On the Orthomolecular Environment of the Mind: Orthomolecular Theory
by Linus Pauling, Ph.D.Journal Of Orthomolecular Medicine Vol. 7, No. 1, 1995
“Varying the concentrations of substances normally present in the human body may control mental disease.” – Linus Pauling
“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 chlorpromazine, or powerful natural products from plants, such as reserpine), and convulsive shock therapy (electroconvulsive therapy, insulin coma therapy, pentylenetetrazol shock therapy). I have reached the conclusion 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.” – Linus Pauling, Science, April 19, 1968, p. 265
The author defines orthomolecular psychiatry as the achievement and preservation of good mental health by the provision of the optimum molecular environment for the mind, especially the optimum concentrations of substances normally present in the human body, such as the vitamins. He states that there is sound evidence for the theory that increased intake of such vitamins as ascorbic acid, niacin pyridoxine, and cyanocobalamin is useful in treating schizophrenia. The negative conclusions of APA Task Force Report 7, Megavitamin and Orthomolecular Therapy in Psychiatry, he says, result not only from faulty arguments and from a bias against megavitamin therapy but also from a failure to deal fully with orthomolecular therapy in psychiatry- Three psychiatrists comment on Dr. Pauling’s presentation.
Orthomolecular psychiatry is the achievement and preservation of mental health by varying the concentrations in the human body of substances that are normally present, such as the vitamins- It is part of a broader subject, orthomolecular medicine, an important put because the functioning of the brain is probably more sensitively dependent on its molecular composition and structure than is the functioning of other organs (1) . After having worked for a decade on the hereditary hemolytic anemias, I decided in 1954 to work on the molecular basis of mental disease. I read the papers and books dealing with megavitamin therapy of schizophrenia by Hoffer and Osmond (2,4) as well as the reports on studies of vitamins in relation to mental disease by Cleckley and Sydenstricker (5,6) and others. In the course of time I formulated a general theory of the dependence of function on molecular structure of the brain and other parts of the body and coined the adjective “orthomolecular” to describe it (1).
There is no doubt that the mind is affected by its molecular environment. The presence in the brain of molecules of LSD, mescaline, or some other schizophrenogenic substance is associated with profound psychic effects. Mental manifestations of avitaminosis have been reported for several vitamins. A correlation of behavior of school children with concentration of ascorbic acid in the blood (increase in “alertness” or “sharpness” with increase in concentration) has been reported by Kubala and Katz (7). A striking abnormality in the urinary excretion of ascorbic acid after an oral loading dose was reported for chronic schizophrenics by VanderKamp (8) and by Herjanic and Moss-Herjanic (9). My associates and I (10) carried out loading tests for three vitamins on schizophrenic patients who had recently been hospitalized and an control subjects. The percentage of schizophrenic patients who showed low urinary excretion of each vitamin was about twice as great as that of the controls: for ascorbic acid, 74 percent of the schizophrenic patients showed low urinary excretion versus 32 percent of the controls; for niacinamide, 81 percent versus 46 percent; and for pyridoxine, 52 percent versus 24 Percent. The possibility that the low values in urinary excretion of thew vitamins for schizophrenic patients resulted from poor nutrition is made unlikely by the observation that the numbers of subjects low in one, two, or all three vitamins corresponded well with the numbers calculated for independent incidence.
There are a number of plausible mechanisms by which the concentration of a vitamin may affect the functioning of the brain. One mechanism, effective COT vitamins that serve as coenzymes, is that of shifting the equilibrium for the reaction of apoenzyme and coenzyme to give the active enzyme. An example is the effectiveness of cyanocobalamin (vitamin B12) given in amounts 1,000 times greater than normal to control the disease methylmalonic aciduria (11-14). About half of the patients with this disease are successfully treated with megadoses of vitamin B12 . In these patients a genetic mutation has occurred and an altered apoenzyme that has a greatly reduced affinity for the coenzyme has been produced. Increase in concentration of the coenzyme can counteract the effect of the decrease in the value of the combining constant and lead to the formation of enough of the active enzyme to catalyze effectively the reaction of conversion of methylmalonic acid to succinic acid.
