Some Aspects of Orthomolecular Medicine*
Linus Pauling
Institute of Orthomolecular Medicine

2700 Sand Hill Road, Menlo Park
California 94025

Nearly forty years ago, after having worked for a decade on the
determination of the structure of ‘relatively simple inorganic and organic
molecules, I became interested in a protein, hemoglobin. This interest arose
.rom the consideration of the structural origin of the sigmoid oxygen equilibrium
curve (Pauling 1935). It was soon extended to include the denaturation of
hemoglobin and other proteins (Mirsky and Pauling 1936) and the
magnetic properties of hemoglobin and its derivatives (Pauling, Coryell,

Stitt, Taylor, Dodson, and Russell 1936 to 1940). The study of magnetic
properties has been especially fruitful in providing information about the
nature of the bonds formed by the iron atoms in hemoglobin with the neigh-

poring atoms of the porphyrin ring system, the globin, and attached

* This article is based in part on addressed given by Linus Pauling at meetings
of the International Academy of Preventive Medicine.
molecules such ag the oxygen molecule (Pauling and Coryell 1936;
Coryell 1939; Coryell and Pauling 1940).

The discovery of the abnormal hemoglobins was the result of the
consideration of hypothetical molecular mechanisms of the disease. In the
spring of 1945 I, together with eight men from medical schools, was
serving as a member of the Medical Advisory Committee of the United
States government. One evening Dr. William B. Castle, Professor of
Medicine in Harvard University, mentioned to the other members of the
Committee the disease sickle-cell anemia, with which he had had some
experience. He told about the discovery of the disease by Dr. J. B.
Herrick, in 1910, and described the characteristic change in shape of the
red corpuscles and the effect of oxygen in preventing the sickling and of
carbon dioxide in accelerating it. I suggested that the action of carbon
dioxide was to accelerate the dissociation of oxygen from oxyhemoglobin,
and I pointed out that the relation of sickling to the presence of oxygen
clearly indicated that the hemoglobin molecules in the red cell are in-
volved in the phenomenon of sickling, and that the difference between
sickle-cell -anemia red corpuscles and normal red corpuscles could be
explained by postulating that the former contain an abnormal kind of

hemoglobin, which whe when deox genated has the Dewey oy of combining with

itself into long aan rods, Whibh = re ear noe Kod cell out of shape. The
opportunity to test this idea arose when Dr. Harvey A. Itano, a young
physician, came to the California Institute of Technology in the fall of 1946
to work with me. Ina letter to Dr. Itano before his arrival I suggested
that he investigate the hemoglobin from the red cells of sickle-cell-anemia
patients, in order to see whether it was different from normal adult human
hemoglobin. On his arrival in Pasadena in September 1946 he began this
investigation. He verified the published reports (Hahn and Gillespie,

1927) that carbonmonoxyhemoglobin, like oxyhemoglobin, prevents sickling
of the red cells, and found that some other hemoglobin derivatives, includ-

ing alkylisocyanide-ferrohemoglobin, ferrihemoglobin, ferrihemoglobin
azide, and ferrihemoglobin cyanide similarly prevent sickling. He
developed a rapid diagnostic test for sickle-cell anemia and sickle-cell
trait, based on the use of a chemical reducing agent (Itano and Pauling,
1949). Most of the properties of the hemoglobin from the blood of
sickle-cell-anemia patients were found to be the same, to within the
error of determination, as those of hemoglobin from normal individuals,
but it was finally clearly shown, by careful measurement of electro-
phoretic mobility, that the blood of the patients contains nearly 100
percent of an abnormal hemoglobin, differing from normal adult human
hemoglobin, and that the blood of the parents of patients contains an
approximately half-and-half mixture of the abnormal hemoglobin and
normal adult human hemoglobin. This electrophoretic work was
carried out with the collaboration of Dr. S. J. Singer and Dr. Ibert C.
Wells.

In 1949 we published a paper with the title Sickle-cell Anemia,
A Molecular Disease (Pauling, Itano, Singer, and Wells 1949). In this
paper we communicated our discovery that patients with the disease
sickle-cell anemia have in their erythrocytes a form of hemoglobin
differing from that manufactured by other people. We pointed out that
the difference in molecular structure of the hemoglobin manufactured by
persons suffering from this disease leads to a difference in properties of
the hemoglobin molecules from those manufactured by other people, and
that this difference in properties is responsible for the manifestations of
the disease. The disease can properly be described as a disease of the
hemoglobin molecule, rather than of the erythrocyte itself, and in conse-
quence it may be called a molecular disease.

Later work in our laboratories in the California Institute of
Technology and by other investigators elsewhere showed that the hemo-
globin molecule contains four polypeptide chains, two of one kind, the
alpha chains, and two of another kind, the beta chains (Rinesmith,
Schroeder, and Pauling 1957; Rhinesmith, Schroeder, and Martin 1958).
It was then shown by Ingram (1957) that sickle-cell-anemia hemoglobin
differs from normal hemoglobin in having one of the 146 amino-acid
residues in each beta chain different from that in normal human hemo-
globin, the difference being a replacement of a glutamic-acid residue in
the sixth position from the amino end of the beta chain in normal adult
human hemoglobin by a residue of valine. Many other abnormal forms

of human hemoglobin have now been discovered, and many diseases have
been recognized as diseases of the hemoglobin molecule. Other molecular
diseases have also been identified. These diseases for the most part are
genetic diseases, the result of a gene mutation.

