This white male patient was first seen at the Center in 1985 for treatment of angina and essential hypertension. He was 51 years of age with a long history of essential hypertension. He was told at about age 18 that he had “high blood pressure” with a systolic blood pressure of 180 mm/Hg. No treatment was prescribed at that time. The history also revealed that both his mother and father died at age 69 of myocardial infarcton. While in his 20s, he became a private pilot and passed three separate FAA flight physical examinations. On each examination a comment was made that “his blood pressure was a little high”. Later, on a physical examination with a different physician, his blood pressure was a 170/100 mm/Hg and he was diagnosed with essential hypertension. His medication consisted of daily doses of 120 mg of Inderal,r 3 “diazide capsules”, and 3 SLOKr tablets. He failed his next FAA flight physical because of his essential hypertension and the medication being taken.

He continued on medication over a period of fifteen years with fluctuations in his blood pressure. When first seen at the Center, his blood pressure was 140/85 with medication; 180/100 without medication. He was given an initial intravenous infustion of EDTA which consisted of 3.0 g EDTA (Keylate,r Edtite sodium, The Key Company), 15.0 g ascorbic acid buffered in sodium ascorbate (Bronson Pharmaceuticals), 800 mg magnesium chloride, 40.0 mg procaine and 1000 units of heparin delivered in 500 mL of sterile, deionized water. Pre and post-chelation 24 hour urine samples were collected and aluminum, cadmium, lead, mercury, manganese, chromium, copper, iron, zinc, calcium, and magnesium levels measured. The lead level was of particular interest as several published studies demonstrated a relationship of lead levels and hypertension.1-4 His pre-chelation urine lead level was 14.0 mg/24 hours. The post-chelation urine lead level was 91 mg/24 hours. The Center considers a 5-fold increase in urine lead excretion after chelation an indication of increased body load of lead. He was then started on a series of 30 EDTA intravenous infusions administered at approximately weekly intervals over a period of seven months. Each treatment was transfused over a period of 3-5 hours.

Other post-chelation urine studies were performed over a period of time and showed urine lead level of 39, 40, and 50 mg/24 hours respectively. Complete blood counts, urinalysis and chemistry profile were done throughout the treatment and showed no adverse effects of the treatment.

The patient slowly decreased his medication during the EDTA treatment and stopped them completely at the last chelation (March 14, 1986). His blood pressure at the last chelation was 124/84 mm/Hg. He has not taken any blood pressure medication since the last chelation treatment. He also decided to take another flight physical to renew his private pilot license. He passed without any problems.

References
1. Riordan HD, Cheraskin E and Dirks BD: Mineral excretion associated with EDTA chelation therapy. J. Adv. Med. 3: 111- 123, 1990.
2. Pirkle JL et al: The relationship between blood lead levels and blood pressure and its cardiovascular risk implications. Am. J. Epi. 121: 246-258, 1985.
3. Batuman V et al: Contribution of lead to hypertension with renal impairment. N. Engl. J. Med. 309: 17-21, 1983.
4. Harian WR et al: Blood lead and blood pressure. JAMA 253: 530-534.

1. Professor and Chair, Clinical Sciences Department, The Wichita State University, Wichita, Kansas 67208.
2. The Center for the Improvement of Human Functioning International, Inc., 3100 N. Hillside, Wichita, Kansas 67219.

Nutritional factors are neglected for a number of reasons. Much of the literature on nutritional treatments has yet to evolve beyond the early stages of scientific investigation. Physicians learn so little about nutritional medicine during their training that they feel too uninformed to include it in their practices. Sub-optimal nutrition is generally believed to be rare in industrialized societies – even though up to 50% of the population may fail to ingest the Recommended Dietary Allowance for one or more vitamins or minerals.2 In regard to behavioral syndromes, nutritional factors are neglected, in part, because marginal nutritional deficiencies are not believed to affect behavior despite growing evidence to suggest that that belief may be false. (For example, subtle neuropsychological impairment has been documented by EEG recordings of older subjects in association with any of a number of marginal nutritional deficiencies. 3 Literature Review

1. Vitamins
Deficiencies of several vitamins are known to be associated with irritability. These include niacin,4 pantothenic acid,5 thiamine,6 vitamin B67 and vitamin C.8 In industrialized societies, the classic vitamin deficiency diseases are rare, although marginal vitamin nutriture due either to inadequate intake or to vitamin dependency appears to be fairly common. Moreover, under laboratory conditions, adverse behavioral changes precede specific clinical findings in a number of vitamin deficiencies.9

It is not known how frequently overaggressive behaviors are a manifestation of marginal vitamin nutriture. While little has been published to prove a relationship between the aggressive behavioral syndrome in humans and marginal vitamin nutriture, Lonsdale and Shamberger, writing in The American Journal of Clinical Nutrition, reported on twenty people eating “junk food” diets who were found to have biochemical evidence of marginal thiamine deficiency. Their subjects, and particularly the adolescents, were impulsive, highly irritable, aggressive and sensitive to criticism.

Following thiamine supplementation, their behavior improved concurrent with laboratory evidence of improved thiamine nutriture, suggesting that marginal thiamine deficiency may have contributed to their aggressive behavioral syndrome.6 Hopefully, well-controlled studies will eventually provide a clearer picture of the importance of marginal vitamin deficiencies in promoting overaggressive behaviors.