In the human population there may be several alleles of the gene controlling the manufacture of each apoenzyme; in consequence the concentration of coenzyme needed to produce the amount of active enzyme required for optimum health may well be somewhat different for different individuals- In particular, many individuals may require a considerably higher concentration of one Or more coenzymes than other people do for optimum health, especially for optimum mental health. It is difficult to obtain experimental evidence for gene mutations that lead to only small changes in the properties of enzymes. The fact that genes that lead to large and more easily detectable changes in the properties of enzymes occur, as in individuals with methylmalonic aciduria, for example, suggests that mutations that lead to small changes also occur.
Significant differences in enzyme activity in different individuals have been reported by many investigators, especially by Williams , who has made many studies of biochemical individuality. It is likely that thorough studies of enzymes would show them to be similar to the human hemoglobins. A few of the abnormal human hemoglobins, most of which involve only the substitution of one amino-acid residue for another in either the alpha chain or the beta chain of the molecule, differ greatly in properties from normal adult hemoglobin, leading to serious manifestations of disease.
It was in the course of the study of one of these diseases, sickle cell anemia, that the first abnormal hemoglobin was discovered (16). Most of the abnormal human hemoglobins, however. differ from normal hemoglobin in their properties to only a small extent, so that there is no overt manifestation of diseaseThere is, nevertheless, the possibility that even the small changes in properties of an abnormal hemoglobin associated with a mild hemoglobinopathy will have deleterious consequences. An example is the intolerance to sulfa drugs associated with the substitution of arginine for histidine in the locus 58 in the alpha chain or 63 in the beta chain. It is likely that individual differences in enzyme activity will in the course of time be shown to be the result of differences in the amino-acid sequences of the polypeptide chains of the apoenzymes.
More than 100 abnormal human hemoglobins are now known, and the human population may be expected to be similarly complex with respect to many enzymes, including those involved in the functioning of the brain. A tendency to schizophrenia is probably polygenic in origin. I have suggested (1) that the genes primarily involved in this tendency may well be those which regulate the metabolism of vital substances such as the vitamins.
Some vitamins are known to serve as coenzymes for several enzyme systems. We might ask if the high concentration of coenzyme required to produce the optimum amount of one active enzyme might not lead to the production of far too great an amount of another active enzyme. The answer to this question is that the danger is not very great. For most enzymes the concentration of coenzyme and the value of the combination constant are such that most (90 percent or more) of the protein is converted to active enzyme. Accordingly, a great increase in concentration would increase the amount of most active enzymes by only a few percentage points, whereas it might cause a great increase for a mutated enzyme.
The Orthomolecular Treatment of Schizophrenia
Hawkins (18) stated that his initial combination of vitamins for the treatment of schizophrenia was I gin. of ascorbic acid, I gm, of niacinamide, 50 mg. of pyridoxine, and 400 I.U. of vitamin E four times a day. Other vitamins may also be given. A larger intake, especially of niacinamide or niacin may be prescribed; the usual amount seems to be about 8 gm. a day after an initial period on 4 gm. a day.
The vitamins, as nutrients or medicaments, pose an interesting question. The question is not, Do we need them? We know that we do need them, in small amounts, to stay alive. The Teal question is, What daily amounts of the various vitamins will lead to the best of health, both physical and mental? This question has been largely ignored by medical and nutritional authorities.