The disease phenylketonuria, discovered about forty years ago
by Folling in Norway, is another example of a molecular disease. This
disease involves a gene mutation such that the patient fails to manufacture
molecules of an enzyme normally present in the liver, which catalyzes the
oxidation of phenylalanine to tyrosine, or produces an abnormal enzyme,
with greatly reduced catalytic activity. The patients are homozygotes, who
have inherited the gene in double dose, usually from a heterozygotic father
and a heterozygotic mother. The patients on a normal diet have in their
tissues abnormally high concentrations of phenylalanine and some of its
reaction products, which cause the physical and, #4& mental manifestations
of the disease--severe eczema, mental deficiency, and so on. ‘The treat-
ment that has ,considerable success is to place the patients, from the age
of one month or two months, on a diet of foods from which a considerable
amount of phenylalanine has been removed. This decrease in the amount of
phenylalanine ingested by the patients results in an approximation to the
normal or optinh concentrations of phenylalanine and its reaction p: oducts
in the body fluids, and to the alleviation of the physical and mental mani-
festations of the disease.

Another molecular disease for which a molecular treatment is
available is diabetes. This disease results from a gene abnormality such
that the patient does not manufacture the proper amount of the hormone in-

sulin. The disease can be controlled by the injection of insulin, to bring
the concentration to approximately the normal or optimg# value.

Orthomolecular Medicine

 

Phenylketonuria involves the presence in the body of phenylalanine
and its reaction products in amounts greater than normal. It is treated by
reducing the intake of phenylalanine and in this way reducing the concentra-
tion of this substance and its reaction products to approximately the normal
level. Diabetes involves a deficiency of insulin. It is treated by injecting
insulin,’ and increasing the concentration to approximately the normal value.
These diseases are controlled by changing the concentrations of substances
that are normally present in the body.

I have reached the conclusion, through arguments summarized in
the following paragraphs, that a general method of treatment of disease,
which may be called orthomolecular medicine, may be found to be of great
value, and may turn out often to be the best method of treatment for many
patients (Pauling 1968).

Orthomolecular medicine is the preservation of health and the
treatment of disease by the provision of the optima molecular constitution
of the body, especially the optim concentration of substances that are
normally present in the human body and are required for life. The adjective
orthomolecular is used to express the idea of the right molecules in the
right concentration.

An example of orthomolecular medicine, in addition to the two
mentioned above, is the prevention of death by starvation through the pro-
vision of an adequate daily intake of carbohydrates, essential fats, proteins
(including the essential amino acids), essential minerals, and vitamins. To
achieve the best of health, the rate of intake of essential foods should be
such as to establish and maintain the optimum concentrations of essential
molecules, such as those of ascorbic acid. There is no doubt that a proper
concentration of ascorbic acid is needed to provide the maximum protection

against infection} and to permit the rapid healing of the wounds. I believe
that in general the treatment of disease by the use of substances, such as
the vitamins, that are normally present in the human body and are re-
quired for life is to be preferred to the treatment by the use of synthetic
drugs or plant products, which may have undesirable side effects.

Another example of orthomolecular medicine is the use of
iodine to prevent goiter. lodine is required by a human body, in the
amount about 0.3 mg per day. In some parts of the world the food and
water are deficient in this element, and in these regions goiter tends to be
endemic.

The element iodine was discovered in 1811 by Courtois, in an
extract of kelp. By 1820 a physician in Geneva had used tincture of
iodine in the successful treatment of patients with goiter. In fact, iodine
had,been used in treating and preventing goiter for some centuries, in
both Europe and Asia--a folk remedy for goiter was to eat seaweed and
the ashes of burned seasponge. For some years after 1820 there was
much enthusiasm for the use of iodine. A French chemist, Chatin, carried
out a systematic study of the iodine content of soil, water, and air in re-
gions where goiter was endemic and in other regions, and showed that
goiter spas associated with a deficiency of iodine in the environment. By
1831 it had been suggested (by Boussingault) that the salt should be iodized

Cape. :
in goitrowe regions.

The opinion of medical authorities changed, however, because
of the possibility of damage from the toxicity of iodine when used in too
large amounts, and the use of added iodine in the diet to control goiter re-
mained without medical sanction for approximately one century, although
many people continued to act on the widespread popular belief that iodine
was effective against goiter.

In 1895 it was discovered that iodine is present in the thyroid
gland in far larger concentrations than in other parts of the body. An

American investigator, David Marine, began the study of iodine in rela-
tion to goiter. In 1917 and 1918 he carried out a study of the effect of small
doses of iodine given to school children in Akron, Ohio, and found that
these small doses greatly reduced the incidence of simple goiter in the
children in that goitrogenic area. Other investigators verified his re-
sults, and the use of iodine for control of goiter soon became general.
Iodized salt as used in the United States contains about 1 mg of iodine per
10 grams of sodium chloride. The daily intake of iodine by human beings
that is required for good he alth is not known with certainty, but is es-

timated to be about 0. 3 mg per day.

Orthomolecular Treatment of Mental Disease

I believe that orthomolecular therapy may have a special value
in the treatment of mental disease. The functioning of the mind is de-
pendent on its molecular environment, the molecular structure of the

“am,
brain. The presence in the brain of molecules N, N-diethyl-D-lysergamide,
aN =

mescaline, or some other schizophrenogenic substance often is associated
with profound psychic effects. The phenomenon of general anesthesia also
illustrates the dependence of the mind (consciousness, ephemeral memory)
on its molecular environment.

