Molecular Medicine

ORTHOMOLECULAR PSYCHIATRY
By Linus Pauling*
Center for the Study of Democratic Institutions, Santa Barbara, California

Communicated >» 1967

The methods principally used now for treating patients with
mental disease are psychotherapy (psychoanalysis and related efforts
to provide insight and to decrease environmental stress), chemotherapy
(mainly with the use of powerful synthetic drugs, such as chlorpro-
mazine, or powerful natural products, such as reserpine), and convul-
sive or shock therapy (electroconvulsive therapy, insulin coma therapy,
pentylenetetrazol shock therapy). I have reached the conclusion,
through arguments summarized in the following paragraphs, that another
general method of treatment, which may be called orthomolecular therapy,
may be found to be of great value, and may turn out to be the best
method of treatment for many patients.

Orthomolecular? psychiatric therapy is the treatment of mental

‘disease by the provision of the optimal molecular environment of

the mind, especially the optimal concentrations of substances normally
present in the human body. An example is the treatment of phenyl-
ketonuric children by use of a diet containing a smaller than normal
amount of the amino acid phenylalanine. Phenylketonuria results from
a genetic defect that leads to a decreased amount or effectiveness

of the enzyme catalysing the oxidation of phenylalanine to tyrosine.
The patients on a normal diet have in their tissues abnormally high
concentrations of phenylalanine and some of its reaction products,
which cause the mental and physical manifestations of the disease
(mental deficiency, severe eczema, etc.). A decrease in the amount

of phenylalanine ingested results in an approximation to the normal

or optimal concentrations and to the alleviation of the manifestations
of the disease, both mental and physical.

The functioning of the mind is dependent on its molecular environ-
ment: The presence in the brain of molecules of N, N-diethyl-D-
lysergamide, mescaline, or some other schizophrenogenic substance is
associated with profound psychic effects. Cherkin has recently
pointed out that in 1799 Humphrey Davy described similar subjective
reactions to the inhalation of nitrous oxide. The phenomenon of

eneral anesthesia also illustrates the dependence of the mind
consciousness, ephemeral memory) on its molecular environment.

 

——
Fellow of the John Simon Guggenheim Memorial Foundation. I am
grateful to this Foundation and to The Ford Foundation for partial

support of the work resulting in this paper.
Orts....0lecular Psychiatry Page Tw.

The proper functioning of the «.:nd is known to require the
presence in the brain of molecules of many different substances.
For example, mental disease, usually associated with physical disease,
results from a low concentration in the brain of any one of the
following vitamins: thiamine (Bl), nicotinic acid or nicotinamide
(B3), pyridoxine (B6), cyanocobalamin (B12), biotin (H), and
ascorbic acid (C3 mental depression accompanying scurvy). There is
evidence that mental function and behavior are affected by changes
in the concentration in the brain of:any of a number of other sub-
stances that are normally present, such as L(+)-glutamic acid, uric
acid, and y-aminobutyric acid.

Optimal Molecular Concentrations. - Several arguments may be
advanced in support of the thesis that the optimal molecular concen-
trations of substances normally present in the body may be aifferent
from the concentrations provided by the diet and the gene-controlled
synthetic mechanisms, and, for essential nutrilites(vitamins, essential
amino acids, essential fatty acids) different from the minimal daily
amounts required for life or the "recommended" (average) daily amounts
suggested for good health.