2. Minerals
Note: for the sake of completeness, minerals which do not function as nutrients are included in this review.

Iron
The most common nutritional deficiency in industrialized societies, 10% of American males and 3% of American females are overtly iron-deficient (ferritin less than 10 mg/mL.10 A deficiency of iron is known to interfere with proper brain function. Dopamine is a major neurotransmitter in the brain, iron is highly concentrated in the dopamine pathways, and animal studies have shown that iron deficiency may cause learning deficits and consequent behavioral impairment by diminishing dopamine neurotransmission.11 Iron is also needed as a co-factor for the enzymes which metabolize not only dopamine, but also serotonin and norepinephrine, which also have a potent influence on behavior.

Evidence is now emerging that iron deficiency may be an important contributor to the aggressive behavioral syndrome. Among adolescent males, iron deficiency has been shown to be directly associated with aggressive behavior (Conduct Disorder).12 Moreover, in a population of incarcerated adolescents, the prevalence of iron deficiency was nearly twice that found in their non-incarcerated peers.13

Lithium
There is considerable evidence that pharmacologic doses of lithium, which has no known essential function, can reduce abnormal aggressive behaviors including self-mutilation.14 Lithium has been used successfully with treatment-resistant hospitalized children with diagnoses of Conduct Disorder, Aggressive Type,15 as well as with brain-injured16 and mentally retarded17 patients with aggressive, combative or self-destructive behavior. While often effective, lithium at pharmacologic doses (generally 900,000 micrograms or more daily) has serious limitations. It suffers from many potential side effects, some of which are common. Because it becomes toxic at a serum level which is not much higher than the therapeutic range, serum lithium levels must be tested periodically. For these reasons, patients must be under medical supervision so long as they are taking the drug. It is possible that lithium may exert a powerful effect on overaggressive behaviors at far lower levels of intake. Using data from 27 Texas counties, Schrauzer and Shrestha found that the incidences of suicide, homicide and rape were significantly higher in counties whose drinking water supplies contained little or no lithium than in counties with higher water lithium levels, even after correcting for population density. Corresponding associations with the incidences of robbery, burglary and theft were also significant, as were associations with the incidences of arrests for possession of opium, cocaine and their derivatives. Only the incidences of arrests for possession of marijuana, driving under the influence of alcohol, and drunkenness failed to correlate with the water lithium level.18

While the effect of low-dose lithium supplementation on overaggressive behaviors has not been reported, results of an uncontrolled study suggest that low-dose lithium derived from vegetable concentrates may have a powerful effect on mental state and behavior. Thirteen depressed patients with bipolar disorder were treated with natural lithium derived from vegetable concentrates. All improved in about ten days and there were no adverse effects. After six weeks, they were taken off of lithium and all regressed to their former depressed state within three days. Two days after lithium was resupplied, their depressions lifted again.19

If we assume that a person consumes about one liter of water daily from municipal supplies, it is striking that the level of lithium provided from the vegetable concentrates approximates that consumed by residents of the Texas counties with higher lithium levels: “Natural” lithium dosage – 150 micrograms daily; Lithium level of drinking water in the Texas counties with higher levels18 – 70-170 micrograms per liter.

Magnesium
Rodent studies suggest that magnesium has a complex relationship with aggressive behaviors. Magnesium deficiency reduces offensive aggressive behavior but increases defensive aggressive behavior.20 Lower levels of magnesium supplementation increase the number of attacks on intruders while higher levels have the opposite effect.21

In humans, magnesium deficiency, which enhances catecholamine secretion and sensitivity to stress, may promote aggressive behavior. Increased catecholamines, in turn, induce intracellular magnesium losses and, eventually, increased urinary losses of magnesium.22 It has been suggested that the Type A behavior pattern – which is associated with chronic stress and aggressive behavior – may both cause and be caused by magnesium deficiency.22 Also, suicide attempts, which are violently aggressive acts against the self, have been correlated with lowered magnesium levels in the cerebrospinal fluid.23

Manganese
Manganese is an essential trace mineral. Massive overexposure produces “manganese madness” which may initially be marked by violence, criminal acts and a state of mental excitement; later, neurological impairment slowly develops, with signs and symptoms which resemble Parkinson’s disease.

The behavioral effects of marginal levels of manganese toxicity have not been described. Recently, Gottschalk and his associates consistently found elevated hair manganese in a population of violent male offenders, suggesting that marginal manganese toxicity may be associated with violent criminal behavior. Compared to the hair manganese levels which they found, people exposed to levels of manganese pollution which are known to be toxic possess hair values that are two to six times higher.24

Elevated hair manganese levels have also been reported in hyperkinetic children,25, 26 and men with a history of childhood hyperactivity have an increased rate of antisocial and drug use disorders.27 In rats, chronic manganese exposure initially produces hyperactivity with an increased tendency to fight.28 While any hypothesis concerning the behavioral effects of marginal manganese toxicity in humans is highly speculative, these findings suggest that marginal manganese toxicity may promote overaggressive behaviors in adults.

Heavy Metals
Brain damage due to toxic metal exposure may promote aggressive, antisocial and violent behaviors. Lead exposure is known to cause learning and behavioral problems, problems which are found in a substantial portion of juvenile delinquents.