The proper functioning of the mind is known to require the pres-
ence in the brain of molecules of many different substances. For example,
mental disease, usually associated also with physical disease, results from
a low concentration in the brain of thiamine (Vitamin B,)s nicotinic acic or
nicotinamide (Ba), pyridoxine (Bg). cyanocobalamin (Big) biotin (H), aa@ 6
ascorbic acid (Vitamin C). Also, there is evidence that mental function
and behavior are affected by changes in the concentration in the brain of any
one of a number of other substances that normally present, such as glutamic

acid, uric acid, and gamma-aminobutyric acid.

Optime? Molecular Concentrations
s*

 

Several arguments may be advanced in support of the thesis that
(we

the optimagi molecular concentrations of substances normally present in
the body may be different from the concentrations provided by the diet and
by the gene-controlled synthetic mechanisms of the body, and also, for
essential nutrilites, such as vitamins, essential amino acids, and essen-
tial fatty acids, different from the minim gaily amounts required for
life for the average human being or the recommended" daily amounts
suggested for good health. |

One argument can be developed through consideration of the
process of evolution and natural selection. The process of evolution does
not necessarily result in the normal provision of optim# molecular con-
centrations. Let us use ascorbic acid as an example. Irwin Stone (1966)
has pointed out that of the mammals that have been studied in respect to
their need for ascorbic acid, the only species that have lost the power to
synthesize this substance and that accordingly require it in the diet are
man, other primates (Rhesus monkey, Formosan long-tail monkey,
ringtail or brown Capuchin monkey), the guinea pig, and an Indian fruit-
eating bat (Pteropus medius); in addition passeriform birds, including the
Red-vented Bulbul (Pycnonotus Cafer), some fish (trout and salmon), and
some species of grasshoppers are unable to synthesize their own ascorbic
acid. Presumably the loss of the gene or genes controlling the synthesis
of the enzyme or enzymes involved in the conversion of glucose to ascorbic
acid occurred some twenty million years ago in the common ancestor of
man and other primates, and occurred independently for the guinea pig and
other isolated species mentioned above, in each case in an environment
such that a good supply of ascorbic acid was provided by the available food.
The advantage to the mutant of being rid of the machinery for the synthesis of
ascorbic acid (decrease in cell size and energy requirement, liberation of
machinery for other purposes) might well be large. A disadvantage nearly
as large resulting from aless than optimal supply of dietary ascorbic acid

would not prevent the replacement of the earlier species by the mutant.
Hence the amount of the vitamin provided by the diet available at the time

of the mutation might be less than the optim amount. Moreover, it is
possible that the environment has changed during the last twenty million
years in such a way as to provide a decreased amount of the vitamin for

the average human being. Even a serious disadvantage of the changed
environment would not lead to a mutation restoring the synthetic mechanism,
because of the small probability of such mutations, far smaller than of

those resulting in loss of function.

Individual Variation

 

The human race is characterized by large genetic heterogeneity.
Enzyme concentrations in the tissues of different persons often differ by
the factor of two or even a factor of ten or one hundred, as has been pointed
out especially by Professor Roger J. Williams of the University of Texas.
Heterozygosity in the gene for phenylketonuria halves the amount of the
enzyme phenylalanine hydroxylase, and homozygosity in this gene reduces
the amount of effectiveness of the enzyme by two or more orders of magni-

tude.

Molecular Concentrations and Rate of Reactions

 

The rate of an enzyme-catalysed reaction is approximately pro-
portional to the concentration of re actant until concentrations are reached
that largely saturate the enzyme. The saturating concentration is larger
for a defective enzyme with decreased combining power for the substrate
than for the normal enzyme. For such a defective enzyme the catalysed
reaction could be made to take place at or near its normal rate by ar in-
crease in the concentration of the substrate, @27—. Moreover, an in-
crease in concentration of an enzyme inhibitor can decrease the rate of
reaction; for example, an increase in concentration of nicotinamide, with
the consequent inhibition of the enzyme diphosphopyridine nucleotidase,
decreases the rate of hydrolysis of diphosphopyridine nucleotide. .Also, in-

crease in concentration of a coenzyme (which might be a vitamin) increases
-10 -—

the amount of active enzyme formed by combination of the coenzyme and
the apoenzyme, and may thus compensate for a genetic defect in the
apoenzyme. Some people are of a genotype such that good health can be
achieved by the intake of a far larger amount of a vitamin than is needed
by other people. An example of such a genotype is provided by the
disease methylmalonicaciduria. The patients with this disease are de-
ficient in the active enzyme that catalyzes the conversion of a simple
substance, methylmalonic acid, to succinic acid. It is known that
cyanocobalamin (vitamin By») serves as the coenzyme for this reaction.
It is found that for some patients with the disease the provision of very

large amounts of vitamin B,,, giving concentrations about 1, 000 times

; 12
the normal concentration, causes the reaction to proceed at the normal

rate. There is little doubt that the gene defect in these patients is one
that introduces a change in an amino acid residue in the apoenzyme, which

combines with vitamin Bio to form the active enzyme. This change is of

such a nature as to decrease the combining power of the apoenzyme with

the coenzyme, vitamin B The large increase in the concentration of

12°
vitamin Bio serves to shift the chemical equilibrium between apoenzyme,
coenzyme, and active enzyme in such a way that the amount of the active

enzyme becomes normal.

