defining orthomolecular health

Defining Orthomolecular Medicine – An overview

Defining Orthomolecular Medicine

A. Hoffer, M.D., Ph.D., F.A.P.A.
Psychiatrist

For many years my colleagues and I have used mega-doses of certain vitamins in combination with well-established psychiatric practice for the treatment of schizophrenia and allied conditions. At our meetings we have discussed the terminology and theoretical concepts around which similarly inclined physicians could rally.

We required an easily identifiable term, which would embody the entire nutrient approach. This would include not only the provision of the missing nutrients which were either lacking in the diet or which were required in larger quantities but the proper balance of major nutrients such as protein, fat and carbohydrate. We had uncovered a good deal of evidence that this approach would be helpful not only to schizophrenics but to some seemingly unrelated disorders.

“Orthomolecular psychiatry,” the term originated by Dr. Linus Pauling, provided us with that concept. It identifies a particular trend in psychiatry toward the use of nutritional concepts in the treatment of many mentally ill patients. We will expect major disagreements between proponents of the new school and adherents to the old. Orthomolecular therapy has given us the only major psychiatric advance in 60 years.

Orthomolecular Psychiatry (excerpt)

Linus Pauling, Ph.D.

Linus Pauling has been deeply concerned with the alleviation of human suffering, and he has brought his scientific knowledge to bear on such problems as the causes of genetic mutation, the transmission of aberrant genes, and the deleterious effects of protein molecules with abnormal structure. On occasions, his views have led him to take strong public positions—some decidedly unpopular or unpolitic—against cigarette smoking, against the testing, proliferation and use of atomic and nuclear weapons, and against war in general. His achievements in science, medicine, and the promotion of human welfare have brought him countless honors, such as the Phillips Medal of the American College of Physicians for his contributions in internal medicine, the Gold Medal of the French Academy of Medicine, the Baxter Award in anesthesiology, the Rudolf Virchow Medal, the Thomas Addis Medal of the American Nephrosis Foundation, the Modern Medicine Award, the Humanist of the Year Award, and many others including dozens of honorary degrees and election to membership in twenty scientific societies in twelve countries. He has been awarded two Nobel Prizes: the 1954 Nobel Prize for Chemistry and the 1962 Nobel Prize for Peace. Doctor Pauling’s principal research at present is on the molecular basis of disease, including mental disease.

I feel that the use of substances normally present in the human body for improving health of human beings, and especially their mental health, has been unjustifiably ignored by the medical profession for some 30 or 35 years now and that the possibilities of improvement in the health of the American people and of other people in the world by improved nutrition are truly great. It is astounding to me that the medical profession has paid so little attention to these possibilities during the last few decades.

It is difficult for me to understand why this has come about. There was enthusiasm about vitamins and about nutrition for a rather short period of time, beginning about 1910, when vitamins were first clearly recognized and when it was generally accepted that diseases such as scurvy and beri-beri are not the result of the presence of a toxic substance of some sort in certain foods, which could be neutralized by other foods, but are rather the result of the absence in certain foods of vital substances, the vitamins.
The essential amino acids also were discovered to be vital substances of this sort, required for life and health.

The enthusiasm about vitamins may have been overly great for awhile and the failure of vitamin therapy in some cases may have caused a disenchantment that really was not justified. My friend Dr. Albert Szent-Gyorgyi, who in 1928 prepared it for the first time, isolated vitamin C from natural sources, as a substance that he named hexuronic acid; later he changed the name to ascorbic acid.

Dr. Szent-Gyorgyi has said in a letter to me that he felt that it was a great mistake for the medical profession to have concentrated on the anti-ascorbutic properties of vitamin C, the property of preventing death by scurvy. Scurvy is the final stage; he •called it a “pre-mortal syndrome.” Death by scurvy can be prevented by a small amount of vitamin C; Dr. Szent-Gyorgyi said that we do not yet know the optimum rate of intake of this vitamin. He said that he himself had been taking 1,000 mg. a day for many years, but that he did not know whether or not this was the optimum amount for him and did not know about other people—what their optimum requirements are. He went on to say that one thing is perfectly clear, that any amount can be taken without danger.

I think that this is essentially true, not only for Vitamin C, but also for the other water-soluble vitamins and for vitamin E. These substances have important physiological properties and are substances to which the human body is accustomed, because everyone requires these substances for life and good health and there has been a weeding-out process. The human germ plasm has been affected by the process of evolution in such a way as to give rise to the human race that now exists, consisting of people who can tolerate these important substances.