The strongest evidence to date that lead exposure increases the frequency of aggressive behaviors comes from the Edinburgh Lead Study which included over 500 children between the ages of 6 and 9. After taking 30 possible confounding variables into account, the investigators still found a significant relationship between the log of blood lead levels and teachers’ ratings of the childrens’ behavior on an “aggressive/antisocial” scale and on a “hyperactive” scale, but not on a “neurotic” scale. As in other studies on the relationship between lead exposure and brain damage, a dose-response relationship was found between blood lead and behavior ratings, with no evidence of a threshold.29

Pihl and associates have addressed the relationship of lead exposure and violent behavior in adults. Hair lead levels from 19 violent criminals were found to be elevated as compared with those of 10 nonviolent criminals.30 This study was repeated 8 years later by the same research team with essentially the same results. However, their results were contradicted by those of the recent Gottschalk study on hair manganese levels; in that study, no significant differences were found between hair lead levels of 104 violent criminals, prison guards and local townspeople.24

As with lead, studies comparing hair cadmium levels of violent male offenders to matched controls have had conflicting results. One study published in the Journal of Learning Disabilities looked at hair cadmium levels of 40 apparently normal young men entering US Navy recruit training and found a highly significant relationship between hair cadmium levels and the number of demerits each recruit had received. Moreover, the three recruits who had the highest cadmium levels all displayed serious behavior difficulties during training.31 Exposure to aluminum may also contribute to overaggressive behaviors. Hair aluminum levels of a group of 22 juvenile offenders,32 as well as of another group of 10 severely delinquent, psychotic or prepsychotic adolescent boys,33 were elevated. However, both studies compared aluminum levels to laboratory norms rather than to matched controls; thus other differences between the groups could account for the findings.

3. Amino Acids
Tryptophan
Serotonin, a major neurotransmitter, has been found to play an important role in modulating aggressive behavior. Impulsive, violent and suicidal behaviors have repeatedly been shown to be associated with a reduction in serotonergic activity in the central nervous system.34

Tryptophan, an essential amino acid, is the dietary precursor to serotonin, and several lines of evidence have suggested that the amount of tryptophan in the diet relates closely to aggressive behavior. For example, rats given a diet almost lacking in tryptophan develop aggressive behavior towards mice.35

Tryptophan must compete with other large neutral amino acids to cross the blood-brain barrier; therefore the ratio of the amount of tryptophan to the amount of competing amino acids (the tryptophan ratio) may provide a rough indication of the availability of tryptophan in the brain for conversion into serotonin. Kitahara has calculated the dietary tryptophan ratio for 18 European countries to attempt to relate it to homicide rates. While initially no correlation was found between low tryptophan ratios and homicide, once social and cultural differences were controlled for, low tryptophan ratios were found to be associated with high homicide rates.36 A more direct method of examining the relationship between the tryptophan ratio and aggression is by measuring the actual ratio in the blood plasma. When a group of depressed alcoholics was evaluated in this manner, those with a history of aggression, including suicide attempts, also had the lowest tryptophan ratios.37 If a low ratio of tryptophan to competing amino acids is associated with aggressive behavior, will tryptophan supplementation reduce that behavior? Dietary tryptophan was manipulated in social groups of vervet monkeys by providing them with amino acid mixtures that were tryptophan-free, nutritionally balanced, or excessively high in tryptophan. These mixtures were shown to have a marked effect on plasma tryptophan levels. During spontaneous activity, the only effect of the different mixtures was increased aggression in the males on the tryptophan-free mixture. During competition for food, however, while the tryptophan-free mixture continued to increase male aggression, the high-tryptophan mixture reduced aggression in both males and females.38 These data suggest that tryptophan supplementation may be most effective in reducing aggression during times of stress.

When hospitalized male schizophrenics were given tryptophan, only those patients with high levels of hostility and a high lifetime frequency of aggressive incidents benefited; these patients showed a lessening of hostility and depression, a reduction in ward incidents and improvement on a standardized psychiatric rating scale.39 In another study of twenty aggressive patients, 6 g of tryptophan daily for one month failed to reduce the number of violent incidents, although it significantly reduced the need for potent medications to control violent or agitated behavior.40

The rate of firing of serotonergic neurons in the brain increases as the level of behavioral arousal increases; thus increased serotonin levels would be more likely to influence brain function at higher levels of arousal. Indeed, this fact probably explains why the vervet monkeys only responded to tryptophan supplementation when they were put under competitive stress. It also may explain why altered tryptophan levels failed to affect aggression in a study of normal human males, while overaroused, hostile and aggressive psychiatric patients responded well.

In the conversion of tryptophan to serotonin, the intermediate step is its conversion to 5-hydroxytryptophan. Surprisingly, supplementation with 5-hydroxytryptophan may increase aggressive behavior, apparently because, while tryptophan appears to enhance the serotonergic system exclusively, 5-hydroxytryptophan also appears to enhance the catecholaminergic system.41

4. Reactive Hypoglycemia
There is early evidence that hypoglycemia during glucose tolerance testing is related to hostile, aggressive behavior such as that seen in habitually violent and impulsive criminals.34 Virkkunin, for example, found that a group of habitually violent adult criminals had lower basal glucose levels during glucose tolerance testing than controls.42 Even in the normal population, there is evidence of a relationship between hypoglycemic tendencies and both frustration and hostility.43

Assuming that there is an association between hypoglycemia and the aggressive behavioral syndrome, the question of whether hypoglycemia causes the syndrome remains. One method of investigating the issue of causality is by changing the amount of sugar in the diet and examining the behavioral effects. Since dietary sugar provokes insulin production which may cause a reactive hypoglycemia, a change in behavior following a change in sugar intake would be consistent with the hypothesis that dietary sugar influences that behavior. In a series of increasingly sophisticated double-blind studies, Schoenthaler addressed this question by reducing the sugar intake of thousands of incarcerated juvenile offenders in different locations around the United States. Compared to offenders on a placebo diet, he found a significant reduction in various forms of antisocial behavior (such as assaultiveness, fighting, self-injury and suicide attempts) in offenders restricted to a minimal amount of sugar in their diet – but only for the males.44

While Schoenthaler’s work suggests that dietary sugar may influence behavior, he did not examine blood sugar levels; it thus fails to address the role of reactive hypoglycemia in the aggressive behavioral syndrome. The finding that only males responded may either be because males are more likely to engage in aggressive behaviors, or because males are more sensitive to nutritional influences on aggression. (Remember that the lack of tryptophan in the diet only increased aggression during spontaneous play in the male monkeys.) Further studies are needed to address these important questions.