Evidence from Microbiological Genetics

 

Many mutant microorganisms are known to require, as a
supplement to the medium on which they are grown, a substance that is
synthesized by the corresponding wild-type organism. An example is the
"pyyridoxineless'' mutant of Neurospora Sitophila reported by G. W. Beadle
and E. L. Tatum in their first Neurospora paper, published in the Pro-
ceedings of the National Academy of Sciences in 1941. They found the rate
of growth of this mutant on their standard medium to be only nine percent
of that of the wild type. When pyridoxine (Vitamin Bg) is added to the

medium, the rate of growth at first increases ne arly linearly with the
-li-

concentration of the added pyridoxine, and then the growth-rate curve
bends rather sharply, and continues to increase with a much smaller

slope Sie The region of concentrations in which the growth increases
rapidly with increase in concentration may be considered to be the region
of vitamin deficiency, and the concentration at which the curve changes to
much smaller slope may be considered to correspond to an "adequate" or
"recommended" amount of the vitamin, in that the growth rate of the
mutant is then only a few percent less than that of the wild strain, and the
amount of the vitamin would have to be increased three-fold to make up

the difference.

Increasing the concentration of the growth substance to thirty-five
times the "adequate" concentration for the mutant causes an increase in
growth rate by about twenty-five percent. The growth rate of the mutant
is then ten percent greater than that of the wild type. An increase in
growth rate or in some other function of magnitude twenty-five percent or
ten percent might under some circumstances be of great value, and might
mean the difference between life and death or between good health and poor
health, either physical or mental. Especially if the growth substance is
non-toxic and free from side reactions, its therapeutic use in large amounts
might well be justified.

Ascorbic acid, for example, is non-toxic for all or almost all
human beings. It is required for life in amounts of a few milligrams per
day. The ingestion of large amounts, three or five grams per day, seems
to improve the general health of human beings, and to provide greater
resistance to colds and other infectious diseases. I believe that it is likely
that the optim? | intake of ascorbic acid is far greater than the "approved" or
"recommended" intake, and that a significant improvement in the heaith of

human beings could be achieved by approximating this optima intake

Orthomolecular Psychiatry

 

The functioning of the brain is more sensitively dependent on the

rate of chemical reactiémthan the functioning of other organs and tissues.
-12-

I believe that mental disease is for the most part caused by abnormal
molecular concentrations of essential substances. The operation of chance
in the selection, for the child, of half of the complement of genes of the
father and mother leads to bad as well as to good genotypes, and the selec-
tion of foods (and drugs) in a world that is undergoing rapid scientific and
technological change may often be far from the best. Significant improve-
ment in the mental health of many persons, especially those with border-
line or mild mental illness or mental retardation, might be achieved by
the provision of the optima molecular concentrations of substances
normally present in the human body, especially those that are not toxic or
have low toxicity.

Among these substances, the essential nutrilites may be the
most worthy of extensive research and more thorough clinical trial than
they have yet received.

Nicotinic acid, when its use was introduced, cured hundreds of
thousands of pellagra patients of their psychoses, as well as of the physical
manifestations of their disease. For this purpose only small doses are
required; the recommended daily allowance (U.S. National Research Council)
is twelve milligrams per day. In 1940 Streitwieser and his associates re-
ported some success in the treatment of severe depression and other forms
of mental disease by use of large doses of nicotinic acid, three grams or
more per day. Other investigators, especially A. Hoffer of Saskatchewan
and H. Osmond of New York, have advocated and used nicotinic acid in
large doses for the treatment of schizophrenia. The dosage recommended
by Hoffer is three grams per day, or more, up to eighteen grams per day,
as determined by the response of the patient, of either nicotinic acid or
nicotinamide, together with four grams per day of ascorbic acid. Nicotinic
acic and nicotinamide are non-toxic (LD 50 not known for humans, bu:
probably over 200 grams), and their side effects, even in continued massive
doses, seem’not to be commonly serious. The advantages of nicotinic acid

therapy have been summarized by Osmond and Hoffer (The Lancet 10 Feb.
~13-

1962, 316) in the following words: "Niacin (nicotinic acid) has some though
not all the qualities of an ideal treatment: it is safe, cheap (less than one
cent per gram), and easy to administer, and it uses a known pharmaceutical
substance which can be taken for years on end if necessary...It does not
seem to affect the more chronic illnesses, and even in acute illnesses

its action is often less dramatic than that of some of the phenothiazines.
Its protective qualities, continuing long after patients have stopped taking
it, are puzzling...It has been proved to reduce the level of cholesterol in
the blood. It seems to benefit some deliria not obviously associated with
vitamin lack, and is claimed to improve many cases of intractable rheu-
matism. In our view, it is a useful adjunct in the treatment of schizo-
phrenia, both for acute cases and to reduce the chance of relapses."

I believe that the study of the functioning of the brain in its rela-
tion to the concentrations and intake of the vitamins, essential amino
acids, and other substances normally present in the brain constitutes a
field of research in which much more work needs to be done. Biochemical
and genetic arguments support the idea that orthomole cular therapy, the
provision for the individual human being of the optim’ concentrations of
important normal constituents of the human body, may be the preferred
treatment for many patients, especially those with mild mental retardation
or mild psychosis. I suggest that this therapy, to be successful, should
involve the thorough study of the individual, and continued attention to him,
such as is customary in psychoanalysis but not in conventional chemotherapy.
There is the possibility that analysis of body fluids and tests of the ability
of the individual to utilize essential substances may indicate the types of
orthomolecular therapy that would be most likely to be effective for the
patient.