Let us consider schizophrenia, Osmond (19) stated that about 40 percent of schizophrenics hospitalized for the first time are treated successfully by conventional methods in that they are released and not hospitalized a second time. The conventional treatment fails for about 60 percent in that the patient is not released or is hospitalized again. Conventional treatment includes a decision about vitamin intake. Usually it is decided that the vitamins in the food will suffice or that a multivitamin tablet will also be given. The amounts of ascorbic acid, niacin pyridoxine, and vitamin E may be approximately the daily allowances recommended by the Food and Nutrition Board of the U.S. National Academy of Sciences-National Research Council: 60 mg. of ascorbic acid, 20 mg of niacin 2 mg. of pyridoxine, and 15 I.U. of vitamin E. Is this amount of vitamins correct? Would many schizophrenic patients respond to their treatment better if the decision were made that they should receive 10 or 100 or 500 times as much of some vitamins? What is the optimum intake for these patients? I believe there is much evidence that the optimum intake for schizophrenic patients is much larger than the recommended daily allowances. By the use of orthomolecular methods in addition to the conventional treatment of schizophrenia, the fraction of patients hospitalized for the first time in whom the disease is controlled may be increased from about 40 percent to about 80 percent. (19)
The individual variation of the need for ascorbic acid may turn out to be one of the contributing factors in the development of the illness. Ascorbic acid is an important substance necessary for optimum functioning of many organs. If we desire, in the treatment of mental illness, to provide the “optimum molecular environment,” especially the optimum concentration of substances normally present in the human body (Pauling,. 1968 (1)), ascorbic acid should certainly be included (2).
There is, moreover, a special reason for an increased intake of ascorbic acid by patients with schizophrenia or any other disease for which there is only partial control. About 60 mg. of ascorbic acid a day is enough to prevent overt manifestations of avitaminosis C (scurvy) in most people. However, there are several significant arguments to support the thesis that the optimum intake for most people is 10 to 100 times more than 60 mg. These arguments are summarized in the papers and books of Irwin Stone (22) and myself (23,24). They constitute the theoretical basis for the customary use of about 4 gin. of ascorbic acid a day in the orthomolecular therapeutic and prophylactic treatment of schizophrenia. A significant controlled trial of ascorbic acid in chronic psychiatric patients was reported in 1963 by Milner (25). The study, which was double-blind, was made with 40 chronic male patients: 34 had schizophrenia, 4 had manic-depressive psychosis, and 2 had general paresis. Twenty of the patients, selected at random, received 1 gm. of ascorbic acid a day for three weeks; the rest received a placebo. The patients were checked with the Minnesota Multiphasic Personality Inventory (MMPI) and the Wittenborn Psychiatric Rating Scales (WPRS) before and after the trial. Milner concluded that “statistically significant improvement in the depressive, manic, and paranoid symptoms-complexes, together with an improvement in overall personality functioning, was obtained following saturation with ascorbic acid” (25). He suggested that chronic psychiatric patients would benefit from the administration of ascorbic acid.
We found (10) that of 106 of the schizophrenic patients we studied who had recently been hospitalized in a private hospital, a county-university hospital, or a state hospital, 81 (76 percent) were deficient in ascorbic acid, as shown by the six-hour excretion of less than 17 percent of an orally administered close. Only 27 of 89 control subjects (30 percent) showed this deficiency. Great deficiency (less than 4 percent excreted) was shown by 24 (22 percent) of the schizophrenic subjects and by only 1 (1 percent) of the controls. I have no doubt that many schizophrenic patients would benefit from an increased intake of ascorbic acid. My estimate is that 4 gm. of ascorbic acid a day, in addition to the conventional treatment, would increase the fraction of acute schizophrenics in whom the disease is permanently controlled by about 25 percent, Except for that of Milner (25), no controlled trial of ascorbic acid in relation to schizophrenia has been made, so far as I know.
Niacin and Niacinamide
Of the three indices of therapeutic effects, global improvement in psychopathology (Brief Psychiatric Rating Scale and Nurses Observation Scale for Inpatient -Evaluation) scores was seen in all three groups: the number of days of hospitalization during the period of the clinical study was lower in both the nicotinic acid and the combined treatment group; and only in the combined treatment group was the daffy average dosage of phenothiazine medication decreased. Thus, improvement in all three indices was noted in the combined treatment group. However, several side effects were observed during the therapeutic trials, indicating that the vitamins used are not completely safe (27).