5. Food Sensitivities
It appears that overaggressive behaviors can be provoked by a reaction to common foods. Reactions range from irritability to a psychotic aggressive reaction. Children who improved after food eliminations had previously been irritable, fretful, quarrelsome and could not get along with others. Often they had to be taken out of school as they upset the classes and were considered incorrigible. After food eliminations, however, their personalities dramatically changed, and they became happy and social.45

A study reported in the Lancet suggests that food sensitivities may be quite common among behaviorally- disturbed children. Eighty-one out of a group of 140 children with behavior disorders (almost two-thirds) experienced significant improvement following the elimination of certain foods along with food additives. When they were challenged with the specific foods which had been eliminated, their behavior problems returned. Moreover, 75% of these children reacted to a double-blind challenge with salicylates but not to placebo.46 The following case study, reported in Psychology Today, illustrates how food sensitivities may affect aggressive behavior:

When he was five years and one month old, G.L. was seen because of uncontrollable temper tantrums. He was believed aphasic because of poor speech development, and was too uncomfortable to do initial IQ testing. The EEG showed 14-per-second spikes, large amounts of sharp activity in the motor leads, temporal single, polyphasic sharp waves, and a long run of sharp waves in the right temporal area. Allergy tests revealed strong reactions to milk, chocolate and yeast.

He was placed on a diet free of milk, chocolate, and cola drinks. Seven and one half months later, his EEG was normal. Six months after the repeat EEG, he was learning better and his behavior was much improved. He was challenged again with the suspected foods for one week, during which time his behavior again became uncontrollable.

The EEG now showed two-and-one-half to six-per-second activity on the right, greater in the mid-temporal and parietal leads, accentuated by drowsiness. Light cerebral dysfunction was diagnosed.47

Adults may also display overaggressive behaviors due to food sensitivities. For example, MacKarness has written of a woman who had been hospitalized thirteen times for violent behavior and depression; after common foods were eliminated from her diet, she no longer became violent or depressed. Instead she felt fine and obtained a regular job.48

While the research literature suggests that any commonly ingested food or food additive may be responsible for provoking pathological psychological and behavioral reactions, milk may be a special case. Schauss and Simonsen found that chronic juvenile delinquents consumed much more milk than matched controls without a history of delinquency. The male offenders consumed an average of a gallon of milk daily compared to a little less than a quart a day for the controls, and the females showed similar differences.49

Schauss believes that overconsumption of milk causes antisocial behavior. He has reported that, when several Michigan detention centers reduced their inmates’ milk consumption, the incidence of antisocial behavior declined; when they permitted milk consumption to increase again, antisocial behavior also increased.50

Discussion and Summary
The literature offers numerous clues, but little scientific verification, consistent with the hypothesis that the aggressive behavioral syndrome can be prevented and treated by manipulating nutritional factors. Epidemiological studies have repeatedly found associations between overaggressive behaviors and deficiencies of several essential nutrients: niacin, pantothenic acid, thiamine, vitamin B6, vitamin C, iron, magnesium and tryptophan. While repletion of frank deficiencies is likely to be beneficial, the benefit of correcting marginal deficiencies remains to be proven.

Not an essential nutrient, lithium has been proven effective in reducing overaggressive behaviors when provided at massive pharmacologic dosages. Moreover, even the relatively tiny daily lithium intake from municipal water supplies has been found to be negatively correlated with measures of the aggressive behavioral syndrome. In an open trial, supplementation with such natural levels of lithium appeared to be effective in treating bipolar depression. These findings suggest that natural lithium supplementation may be effective in the management of the aggressive behavioral syndrome, a hypothesis which remains to be explored experimentally.

There is some evidence that overaggressive behaviors may be promoted by the toxic effects of aluminum, cadmium and lead. Exposures to these elements (especially cadmium and lead) should be avoided; it is unknown whether treatments designed to chelate these metals in order to remove them from the brain are effective in reducing overaggressive behaviors.

Reactive hypoglycemia may be more common among people displaying the aggressive behavioral syndrome and, in an open study, reducing sugar consumption was followed by a reduction in antisocial behavior. Whether treating documented reactive hypoglycemia reduces overaggressive behaviors remains unknown. Finally, sensitivities to foods and food additives appear capable of inducing overaggressive behaviors. Most of the evidence remains anecdotal; however, salicylates have been shown to provoke behavioral disturbances under double-blind conditions.

Despite the relative paucity of scientific evidence from controlled studies, clues from case reports, open trials, observational (correlational) studies and animal studies suggest that attention to nutritional factors may reduce overaggressive behaviors and the devastation resulting from them. Those clues, plus the safety of most nutritional interventions, argue that a nutritional approach should be considered in the treatment of the aggressive behavioral syndrome.