It is my opinion that for those patients for whom it is effective
the control of mental disease by varying the concentrations in the brain of

non-toxic substances that are normally present, such as nicotinic acid and
-14 -

ascorbic acid, is to be preferred to other means of therapy that involve a

greater insult to the body and mind (see Hawkins and Pauling 1973).

Ascorbic Acid and the Common Cold

 

The use of L-ascorbic acid, vitamin C, in preventing the
serious deficiency disease scurvy has long been recognized. During recent
years increasing recognition has been given also to ascorbic acid, ingested
in the proper amounts, as an effective means of decreasing the incidence
of infectious diseases, especially the common cold. This use may be one
of the most important examples of orthomolecular medicine.

Scurvy has been known for hundreds of years. Until about a
century ago the disease was very common among sailors on board ships
taking long voyages, and also among soldiers in an army in campaign, in
communities in times of scarcity of food, in cities under siege, and in
prisons and work houses.

The onset of scurvy is marked by a failure of strength, including
restlessness and rapid exhaustion on making effort. The patient complains
of pains in the muscles, caused by hemorrhages of large size that pene -
trate the muscles and other tissues, giving him the appearance of being
extensively bruised. He is mentally depressed, and his face looks haggard.
His gums ulcerate, his teeth drop out, and his breath is fetid. His joints
loose their integrity. Death then results from profound exhaustion,
diarrhea, and pulmonary and kidney troubles.

four hundred years ago the English Admiral Sir John Hawkins
recognized that sailors with scurvy recovered as soon as they got access
to a supply of succulent plants, and that scurvy could be preventéd by
carrying on the ship fruits of the orange type, including oranges and
lemons. In 1795 the British Admiralty ordered that a daily ration of lemon
juice (called lime juice) be given to the sailors, and scurvy disappeared
from the British Navy. In 1865 the British Board of Trade passed a simi-

lar lime-juice regulation for the Merchant Marine. At the present time
- 15 -

scurvy, complicated by other deficiency diseases, is found in populations
that are ravaged by starvation and severe malnutrition, usually as a
result of poverty, and occasionally in infants six to eighteen months old
who are fed a formula without vitamin supplement, and in middle-aged
or elderly bachelors or widowers who for convenience ingest an unsatis-
factory diet, deficient in vitamins.

The substance L-ascorbic acid was discovered in 1928 by
Albert Szent-GyJUrgyi, who isolated it from cabbages and other vegetables
and the adrenal glands of animals. He soon found that Hungarian paprika
contains large amounts of the substance, and in 1932 this substance was
shown to be vitamin C, the antiscorbutic principle, by Svirbely and
Szent-GyUrgyi and by Waugh and King.

An intake of ascorbic acid of 5 to 10 milligrams per day is
enough to protect almost all people against scurvy. This fact has caused
the Food and Nutrition Board of the United States National Academy of
Sciences to recommend a daily allowance of 60 milligrams for an adult
male. The corresponding British Board recommends only 30 milligrams
per day. .

There is the possibility, however, that a much larger intake of
ascorbic acid would lead to improved general health, including increased
resistance to infectious disease. There is a popular belief that ascorbic
acid provides protection against the common cold. Szent-GyUrgyi himself
has recently made the following statement: "As to ascorbic acid, right
from the beginning I felt that the medical profession misled the public. If
you don't take ascorbic acid with your food you get scurvy, so the medical
profession said that if you don't get scurvy you are all right. I think -nat
this is avery grave error. Scurvy is not the first sign of the deficiency
but a premortal syndrome, and for full health you need much more, very
much more. I am taking, myself, aboutl gaday. This does not mean that
this is really the optimum dose because we do not know what full health

really means and how much ascorbic acid you need for it. What I can tell
-16 -

you is that one can take any amount of ascorbic acid without the least
danger."

The United States Food and Nutrition Board has stated that
there is no convincing evidence that increased intake of ascorbic acid,
above the amount 60 mg per day, leads to improvement in health. A
similar statement is made by almost all authorities in the fields of nutri-
tion and medicine. In particular, it is repeatedly stated by these authori-
ties that there is no convincing evidence that ascorbic acid has any value
in decre asing the incidence or severity of the common cold or in providing
similar protection against other infectious diseases.

A few scientists and physicians have, however, opposed the
official opinion. My attention was called to this situation in April 1966,
when I received a letter from Irwin Stone, a biochemist in Staten Island,
New York, in which he recommended that I follow his regime of increased
ascorbic-acid intake, to achieve an improvement in my health. My own
experience during the years since that time confirmed the statements made
by Stone about the value of ascorbic acid in providing protection against the
common cold. I became aware of the striking contradiction between the
statements of most authorities and the popular belief about the value of
ascorbic acid, and I decided to make a search of the medical literature, in
order to find out what facts had been revealed by carefully controlled studies
of ascorbic acid in relation to the common cold and other infectious diseases.
I found, as has been described in my book Vitamin C and the Common Cold,
published in December 1970, that there exist in the medical literature re-
ports of a number of carefully controlled studies, in which the average in-
cidence and severity of the common cold in a group of subjects regularly
receiving a daily amount of ascorbic acid has been compared with the values
for a group of subjects selected at random from the same populaiion and re-
ceiving an inactive substance (a placebo), with all of the subjects exposed to
cold viruses-in the ordinary way, through contact with other people. As is

described later in this article, several of these careful investigations have
-17-

given results with statistical significance, showing that ascorbic acid

does have value in decreasing the incidence and the severity of the common
cold, and that the effectiveness of the ascorbic acid increases with in-
crease in the amount taken per day. On the other hand, no controlled
study carried out under these conditions have given results that rule out,
with statistical significance, the amount of protective effect of ascorbic
acid described below. It is my opinion that there is no doubt that ascorbic
acid, taken in the proper amount, has value in decreasing both the in-
cidence of the common cold and the severity of individual colds. There is
also evidence that ascorbic acid has value in providing protection against

other infectious diseases.