We do not know how much we need of these various vital substances in order to be in the best of health. There is good evidence that different people need different amounts, as has been pointed out by Professor Roger J. Williams. One of our speakers referred to the recent statements by Dr. Rosenberg, who has been working on the inborn errors of metabolism, the diseases that result from the failure of an individual to manufacture a particular enzyme in the right amount or with the right activity. It is possible to cure some of these inborn errors of metabolism by the administration of amounts of vitamins, such as vitamin B6 or vitamin B12, in amounts as great as 1,000 times the amounts that seem to be essentially satisfactory for other human beings.

I would like to know how to find out what the optimum rate of intake of these vital substances is.

It is soon going to be possible to answer this question and many similar questions. It is required only that scientists and physicians, medical investigators, have an open mind about such matters as the value of vitamins, that they not be inhibited by old and false ideas that have been handed on by the past generation of physicians and
nutritionists to the present generation. Fortunately, the younger generation of physicians and of students generally is less gullible than those of earlier times—more open-minded. I think that the attitude of the young physicians and the students of today gives us hope for the future. I think that there is going to be much progress made in the field of psychiatry during the next decade.

On the Orthomolecular Environment of the Mind: Orthomolecular Theory (abridged version)

Linus, Pauling, Ph.D.

“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),
• 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 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.

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 on 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 the 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 [15], 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.

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

In the book Orthomolecular Psychiatry: Treatment Of Schizophrenia (17) my colleagues and I pointed out that the orthomolecular treatment of schizophrenia involves the use of vitamins (megavitamin therapy) and minerals; the control of diet, especially the intake of sucrose; and, during the initial acute phase, the use of conventional methods of controlling the crisis, such as the phenothiazines. The phenothiazines are not, of course, normally present in the human body and are not orthomolecular. However, they are so valuable in controlling the crisis that their use is justified in spite of their undesirable side effects.

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 real 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)

Ascorbic Acid

It was reported by Horwitt in 1942 (20) and by later investigators that schizophrenic patients receiving the usual dietary amounts of ascorbic acid had lower concentrations of ascorbic acid in the blood than people in good health. The loading-test results of VanderKamp (8), Herjanic and Moss-Herjanic (9), and Pauling and associates (10) have been mentioned above. In his discussion of ascorbic acid and schizophrenia Herjanic (21) concluded:

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.

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

The requirement of niacin (nicotinic acid) for proper functioning of the brain is well known. The psychosis of pellagra, as well as the other manifestations of this deficiency disease, is prevented by the intake of a small amount of niacin, about 20 mg. a day. In 1939 Cleckley, Sydenstricker, and Geeslin (5) reported the successful treatment of 19 patients with severe psychiatric symptoms with niacin and in 1941 Sydenstricker and Cleckley (6) reported similarly successful treatment of 29 patients with niacin. In both studies, moderately large doses of niacin, 0.3 to 1.5 gm. a day, were given. None of the patients in these studies had physical symptoms of pellagra or any other avitammosis. A decade later, Hoffer and Osmond (2,3) initiated two doubleblind studies of niacin or niacinamide in the treatment of schizophrenia. Another double-blind study was reported by Denson in 1962 (26). In 1964 Hoffer and Osmond (4) reported that a 10-year follow-up evaluation of the patients in their initial studies showed that 75 percent had not required hospitalization, compared with 36 percent of the comparison group, who had not received niacin. Similar estimates have been made by Hawkins (18). There are, however, contradictory statements by other investigators. The question of the weight of the evidence is discussed below in the section on the APA task force report.

Pyridoxine

Pyridoxine, vitamin B6 is used in the treatment of schizophrenia in amounts of 200 to 800 mg. a day by many orthomolecular psychiatrists. Derivatives of this vitamin are known to be the coenzymes for over 50 enzymes, and the chance of a genotype with need for a large intake of the vitamin is accordingly great. There is evidence that pyridoxine is involved in tryptophan-niacin metabolism.