References
1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised. Washington, D.C., American Psychiatric Association, 1987.
2. Hanes: Health and Nutrition Examination Survey. U.S. Dept. of HEW Publication No. (HRA) 74-1219-1, Rockville, MD, 1974.
3. Tucker DM et al: Nutrition status and brain function in aging. Am. J. Clin. Nutr. 52:93-102, 1990.
4. Gelenberg AJ: Psychiatric Disorders, in DM Paige, Ed. Clinical Nutrition, Second Edition. St. Louis, The C.V. Mosby Company, 1988.
5. Hodges RE et al: J. Clin. Invest. 38:1421, 1959.
6. Lonsdale D, Shamberger R: Red cell transketo-lase as an indicator of nutritional deficiency. Am. J. Clin. Nutr. 33(2):205-11, 1980.
7. McLaren DS: Clinical manifestations of nutritional disorders, in ME Shils & VR Young. Modern Nutrition in Health and Disease, Seventh Edition. Philadelphia, Lea & Febiger, 1988.
8. Wilmot CA et al: Ascorbic acid inhibits isolation-induced fighting in mice. Fed. Proc. 42:1160, 1983.
9. Brin M: Examples of behavioral changes in marginal vitamin deficiency in the rat and man, in J. Brozek, Ed. Behavioral Effects of Energy and Protein Deficits. United States Department of Health, Education and Welfare Publ. no. (National Institute of Health) 79-1906, 1979.
10. Baily L, Gensburg J, Wagner P et al: Serum ferritin as a measure of iron stores in adolescents. J. Pediatr. 101:774-6, 1982.
11. Youdim MB et al: Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior. Am. J. Clin. Nutr. 50(3 Suppl.):607-15, 1990.
12. Webb TE, Oski FA: Behavioral status of young adolescents with iron deficiency anemia. J. Special Ed. 8(2):153-6, 1974.
13. Rosen GM, Deinard AS, Schwartz S et al: Iron deficiency among incarcerated juvenile delinquents. J. Adolesc. Health Care 6:419-23, 1985.
14. Wickham EA, Reed JV: Lithium for the control of aggressive and self-mutilating behavior. Int. Clin. Psychopharmacol. 2(3):181-90, 1987.
15. Campbell M et al: Behavioral efficacy of halo-peridol and lithium carbonate. A comparison in hospitalized aggressive children with conduct disorder. Arch. Gen. Psychiatry 41(7):650-6, 1984.
16. Glenn MB et al: Lithium carbonate for aggressive behavior or affective instability in ten brain-injured patients. Am. J. Phys. Med. Rehabil. 68(5):221-6, 1989.
17. Spreat S et al: Lithium carbonate for aggression in mentally retarded persons. Comp. Psychiatry 30(6):505-11, 1989.
18. Schrauzer GN, Shrestha KP: Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions. Biol. Trace Elem. Res. 25(2):105-13, 1990.
19. Fierro AA: Natural low dose lithium supplementation in manic-depressive disease. Nutr. Perspectives January, 1988:10-11.
20. Kantak KM: Magnesium deficiency alters aggressive behavior and catecholamine function. Behav. Neurosci. 102(2):304- 11, 1988.
21. Izenwasser SE et al: Stimulant-like effects of magnesium on aggression in mice. Pharmacol. Biochem. Behav. 25(6):1195-9, 1986.
22. Henrotte JG: Type A behavior and magnesium metabolism. Magnesium 5:201-10, 1986.
23. Banki CM et al: Cerebrospinal fluid magnesium and calcium related to amine metabolites, diagnosis, and suicide attempts. Biol. Psychiatry 20(2):163-71, 1985.
24. Gottschalk LA et al: Abnormalities in hair trace-elements as indicators of aberrant behavior. Compr. Psychiatry 32:229-37, 1991.
25. Barlow PJ: A pilot study on the metal levels in the hair of hyperactive children. Med. Hypotheses 11(3):309-18, 1983.
26. Collipp PJ: Manganese in infant formulas and learning disability. Ann. Nutr. Metab. 27:488-94, 1983.
27. Mannuzza S et al:P Hyperactive boys almost grown up. V. Replication of psychiatric status. Arch. Gen. Psychiatry 48:77- 83, 1991.
28. Chandra SV: Psychiatric illness due to manganese poisoning. Acta Psychiatr. Scand. Suppl. 303:49-54, 1983.
29. Thomson GO et al: Blood-lead levels and children’s behaviour: results from the Edinburgh Lead Study. J. Child Psychol. Psychiatry 30(4):515-28, 1989.
30. Pihl RO et al: Hair element content of violent criminals. Can. J. Psychiatry 27:533, 1982.
31. Struempler RE et al: Hair mineral analysis and disruptive behavior in clinically normal young men. J. Learn. Disabil. 18(10):609-12, 1985.
32. Schmidt K et al: Clinical ecology treatment approach for juvenile offenders. J. Behav. Ecology: Biosocial 2(1), 1981.
33. Rees EL: Aluminum toxicity as indicated by hair analysis. J. Orthomol. Psychiatry 8:37, 1979.
34. Roy A et al: Monamines, glucose metabolism, aggression towards self and others. Int. J. Neurosci. 41(3-4):261-4, 1988.
35. Giammanco S et al: Short term diet of precooked corn meal almost lacking in tryptophan and interspecific rat-mouse aggressive behavior. Arch. Int. Physiol. Biochim. 98(1):23-6, 1990.
36. Kitahara M: Dietary trypotophan ratio and homicide in Western and Southern Europe. J. Orthomol. Med. 1(1):13-6, 1986.
37. Branchey L et al: Depression, suicide and aggression in alcoholics and their relationship to plasma amino acids. Psychiatry Res. 12(3):219-26, 1984.
38. Chamberlain B et al: The effect of raising or lowering tryptophan levels on aggression in vervet monkeys. Pharmacol. Biochem. Behav. 28(4):503-10, 1987.
39. Morand C et al: Clinical response of aggressive schizophrenics to oral tryptophan. Biol. Psychiatry 18(5):575-8, 1983.
40. Volavka J et al: Tryptophan treatment of aggressive psychiatric patients. Biol. Psychiatry 28(8):728-32, 1990.
41. Raleigh MJ: Differential behavioral effects of tryptophan and 5-hydroxytryptophan on vervet monkeys: influence of catecholaminergic systems. Psychopharmacology (Berlin) 93(1):44-50, 1987.
42. Virkkunen M: Reactive hypoglycemia tendency among habitually violent offenders: A further study by means of the oral glucose tolerance 43. Benton D et al: Mild hypoglycaemia and questionnaire measures of aggression. Biol. Psychol. 14(1-2):129-35, 1982.
44. Schoenthaler SJ: Int. J. Biosocial Res. Vol. 3-5, 1982-3.
45. Clarke TW: The relation of allergy to character problems in children: A survey. Ann. Allergy March-April, 1950, pp. 175- 87.
46. Swain A et al: Salicylates, oliogoantigenic diets, and behaviour. Letter. Lancet 2:41-2, 1985.
47. Moyer KE: Allergy & aggression: The physiology of violence. Psychol. Today July, 1975, pp. 77-9.
48. MacKarness R: Eating Dangerously. New York, Harcourt, Brace, Jovanovich, 1976.
49. Schauss AG, Simonsen CE: Critical analysis of the diets of chronic juvenile offenders: Part I. J. Orthomol. Psychiatry 8(3):149-57, 1979.
50. Schauss AG: Nutrition and antisocial behaviour. Int. Clin. Nutr. Rev. 4(4):172-7, 1984.