Evolution and the Need for Ascorbic Acid

 

In 1966 Irwin Stone published some arguments to support his
conclusion that most human beings suffer from a deficiency of ascorbic
acid, not great enough to cause manifest symptoms of scurvy, but great
enough to have a significant effect in a decrease in wellbeing. cle suggest~-
ed that most human beings could be described as suffering from hypoascorbemia,
a genetic disease resulting from the inability of human beings to synthesize
ascorbic acid, and from a deficiency in the supply of ascorbic acid provided
by the food that they ingest. The food normally ingested by people in
Europe and the United States is thought to provide an average of 30 mg to
5G mg per day, approximately the daily amounts recommended by the offi-
cial Food and Nutrition Boards. Stone contends that the optim a amounts,
leading to better health, are 20 to 100 times as great, that is, one gram
(1,000 mg) per day or more.

One argument advanced by Stone is the rate of synthesis of
ascorbic acid by the rat, which has the power to synthesize this substance,
and does not depend on a supply of ascorbic acid in its food. It has been ob-
served that rats under ordinary circumstances (not under stress),synthesize

an amount of ascorbic acid corresponding, on a weight basis, for a
-18-

70-kilogram man to 2 g to 4 g per day, and that rats under stress synthesize
a much larger amount. Also, the housefly synthesizes ascorbic acid at
the rate 10 g per day per 70 kg.

In 1949 Bourne pointed at that the gorilla obtains about 4.5 g per
day in his food (bamboo shoots and other green plants), corresponding to
about 2 g per day for man. A somewhat similar argument was developed by
me in 1970, based upon the amounts of various vitamins in raw natural plant
foods. It is known that microorganisms, such as bacteria, yeasts, and molds,
have greater power than man of synthesizing the substances that they need.
These microorganisms are able to synthesize almost all of the vitamins, as
well as the amino acids, whereas man must obtain from his food a supply of
about a dozen vitamins and eight amino acids in order to live. Other animals
are like man in requiring the various vitamins in their food. Every vertebrate
that has been studied in this respect requires thiamine (vitamin By) ribo-
flavin (vitamin Be)s and nicotinic acid (the anti-pellagra factor) in its food.
We may consider the epoch, early in the history of life on earth, when the
early animal species from which present-day birds and mammals have
evolved populated a part of the earth. We assume that the animals of this
species nourished themselves by eating plants, possibly together with other
food. Nearly all plants contain thiamine, and accordingly the animals would
have in their bodies the thiamine that they had ingested with the foods that
they had eaten, as well as the thiamine that they themselves synthesized by
use of their own synthetic mechanism. Let us assume that a mutant animal
appeared in the population, which, as the result of action of some mutagenic
agent, had lost the biochemical machinery that still permitted the other
animals of the species to manufacture thiamine from other substances. The
amount of thiamine provided by the ingestion of food would suffice to keep the
mutant weil nourished, essentially as well nourished as the unmutated animals.
The mutant would accordingly have an advantage over the unmutated animals,
in that it would be liberated of the burden of the machinery for manufacturing
its own thiamine. As aresult, the mutant would be able to have more off-

spring than the other animals in the population. It would pass its advantage-
-19 -

ously mutated gene along to some of its offspring, and they too would have
more than the average number of offspring. In the course of time this ad-
vantage, of not having to do the work of manufacturing thiamine or to carry
within itself the machinery for this manufacture, would permit the mutant
type to replace the original type.

The fact that all animal species require thiamine, riboflavin,
and nicotinic acid as vitamins strongly indicates, according to this argument,
that the amounts of these vitamins in the food available in the early period
of vertebrate evolution were sufficient to supply the needs of the animals for
these vitamins.

I made a study of 110 raw natural plant foods for which informa-
tion about vitamin content was available, referring the vitamin content in
each case to the amount of food giving 2500 kilocalories of food energy, a
day's supply for aman. The average amounts of vitamins in these 110 raw
natural plant foods came out 5.0 mg for thiamine, 5.4 mg for riboflavin,
and 41 mg for nicotinic acid. These amounts are 3.8, 3.6, and 2.5 times,
respectively, the recommended daily allowances, as set by the United
States Food and Nutrition Board. These three numbers indicate that the
recommended daily allowances of these three vitamins are reasonable, in
that they are smaller than the amounts available in plant food, which
accordingly, by the foregoing argument about evolution, would have per-
mitted the mutations involving loss of the ability to synthesize the substances
to take place.

The situation with ascorbic acid is, however, quite different.

In the first place, only a few animals require ascorbic acid as a vitamin;
almost all animals are able to synthesize the substance, and do not require
that it be ingested with their food. We now ask why most species of animals
continue to carry the burden of the machinery for manufacturing thei: own
ascorbic acid. The answer surely is that the amount of ascorbic acid avail-
able in the diet of these animals and of their ancestral species has never been

great enough to permit the ability of manufacturing their own ascorbic acid
- 20 -

to be given up.

