinogen oxidase, causing variegate prophyria and
neuropsychiatric complications, including motor neuropathy are likely to respond to very
Ames and coworkers identified a series of diseases and disorders, caused by genetic
mutations, that result in the corresponding enzyme having a decreased binding affinity for
niacin, its coenzyme. These health problems, therefore, can only be logically addressed by
treatment with high dose vitamin B-3. Such potentially defective enzymes, for example,
(mitochondrial transfer RNA mutations) which is associated with complex 1 deficiency,
elevated blood lactate and pyruvate. Similarly, two other enzymes, dihydropteridine
reductase and long-chain-3-hydroxyacyl-CoA dehyrogenase, that can occur in low coenzyme
binding forms because of polymorphism, also use niacin as a cofactor. The former is
associated with phenylketonuria II, hyperphenylalaninemia and cognitive dysfunction, while
the latter has links to Beta-Oxidation defect, hypoglycemia, cardiomyopathy and sudden
It follows, therefore, that for many of the 50 or so known genetic disorders, caused by
very high dosages of cofactors, which in many cases are vitamins.
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