March 12, 1992, Natalie Angier wrote an article entitled “Vitamins Revitalized as Health Agents”, International Herald Tribune, which appeared in the New York Times and in the Globe and Mail March 14th. What is interesting in this report is not what it said, but the fact that it was said. The use of vitamins in megadoses was described without the usual massive attention to toxicity and a major warning to the readers to avoid these things as much as possible since they could get all they needed from food alone. Scientists have lost their fear of these high dosages. For example, Dr. S. N. Meydani of the Human Nutrition Research Center on Aging, at Tufts University in Boston said, “Now we are starting to think about what is the optimal level of vitamins for lifelong diseases and to prevent age-associated diseases.” This university has been headed by a nutrition scientist who at every opportunity had derided the use of vitamins in his popular columns of advice to the American public. I assume that Dr. Meydani will not be fired. The impressive results achieved by the use of vitamins is gradually overcoming the reluctance of physicians to use them, even though they might be reluctant to advise patients to take them. Thus, Dr. I Jialal of the University of Texas Southwestern Medical Center in Dallas, is “… not yet willing to advise that the public start taking vitamin tablets, and he, like so many researchers, emphasizes the need for more studies. But he did admit that given his preliminary results and the relative harmlessness of Vitamin E, he himself planned to start a supplement of the nutrient daily.” I have some good news for Dr. Jialal. Up to 60% of the population are already taking vitamin supplements and have been doing so for years.

Contributors to this journal have been describing the use of optimum amounts of nutrients including vitamins ever since this journal was first published. Readers are not surprised by the information in the public media, and they may well wonder why it has taken so long. Angier opened her story with the following statement, “Long consigned to the fringes of medicine and accorded scarcely more credibility than crystal-rubbing or homeopathy, the study of how vitamins affect the body and help prevent chronic diseases is now winning broad attention and respect among mainstream medical researchers.” She added, “They are gathering provocative evidence that vitamins influence nearly every organ, and that these enigmatic chemicals may help forestall or even reverse many diseases of aging, including cancer, heart disease, osteoporosis, a flagging immune system, neurodegeneration and other chronic disorders.”

Equally interesting is the prominent attention given to these vitamins in the New York Times. This presitgious national newspaper has, since at least 1966, consistently ignored or criticized the use of megavitamins. This was the policy of their editorial board. Many years ago at a meeting of the Huxley Institute of Biosocial Research in New York, I was approached by a writer who had been commissioned by the New York Times to attend our meeting and to prepare a report. He did attend for the day and one-half. This was the meeting which was greeted by Mayor Koch. At the end of the meeting this reporter approached me and asked whether I would spend some time answering his questions. I replied that I saw no point in doing so, since if he wrote anything favorable the New York Times would not publish it. He was astounded at my statement, and reassured me that so far he had not had any of the articles, which they had asked him to write, rejected. I agreed to see him on Monday at my hotel. He came to my room mid-afternoon and stayed until 7 p.m., until my wife and I had to leave to attend the opera. He assured me that his report would appear in the Sunday Supplement within two weeks. After several months had passed I called him to find out what had happened and would his article ever appear. He said that the editorial board had wanted a few points clarified and could we meet again next time I was there. I agreed. Again I spent several hours with him. The story never appeared. I assumed it was favorable, although the writer did not tell me what the tenor of his report would be like. I assumed that a senior editor who had been writing major articles against the use of vitamins had killed the story. It is possible the writer was a fraud and had nothing whatever to do with the New York Times, but I considered this highly unlikely after getting to know him so well. This little episode merely illustrates the entrenched opposition of the Times to orthomolecular nutrition. They had shown similar opposition to articles written by my friend, Dr. Walter Alvarez. After a particularly critical article against psychoanalysis appeared in his column in the New York Times, the newspaper concealed his column. It looks as if the New York Times has undergone a conversion experience.