The average amount of ascorbic acid in the 110 raw natural
plant foods investigated turned out to be 2.3 grams, about 40 times the re-
commended daily allowance for a 70-kilogram man. This amount, which
presumably was available to ancestors of most animal species, was not
sufficient to permit the mutation to take place; accordingly it probably can
be considered to be a minimum value of the optimum daily requirement for
a representative 70-kilogram animal.

Some plants contain more ascorbic acid, per 2500 kilocalories
of food energy, than others. The average for the 14 plants containing the
largest amount of ascorbic acid is 10 grams. It seems likely that at some
time in the past, about 25 million years ago, the common ancestor of man
and the other primates was living in an environment where the available food
contained this much ascorbic acid, and that under these conditions it was
advantageous for the mechanism of synthesis of the substance to be given up.

Since then man has expanded his territorial range into areas
where the food supply is deficient in ascorbic acid. He may have developed
some mechanisms, such as tubular reabsorption in the kidney, to conserve
ascorbic acid; but, as pointed out by Irwin Stone, it is likely also that most
human beings would be improved in health by ingesting more of this vaiuable
substance than is provided by the ordinary food supply. The loss of ascorbic
acid in foods resulting from modern methods of processing and storage and
from changes in the diet may have exacerbated the hypoascorbemia for many
populations.

The conclusion that the optimum intake of human beings for weight
70 kg lies between about 2 g per day and about 10 g per day is not to be inter
preted as applying to every human being. In 1967 Roger J. Williams and
Gary Deason published results of studies made by them of the rate of growth
of guinea pigs as a function of the amount of ascorbic acid provided to them.

They found that the requirements of individual guinea pigs varied over a
- 2) -

20-fold range, and concluded that, inasmuch as human beings are probably
more heterogeneous genetically than the guinea pigs used in their studies,
the requirements for individual human beings might well vary over a more
than 20-fold range. The conclusion that I have reached, and presented in
my book Vitamin C and the Common Cold, is that for some people a daily
intake of 250 mg of ascorbic acid, or even less, may suffice to provide
optimal health; for many people a larger intake, between 1 g and 2 g per day,
is needed, and for others even more. A good measure of the amount of
ascorbic acid required by an individual is, in my opinion, provided by his
resistance to the viruses of the common cold. A daily intake that protects

essentially completely from the common cold (no more than one cold per

year) may be considered to be approximately the amount that he needs.

Evidence about Ascorbic Acid and the Common Cold

 

Several careful studies of ascorbic acid and the common cold
have been carried out, in which regular daily amounts of ascorbic acid were
ingested by one group of subjects selected at random from a population, and
tablets of an inactive substance, a placebo, were provided to another group
of subjects from the same population. The subjects were exposed to cold
viruses in the ordinary way, through contact with other people. Most of the
studies described below were double-blind, with neither the subjects nor the
physicians who kept the records knowing which of the subjects received the
ascorbic acid and which received the placebo. The results were then sub-

jected to statistical analysis. © fas
J y a AN a ) pease

I shall discuss in some detail pao . investigations, one carried

out by Dr. G. Ritzel, a physician with ag Medical Service of the School Dis-
trict of the city of Basel, Switzerland, WES by s. s. Charleston and

K. M. Clegg of the Department of Food Science of the University of Strathclyde,
Glasgow, and £F third by Drs. Cowan, Diehl, and Baker, physicians connected
with the School of Medicine of the University of Minnesota.

The study carried out by Ritzel, reported in 1961, was made with
~ 22 -

279 schoolboys, 15 to 17 years old, in a ski resort, during two periods of
five to seven days. The conditions were such that the incidence of colds
during these short periods was large enough (approximately 20 percent) to
permit results with statistical significance to be obtained. The subjects
had similar nutrition during the period of the study. The tablets of ascorbic
acid (1000 mg) or placebo were distributed every morning and were taken by
the subjects under observation such that the possibility of interchange of
tablets was eliminated. The subjects were examined daily as to symptoms
of colds and other infections. The records were largely on the basis of
subjective symptoms, partially supported by objective observations (mea-
surement of body temperature, inspection of the respiratory organs,
auscultation of the lungs). Persons who showed cold symptoms on the first
day were excluded from the investigation.

After the completion of the investigation a completely independent
group of professional people was provided with the identification numbers
for the ascorbic-acid tablets and placebo tablets, and this group carried
out the statistical evaluation of the observations.

The number of colds for the 140 persons in the placebo group
was 3l, and that for the 139 persons in the ascorbic-acid group was 17. There
was accordingly observed a decrease in the incidence of colds of the as-
corbic-acid group, as compared with the placebo group, of 45 percent

This decrease in incidence is statistically significant, at the
leve. P(one-tailed) less than 0.02. This result means that the probability
that a decrease in incidence as great as this, or greater, and in this direc-
tion (protective effect of ascorbic acid), would be observed in the two groups
from a uniform population, with ascorbic acid and placebo having the same
effect, only in two percent of a large number of similar tests. Hence the
soservation of a protective effect by ascorbic acid, decreasing the inci-
dence of colds, is reliable at the 98-percent level of confidence.

It applying statistical analysis to this study and other studies I
have calculated the value of P(one-tailed), rather than P(two-tailed), be-
- 23 -

cause the question under dispute is whether or not ascorbic acid has greater
protective power than a placebo; no one contends that the placebo would
have greater protective power than ascorbic acid. The statements made by
me, as the result of my own statistical analysis, agree with those made by
Ritzel, based on statistical analysis made by a team of professionals, with
the difference that my statements refer to P(one-tailed), rather than
P(two-tailed).