Evolution and Natural Selection. - The process of evolution does
not necessarily result in the normal provision of optimal molecular
concentrations. Let us use ascorbic acid as an example. Of the
mammals that have been studied in this respect, the only species that
have lost the power to synthesize ascorbic acid and that accordingly
require it in the diet are man, other primates (rhesus monkey,
Formosan long-tail monkey, ring-tail or brown capuchin monkey), the
guinea pig, and an Indian fruit-eating bat (Pteropus medius).
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 for this species of bat, in each case in an environ-
ment such that ascorbic acid was provided by the food. For a mutation
rate of 1/20,000 per gene generation and for even a very small
advantage for the mutant (0.01 percent more progeny) the mutant would
replace the earlier genotype within one or two million years. The
advantage to the mutant of being rid of the ascorbic-acid-synthesis
machinery (decrease in cell size and energy requirement, liberation
of machinery for other purpose) might well be large, perhaps as much
as 1 percent; a disadvantage nearly as large (less by 0.01 percent)
resulting from a less 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 optimal 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. Even a serious disadvantage of the changed
environment would not lead to a mutation restoring the synthetic
mechanism within a period of a few million years, because of the small
probability of such mutations, far smaller than of those resulting
in loss of function.
Orthomolecular Psychiatry Page Three

individual Variation. - The human race is characterized by
large genetic heterogeneity. Enzyme concentrations in tissues of
different persons often differ by the factor two or even 10 or 100.
Heterozygosity in the gene for phenylketonuria halves the amount of
the enzyme phenylalanine hydroxylase, and homozygosity reduces its
amount or effectiveness by two or more orders of magnitude. Roger
J. Williams especially has emphasized the significance of individual
variation of human beings in relation to health, nutrition, and
therapy.

 

Molecular Concentrations and Rate of Reactions. - The rate of
an enzyme-catalysed reaction is approximately proportional to the
concentration of the reactant 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 an increase in the substrate concentration. Also,
an increase in concentration of an enzyme inhibitor can decrease the
rate of a reaction; for example, an increase in nicotinamide concen-
tration, with the consequent inhibition of the enzyme diphospho-
pyridine nucleotidase, decreases_the rate of hydrolysis of diphospho-
pyridine nucleotide.

The functioning of the brain and nervous tissue is more sensitively
dependent on the rate of chemical reactions than the functioning of
other organs and tissues. I believe that mental disease is for the
most part caused by abnormal reaction rates, as determined by genetic
constitution and diet, and 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 selection of foods
(and drugs) in a world that is undergoing rapid scientific and tech-
nological change may often be far from the best. I believe that .
significant improvement in the mental health of many persons, especially
those with borderline or mild mental illness or mental retardation,
may be achieved by the provision of the optimal molecular concentrations
of substances normally present in the human bodys 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. The use of L(+)-glutamic acid (not an essential
amino acid) in treating mental retardation suggests also that other
substances normally present in brain and nerve tissue and either
synthesized in the body or normally provided in the diet may be of
value in increased or decreased amount.

The Treatment of Mental Disease by Use of Substances Normally
Present in the Body. - L(+)-glutamic acid is a non-essential amino
acid that is present at rather high goncentration in brain and nerve
tissue, and plays an essential role. It is normally ingested (in
protein) in amounts of 5 or 10 grams per day. It is not toxic; large

 

 
Orthomolecular Psychiatry Page Four

doses may cause. increased motor activity and nausea. In 1944, Price,*.,
Waelsch, and Putnaml9 reported favorable results for Zlutamic acid
therapy of convulsive disorders {penefit to one out of three or four
patients with petit mal epilepsy“+).

Zimmerman and Ross then reported an increase in maze-yyunning
learning ability of white rats given extra glutamic acid. Zimmer-
man and many other investigators then studied the effects of glutamic
acid on the intelligence and hebaviour oF pggsons with different
degrees and kinds of mental retardation.+3~ L(+)-glutamic acid is
apparently more effective than its sodium or potassium salts. The
effective dosage is usually between 10 g and 20 g per day (given in
three doses with meals), and is adjusted to the patient as the amount
somewhat less than that required to cause hyperactivity. Improvement
in personality and increase in intelligence (by 5 to 20 IQ points)
have been reported for many patients with mild or moderate mental
deficiency by several investigators. ,