The investigators reached the conclusion that “on balance, these results suggest that the addition of pyridoxine may potentiate the action of nicotinic acid. Thus pyridoxine seems to be a useful adjunct to nicotinic acid therapy” (27). Hawkins (18) commented on this work in the following way:
The therapeutic effect was demonstrable even though the patients had been hospitalized for an average of 10.9 years, were not on hypoglycemic diets, and the doses of both pyridoxine (75 mg. daily) and vitamin B3 (3 gm. a day) were considerably below the dosages we routinely prescribe (18).
Minerals and Other Vitamins
The APA Task Force Report
Some Errors in the Report
The two theoretical bases adduced by megavitamin proponents for the effectiveness of NA therapy (nicotinic acid as a methyl acceptor and NAD deficiency) are in fact generally incompatible, because NAA [nicotinamide], when functioning as a vitamin, is bound to the remainder of the coenzyme molecule by the nitrogen of its pyridine ring and hence can no longer accept methyl groups. Essentially, then, the two views of NA as a vitamin precursor of NAD and as a methyl acceptor are incompatible, except for the possibility that there is in schizophrenia double deficit – both a vitamin deficiency and a transmethylation defect and that nicotinic acid has the happy fortune to serve two purposes simultaneously (pp. 40-42).
There is an obvious error in this task force argument. There is no incompatibility between two functions of nicotinic acid; some molecules may engage in one function and others in the other. A defect in either function might be controlled by increasing the intake of the vital substance. A “double deficit” is not needed. The authors of the report would have wen the fallacy in their argument if they had set up some equilibrium and reaction rate equations, as was done in my 1968 paper (1). The task force expresses an interesting misunderstanding of the nature of vitamins, in the following words: “By common definition a vitamin is not only an essential nutrient, but it is essential because it is transformed into a coenzyme vital for metabolic reactions” (p. 41). In fact, this is not the common definition of a vitamin; it is wrong. Some vitamins, including vitamin C, are not known to be transformed into a coenzyme. This misunderstanding by the task force may have contributed to the misinterpretation of the evidence for and the theoretical basis of orthomolecular psychiatry.
The Failure To Discuss Ascorbic Acid and Pyridoxine
Nonetheless, the massive use of niacin has always been the cornerstone of the theory and practice of megavitamin advocates. Since this has proved to have no value when is it employed as the sole variable along with conventional treatments of schizophrenia, the burden of proof for the complex and highly individualized programs now advocated would appear to be on the proponents of such treatment (p. 46).
I shall point out below that the principles of medical ethics prevent orthomolecular psychiatrists from withholding from half of their patients a treatment that they consider to be valuable. Controlled tests can be carried out only by skeptics. I now ask whether the task force is justified in saying that the massive use of niacin has been proved to have no value when it is employed as the sole variable along with conventional treatments of schizophrenia. My answer to this question, from a study of the evidence quoted in the report, is that it is not justified. The evidence that niacin has no value is far from conclusive. A beneficial effect of niacin or niacinamide was reported for three double-blind studies (two by Hoffer and Osmond and their collaborators (2,3,32) and one by Denson (26)) and in 12 open clinical trials by other investigators referred to in the report. On the other hand, the report mentions 7 doubleblind studies in which a statistically significant difference between the niacinamide subjects and the controls was not observed.
The Hoffer-Osmond Diagnostic Test
The Question of Controlled Experiments
The Bias of the Task Force
Under these circumstances this Task Force considers the massive publicity which they promulgate via radio, the lay press and popular books, using catch phrases which are really misnomers like “megavitamin therapy” and “orthomolecular treatment,” to be deplorable (p. 48).