The severity of individual colds was observed by Ritzel in two
ways: first, by recording the average number of days of illness per cold,
and second, by recording the total number of individual symptoms per
cold (as recorded each day). The severity of individual colds was found to
be 29 percent less for the ascorbic-acid group than for the placebo group
as measured by the average number of days of illness per cold, and 36 per-
cent less as measured by the number of individual symptoms recorded per
cold. Each of these decreases has statistical significance at the level
P(one-tailed) less than 0.05.

A third quantity, which may be taken to represent the total pro-
tective effect of ascorbic acid, is the integrated morbidity, defined as the
product of the incidence of colds and the severity of individual colds. In
the Ritzel study the integrated morbidity was found to be 61 percent less
for the ascorbic-acid group than for the placebo group as measured by the
average number of days of illness per subject in the group, and 64 percent
less as measured by the average number of individual symptoms per person
in the group. Each of these observations is statistically significant at the
level P (one-tailed) less than 0.095. This investigator, Ritzel, has accord-
ingly reported, in his carefully prosecuted double-blind study of 279 subjects,
that the administration of 1,000 mg per day of ascorbic acid , in comparison
with a placebo, leads to a decrease in incidence, severity, and integrated
morbidity of the common cold, with high statistical significance. The inte-

grated morbidity is correlated with the incidence and severity; accordingly
- 24 -

the statistical significance of the investigation as a whole can be taken to
be rejection of the null hypothesis that ascorbic acid aes the same value
as the placebo at the level P(one-tailed) less than f<€r; that is, at the
confidence level 99 percent.

_ The second study, by Charleston and Cle gg (1972), was also
carried out with 1000 mg of ascorbic acid per day. Of the 90 subjects
(staff and students of the University of Strathelyde), 47 received ascorbic
acid and 43 received the placebo. In the 15 weeks of the study the ascorbic -
acid subjects had 44 colds and the placebo subjects had 80 colds. The de-
crease in incidence was accordingly 49 percent (P < 0.002), as compared
with Ritzel's 45 percent. The average duration of colds (3.5 vs. 4.2 days)
was also decreased, by 17 percent, so that the integrated morbidity was 58
percent less for the ascorbic-acid subjects than for the placebo subjects,
as compared with Ritzel's 61 64 percent. These two studies agree well
with one another in indicating about half as much illness with an intake of
1000 mg of ascorbic acid per day as with a placebo.

Another very careful study of ascorbic acid and the common
cold was reported in 1942 by Cowan, Diehl, and Baker. Their principal
work was done during the winter of 1939-1940, over a period of 28 weeks.
The subjects were all students in the University of Minnesota who volunteered
to participate in the study because they felt that they were particularly
susceptible to colds. Persons whose difficulty seemed to be due primarily
to chronic sinusitis or allergic rhinitis, as shown by examination of the
nose and throat and consideration of symptoms of allergy, were excluded
from the study. The subjects were assigned alternately and without selec-
tion to an experimental group and acontrol group. The subjects in the con-
trol group were treated exactly like those in the experimental group, ex-
cept they received a placebo instead of the ascorbic acid. The subjects were
instructed to report to the health service whenever a cold developed, so that

report cards could be filled in by a physician. This study was. a double-blind
-25-

one, with neither the subjects nor the physicians knowing which group a
subject was in. There were 183 subjects in the ascorbic-acid group, who
received an average of 180 mg per day of ascorbic acid during the 28-week
period, and 155 subjects in the placebo group.

The amount of ascorbic acid used in this study, 180 mg per day,
is a little less than one-fifth of the amount used by Ritzel and by Charleston
and Clegg. The effects are also somewhat smaller. The incidence of colds
was 14 percent less for the ascorbic-acid group than for the placebo group,
with P(one-tailed) less than 0.02; the severity (average days of illness per
cold) was 21 percent less, with P( one-tailed) less than 0.02; and the integrated
morbidity (average days of illness per person) was 31 percent less, with
P(one-tailed) less than 0. 02.

A very important study was reported in 1972 by Anderson, Reid,
and Beaton of the University of Toronto Medical School. They gave 1 g per
day of ascorbic acid (plus 3 g per day for three days when a cold began) to half
of 818 subjects, and a placebo to the other half. The amount of respiratory
illness was 30 percent less for the ascorbic-acid subjects than for the placebo
subjects, significant at the level P(one~tailed) less than 0.002. The
amount of illness other than respiratory was 40 percent less.

Three other studies were reported in August 1973 at the symposium
on vitamin C and the common cold held at Stanford University. Dr J.L.
Coulehan of Ganado, Arizona reported on a study made with 635 students
in an Indian school, half of whom received ascorbic acid (1 g per day for
the younger students, 2 g per day for the older) and the other half a placebo.
The younger ascorbic-acid group had 29 percent less respiratory illness
and the older ascorbic-acid group 36 percent less than their placebo counter-
parts. Dr R.H. Colby of Stockton State College, New Jersey, reported the
results for 67 students, half of whom received 1 g of ascorbic acid and the
other half a placebo. The amount of illness was 18 percent less for the
ascorbic-acid group than for the placebo group. Also, Dr T.C. Chalmers
reported on a study carried out by him and Dr T.R. Karlowski in Bethesda,
Maryland, with 190 subjects, half of whom received 3 g per day of ascorbic

acid and the others a placebo. The decreased amount of iliness for the ascorbic-