Almost every modern, acceptable treatment needed forty or more years before that treatment became acceptable. I have for many years predicted that it would take about forty years before megavitamin therapy would become widely accepted. I had started the clock at 1957 when we first published our paper describing the use of large doses of Vitamin B3 for the treatment of acute schizophrenia. I assumed that by the year 1997 this would become the recognized best treatment. Orthomolecular treatment originated from that particular study as one of the main roots. The other was the work by Linus Pauling who defined the term orthomolecular and placed his immense scientific prestige and knowledge behind the concept. His seminal work on Vitamin C and the cold and flu, and more recently on the use of this vitamin in the treatment of cancer, and very recently on the role Vitamin C plays in preventing hardening of the arteries, has been the most potent factor in swaying public opinion and, sometime after that, scientific opinion. But I now think that general medicine will be ahead of psychiatry, which requires much more effort to be persuaded to look at different findings and treatment philosophies.

A. Hoffer, M.D., Ph.D.
#3A – 2727 Quadra Street
Victoria, B.C. V8T 4E5

Depression affects about 17 to 19 million American adults each year. We take a somewhat different approach to depression at The Center.

It is possible to become depressed because of the lack of a sufficient amount of a single trace element.

Did you know every medical text book, at least up until a few years ago, indicated that one of the most common effects of inadequate vitamin C is depression? We very seldom go to a psychiatrist who measures our vitamin C level.

Many years ago, I had a lady who was a teacher and she was profoundly depressed. She had three years of psychotherapy prior to coming to The Center. She had profound fatigue and was barely able to function at all. Our testing revealed she had no detectable vitamin C, so we gave her 500 milligrams of vitamin C a day-not very much by our standards.

In a couple of weeks, she thought a miracle had occurred. No miracle had occurred. She was low on vitamin C and depression is the natural consequence of that. She had very good insurance. A psychotherapist could have seen her every week for two years and the i nsurance company would have paid the entire bill. Our bill was for two office calls and three vitamin C levels. The company would not pay because vitamin C had nothing to do with depression, according to their payment schedule. If you are depressed, vitamin C is worth considering.

In studies at two area health care centers, 30% of new admissions with a diagnosis of depression had low plasma vitamin C levels. Actually, we did this study a number of years ago and found that if you took a hundred people who are depressed without checking their level and gave them all vitamin C, 30% would get better. Statistically that would be below the placebo level. That is why it is important to separate out the 30% from the large group, so the people who are low in vitamin C will obviously respond more to the vitamin C than the people who are not.

Of course, man and woman does not live by vitamin C alone. It is possible to become depressed because of the lack of a sufficient amount of a single trace element. The following is from an audio tape of a person who had this problem:

“I was getting more depressed. I had two grand babies coming at the end of July and I didn’t want to see them. That’s rather odd for a grandmother. I knew I wasn’t up to helping my children with their children. I knew I had to teach. We needed the income. I never got any sleep and I wasn’t worrying about my students. I teach learning disabled students. I love my job. I just didn’t feel up to it and I knew something was wrong.

“I tried hypnosis to no avail. I tried several psychiatrists. I responded completely opposite of what the medication I took was supposed to do. One psychiatrist knew enough to send me to The Center.

‘This wasn’t just a light depression. It was an inability to cope with life, inability to enjoy my family. We couldn’t go out to dinner because I was allergic to so many foods.

The thing that changed my life was calling back The Center and letting them know that I wasn’t feeling any better. They decided to give me double the amount of liquid zinc. Dr. Riordan told me how to take it. Instead of having it in a whole lot of water, I just had a smidgen of water. In two day’s time when I had double the zinc, my husband said he had a new wife and he wasn’t sure he could cope with me.

“We even brought my daughter here who is severely depressed and we know she will get help. She has some of the same nutrient needs that I have but not the need for zinc. But we are all happy about the two new grand babies. I have even been able to do better with my students.”

There were several important points mentioned in that little piece. One point is to measure what’s going on. If you gave zinc to 100 people who are depressed, 99 are not going to do much with that. In her case, zinc seemed to be her particular thing. It is very important to look at the individual biochemistry to see what is missing and what needs to be improved. Then you can do a great deal. She also indicated that she wasn’t doing very well initially and that’s why we have follow-up to seewhat’sgoingon.Herinitial zincwe knew was low and the initial amount we gave her was not sufficient to raise it to the level that she needed. Increasing her zinc was what eliminated her continued on page 3

Keep in mind that zinc is involved in at least 100 enzyme systems in the brain alone. So, it’s a very important trace mineral. Certainly not the only one, but one that is worthy of consideration when brain tissue function is not optimum.

Serotonin tends to improve mood and promote relaxation. If you’re going to do a study on serotonin, you need to collect the urine for 24 hours. The lab will inform you that avocados, pineapple, eggplant, plums, walnuts, and pregnancy are going to affect the serotonin level.

According to a study done in Great Britain, 80% of people with mood disorders noticed that food choices affected how they felt. The food you choose ‹ avocados, bananas, and some walnuts, should pick up your serotonin level and, thus, enhance how youfeel if you are depressed.

Sugar and alcohol are considered ‘Tood stressors,” according to a British study. In the same study, water, vegetables, fruit, and fish were considered “tood supporters.” Actually, the researchers said water was number one for subjects wanting to improve how they felt. As we get older, one of the major problems is dehydration. When we were young, the ratio of water inside the cell to outside the cell is 1.2 to 1. There is more water inside the cell than there is outside. By the time we are 60, the ratio is 0.8 to 1. Even if you are drinking enough water, you are dehydrating all the time. So the goal is to drink sufficient water.

The incidence of depressive disorders varies throughout the world. Japan has the lowest incidence of depression as does Korea-2%. Taiwan has 3%. The USA has 7%, New Zealand has 11%, and France has 16%. It would appear that the dietary choices people make have somethingtodowithwhether or not they are depressed. Japanese and Koreans eat fish. The omega-3 fat in most fish manipulates brain chemicals in ways that boost mood. You can, of course, measure fatty acids to see what levels you have. If the brain is not working well, feed it what it needs!