This sentence, like others in the report, shows the presumably unconscious bias of the task force. “Promulgate” (misused here) is a pejorative word, and “catch phrases” is a pejorative expression. I do not understand why megavitamin therapy and orthomolecular treatment should be called misnomers. This concluding sentence, like many others in the book, seems to me to have been written in order to exert an unjustifiably unfavorable influence on the readers of the report.
-Based on a lecture given at a meeting of the American College of Neuropsychopharmacology, Palm Springs, Calif., Dec 47 7 1973 . Reprinted with permission: Am J. Psychiatry, 131:11, November 1974. Copyright 1974 American Psychiatric Association.
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5.Cleckley, H.M., Sydenstricker, V,P., Geeslin, LE-: Nicotinic acid in treatment of atypical psychotic states associated with malnutrition. JAMA 112:2107-2110, 1939
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7.Kubala, A.L., Katz, M.M.: Nutritional factors in psychological test behavior. J Genet Psychol 96:343-352, 1960
8.VanderKamp, H: A: biochemical abnormality in schizophrenia involving ascorbic acid- Int J Neuropsychiatry 2:204206, 1966
9.Herjanic, M., Moss-Herjanic, B.L. Ascorbic acid test in psychiatric patients. J Schizophrenia 1: 257-260, 1967
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11. Orsenberg, LE., Lilljeqvist, A.C., Hsia, Y.E.: Methylmalonic aciduria: metabolic block localization and vitamin B12 dependency. Science 162: 805-807, 1968
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15.Williams, R.J.: Biochemical Individuality. New York, John Wiley & Sons, 1957
16.Pauling, L., Itano, ILA., Singer, S.J., et al: Sickle cell anemia a molecular disease. Science I 10: 543-548, 1949
17.Hawkins, D., Pauling, L (eds): Orthomolecular Psychiatry; Treatment of Schizophrenia. San Francisco, W.H. Freeman and Co., 1973
18.Hawkins, D.: Orthomolecular psychiatry: treatment of schizophrenia. Ibid, pp. 631-673
19.Osmond, H.: The background to the niacin treatment. Ibid,pp. 194-201
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22.Stone, L: The Healing Factor: Vitamin C Against Disease. New York. Grosset and Dunlap, 1972
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24.Pauling, L: Vitamin C and the Common Cold. San Francisco. W.H. Freeman and Co. 1970
25.Milner, G.: Ascorbic acid in chronic psychiatric patients: a controlled trial- Br I Psychiatry 109:294-299, 1963
26.Denson, R.: Nicotinamide in the treatment of schizophrenia. Dis Nerv Syst 23:167-172, 1962
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28.Edwin, I., Holten, K., Norum, K.R., et al: Vitamin B12 hypovitaminosis in mental diseases. Acta Med Scand 177:689-699, 1965
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30. Task Force Report 7: Megavitamin and Orthomolecular Therapy in Psychiatry. Washington, DC, American Psychiatric Association, 1973
31.Ananth, J.V., Ban, T.A., Lehmann, ILE., et al: Nicotinic acid in the prevention and treatment of methionine-induced exacerbation of psychopathology in schizophrenics. Can Psychiatr Assoc J 15:15-20, 1970
32. Hoffer, A., Osmond, H., Callbeck, J.M., et al: Treatment of schizophrenia with nicotinic acid and nicotinamide. J Clin Exp Psychopathol 18:131-158. 1957
33.Greenbaum, G.H.C.; An evaluation of niacinamide in the treatment of childhood schizophrenia. Am J Psychiatry 127:89-93, 1970
34.Kelm, H.: The Hoffer-Osmond Diagnostic Test (HOD), in ‘Orthomolecular Psychiatry: Treatment of Schizophrenia. Edited by Hawkins, D., Panting, L San Francisco. W.H. Freeman and Co. 1973, pp. 327-341
35.Pauling, L: No More War! New York. Dodd, Mead and Co. 1958