Nicotinic acid (niacin), 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 ”
(National Research §guncil) is 12 mg per day (70 kg male). In 1940
Streitwieser et al. reported some success in the treatment of
severe depression and other forms of mental disease by use of large
doses of nicotinic acid (3 g or more per day). Other investigators,
especially Osmond, Smythies, and Hoffer, have advocated and used
nicotinic acid in large doses for the treatment of schizophrenia. 20-30
The dosage recommended by Hoffer is 3 g per day (or more, up to 18 g
per day, as determined by the response of the patient) of either
nicotinic acid or nicotinamide, together with 3 g per day of ascorbic
acid. Nicotinic acid and nicotinamide are nontoxic (LD50 not known
for humans, but probably over 200 g; LD50 for rats 7.0 g per kg for
nicotinic acid, 1.7 g per kg for nicotinamide), 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 Hoffer31; "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 phenothiazénes. 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 rheumatism.
In our view it is a useful adjunct in the treatment of schizophrenia,
both for acute cases and to reduce the chance of relapses..." :

It is my opinion, for reasons presented in the opening arguments
of this paper, that, for those patients for whom it is effective, the
control of mental disease by varying the concentrations in the brain
of nontoxic substances that are normally present, such as nicotinic
Orthomolecular Psychiatry Page Five

acid and ascorbic acid, is to be preferred to the use of phenothi-
azenes and other means of therapy that involve a greater insult
to the body and mind.

Varying the intake of other vitamins has also been used in
psychiatry. The mental deterioration accompanying aging and
cerebrovascular disease may be alleviated by supplementary bio-
flavonoids (vitamin P) and ascorbic acia.32 The use of cyanocobal-
amin (B12) in the treatment of mental disease has been reported. 33
The observed decreased level of pyridoxyl phosphate enzymes in the
brain tissue of mental patients, especially the aged, suggests that
pyridoxine (B6) therapy would be useful. A field of research in
which much more work needs to be done is that of the functioning of
the brain in its relation to the concentrations and intake of the
vitamins, the essential amino acids, and other substances normally
present in the body.

Summary. - The functioning of the brain is affected by the molecular
concentrations of many substances that are normally present in the
brain, such as L(+)-glutamic acid, nicotinic acid, and some other
vitamins. Some of these substances are nontoxic. The optimal con-
centrations for a person may differ greatly from the concentrations
provided by his normal diet and genetically determined biochemical
machinery. It is known that massive therapy with L(+)-glutamic acid
benefits many mental retardates and that massive therapy with nicotinic
acid or nicotinamide, together with ascorbic acid, benefits many
schizophrenics and other persons with mental disease. Biochemical
and genetic arguments support the idea that orthomolecular therapy,
the provision for the individual person of the optimal concentrations
of important normal constituents of the brain, 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 and attention to
the individual, such as is customary in psychotherapy (psychoanalysis),
but not in conventional chemotherapy.35
Orthomolecular Psychiatry Page Six

References
(The list of references is incomplete)

1

The word orthomolecular may be criticised as a Greek-Latin
hybrid. I have not, however, found any other word that expresses
as well the idea of the right molecules in the right amounts.

H. Weil-Malherbe, Biochem. J. 30, 665 (1936).

10 ;
J. G. Price, H. Waelsch, and T. J. Putnam, J. Am. Med. Assn.
122, (1944). .

11
H. Waelsch, Am. J. Mental Deficiency 52, 305 (1948).

12
F, [T. Zimmerman and S. Ross, Arch. Neurol. Psychiatry 56, (1944).

al

A recent survey of the role of glutamic acid in cognitive
behaviors has been published by W. Vogel, D. M. Broverman, J. G.
Draguns, and E. L. Klaiber, Psycho. Bull. 65, 367 (1966).

25
Streitwieser

26
H. Osmond and J. Smythies, (1952).

31 . )
H. Osmond and A. Hoffer, The Lancet.10 Feb., 316 (1962).

32
E. T. Gale and M. W. -Thewlis, Geriatrics 8; 80 (1953), and
references given by them.

See The Lancet, 29 Oct.,-5 Nov. (1966).

34
Snell

35

In the course of time it should be possible to develop a method
of diagnosis (analysis of blood and urine, etc.) that could be used
as the basis of calculating the optimal molecular concentrations
for the individual.