A double-blind placebo-controlled study has been made of pyridoxine and niacin by Ananth, Ban, and Lehmann (27). Their experimental population consisted of 30 schizophrenic patients: 15 were men, 15 were women, their mean age was 41.7 years, and their mean duration of hospitalization was 10.9 years. They were randomly assigned to three treatment groups: 1) the combined treatment group, which received 3 gm. of nicotinic acid a day for 48 weeks and 75 mg. of pyridoxine a day during three 4-week periods; 2) the nicotinic acid group, which received 3 gm. of nicotinic acid a day for 48 weeks and a pyridoxine placebo; and 3) the pyridoxine group, which received 75 mg- of pyridoxine a day during three 4 week periods and a nicotinic acid placebo. In addition, neuroleptic preparations were administered according to clinical requirements for the control of psychopathology. The investigators reported that “of the ten patients in each treatment group, seven improved and three deteriorated in the nicotinic acid group, nine improved and one deteriorated in both the combined treatment group and in the pyridoxine group” (27). They also stated:

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).

Cyanocobalamin

A deficiency in cyanocobalamin (vitamin B12), whatever its cause, leads to mental illness as well as to such physical manifestations as anemia. The anemia can be controlled by a large intake of folic acid, but the mental illness and neurological damage cannot. A pathologically low concentration of cyanocobalamin in the blood serum has been reported to occur in a much larger percentage of patients with mental illness than in the general population.

Edwin and associates (28) determined the amount of vitamin B12 in the serum of every patient over 30 years old admitted to a mental hospital in Norway during a period of one year. Of the 396 patients, 61 (15-4 percent) had a subnormal or pathologically low concentration of vitamin B 12, less than 150 pg. per ml. (the normal range is 150 to 1,300 pg. per ml.). This incidence is 30 times as great as that estimated for the population as a whole. Other investigators have reported similar results and have suggested that a low serum concentration of vitamin B12, whatever its origin, may cause mental illness. In addition, of course, mental illness may accompany some genetic diseases, such as methylmalonic aciduria, which can be controlled only by achieving a serum concentration of cyanocobalamin far greater than normal.

Minerals and Other Vitamins

There is some evidence that mental illness may result from deprivation of or abnormal need for minerals and other vitamins. (See, for example, Pfeiffer, Iliev, and Goldstein (29)). Further work in this field by psychiatrists and biochemists is needed.

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
Two-thirds of the report relates to niacin and one-third to the Hoffer-Osmond Diagnostic Test (HOD) (34), which has no special connection with megavitamin or orthomolecular psychiatry except that it was devised by the originators of niacin therapy. The report should have been given the- title Niacin Therapy and the HOD Test, or published as two reports, one on niacin and one on the HOD test. It would have been still better for the task force to have discussed megavitamin and orthomolecular therapy in psychiatry fully.

The Question of Controlled Experiments

The report refers to the low credibility of the megavitamin proponents, whose published results were not duplicated in studies carried out by one of the task force members (p. 48). The penultimate sentence of the report is, “Their credibility is further diminished by the consistent refusal over the past decade to perform controlled experiments and to report their new results in a scientifically acceptable fashion” (p. 48).

I have talked with the leading orthomolecular psychiatrists and have found that they feel the principles of medical ethics prevent them from carrying out controlled clinical tests, with half of their patients receiving orthomolecular therapy in addition to the conventional treatment and the other half receiving only the conventional treatment. It is the duty of the physician to give to every one of his patients the treatment that in his best judgment will be of the greatest value, Some psychiatrists, including Hoffer and Osmond, carried out controlled trials 20 years ago. They became convinced that orthomolecular therapy, along with conventional treatment, was beneficial to almost every patient. From that time on their ethical principles have required that they give this treatment and not withhold it from half of their patients. The task force is wrong in criticizing the orthomolecular psychiatrists for not having carried out controlled clinical trials during the last few years. Instead, it is the critics, who doubt the value of orthomolecular methods, who are at fault in not having carried out well-designed clinical tests.

It is also the duty of a physician to give to a patient a treatment that may benefit him and is known not to be harmful. The incidences of toxicity and other serious side effects of the doses of vitamins used in orthomolecular medicine are low. There is significant evidence that an increased intake of certain vitamins may benefit the patient. It is accordingly the duty of the psychiatrist to prescribe these vitamins for him.

Conclusions

Orthomolecular psychiatry is 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. There is evidence that an increased intake of some vitamins, including ascorbic acid, niacin pyridoxine, and cyanocobalamin, is useful in treating schizophrenia, and this treatment has a sound theoretical basis.

-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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