Most people don’t appreciate that food has something to do with how they feel. In addition to general responses to various food, adverse reactions to specific foods can lead to depression. The Center uses the cytotoxic test to detect adverse food reactions. This test is useful for people who have problems with brain fog or are not thinking well. The test is done by separating out the white cells and then mixing them with various food antigens. If the white blood cells are happy and healthy, that food is fine. If there’s a kill off of white blood cells, then you have a positive cytotoxic test. Limiting cytotoxic foods can improve brain function.

Neurotransmitters are derived from amino acids, which can be measured in blood and urine. Abnormal amino acids can be corrected nutritionally which should improve neurotrans-mitter and brain function. Adequate amounts of fatty acids, which are in every cell membrane, can have a stabilizing effect on mood. The cells talk to each other through fatty acids in the membrane.

Inadequate thyroid function can lead to depression. One can measure a standard thyroid test, thyroid stimulating hormone (TSH), or thyroxine (T4). We measure triiodothyronine (T3), which is the active hormone that gets into the cell.

Hormonal changes, such as low testosterone, have been shown to affect depression. The same thing is true with female hormonal imbalances.

Short term depression in response to unpleasant life events is normal and does not necessarily need an anti depressant. In our culture right now there is the notion that one should never feel depressed about anything. When certain things happen, you ought to feel depressed. If it is a short term thing, it usually doesn’t need treatment.

People who are depressed have been shown to breathe less deeply than people who are not depressed. You can de-stress by deep breathing. Take five deep breaths and hold each for six seconds. Do this four times a day. This decreases tension. You have two sides of the nervous system, the central nervous system and the autonomic nervous system. All day long we are tensing up with whatever is going on and the autonomic nervous system tenses, too. It is like tightening a ratchet. When you take five deep breaths, it is like releasing the ratchet.

Exercise had been shown to be useful in eliminating depression. There are studies at the University of Wisconsin that show that getting people who are depressed to run in groups reduces the depression in about 85% of the people.

A psychologist said that we are all hit by the same hammer, so he made an interesting observation: “A person made three dolls‹one of porcelain, one of plastic, one of steel. If you hit all three with a hammer, the porcelain would smash into pieces, the plastic one would be dented, and the steel doll would give off a musical note.” So, it is not the hammer but how you are made that makes a difference.

Eat well, drink water, and check your nutrient levels and you will be like the doll made of steel.

“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 [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.

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
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 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)

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. 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
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.

The APA Task Force Report
In July 1973 an APA task force of five physicians and one consultant issued a 54-page report titled Megavitamin and Orthomolecular Therapy in Psychiatry (30). In this report the Task Force on Vitamin Therapy in Psychiatry purports to present both theoretical and empirical reasons for completely rejecting the basic concept of orthomolecular psychiatry, which 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.

Some Errors in the Report
It is mentioned in the report that in the treatment program of the orthomolecular psychiatrists “each patient may receive as many as six vitamins in large doses individually determined by the treating physician as well as other psychotropic drugs and hormones whose doses are also individually determined for each patient” (p. 46). The assumption is made by the task force that the optimum intake of vitamins for mental health is the conventional average daily nutritional requirement, with growth and development as the criteria: “In schizophrenia there is apparently an adequate vitamin intake for growth and development until the illness becomes manifest in the teens or early adult life” (p. 40). Mention is made in the report of the well-known genetic diseases with both psychic and somatic manifestations that can be controlled by an intake of a vitamin 100 or 1,000 times the usually recommended daily allowance, but the possibility that less obvious genetic differences could result in an increased individual need for a larger intake of vitamins in order to achieve good mental health, as discussed in my 1968 publication (1) and in the earlier sections of this paper, is rejected on the basis of arguments that have little value or pertinence. One such argument is the following:

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.
Nicotinic acid as a methyl acceptor is referred to in the report: “From Study No. 12: nicotinic acid in the dosage of 3000 mg. per day can neither prevent nor counteract the psychopathology induced by the combined administration of a monoamine oxidase inhibitor (tranylcypromine) and methionine” (p. 16). In fact, the molecular weights of nicotinic acid and methionine (a methyl donor) are nearly the same, 123 and 149, respectively. Instead of 3 gm., 16.5 gm. of nicotinic acid would have had to be given each day to accept the methyl groups donated by the 20 gm. of methionine that was given each day. The study referred to as number 12 (31), which resulted in an exacerbation of the illness of 30 schizophrenic patients who participated in it, has no value as a test of the methyl acceptor theory of nicotinic acid. Consideration of ethical principles may have kept the investigators from repeating the study with use of the proper equimolar amounts of nicotinic acid and methionine.

The Failure To Discuss Ascorbic Acid and Pyridoxine
In several places the APA task force report mentions the use of 1 to 30 gm. of ascorbic acid a day by orthomolecular psychiatrists. There are, however, no references to the literature. Milner’s double-blind study (25) is not mentioned, nor is there any discussion of the many papers in which a low level of ascorbic acid in the blood of schizophrenics was reported. Neither the general theory of orthomolecular psychiatry, as presented in my 1968 paper (1) nor any of the special arguments about the value of ascorbic acid is presented or discussed in any significant way. There is, moreover, no discussion in the report of pyridoxine and no reference to the 1973 work by Ananth, Ban, and Lehmann (27) on the potentiation by pyridoxine of the effectiveness of niacin in controlling chronic schizophrenia. The title of the report, Megavitamin and Orthomolecular Therapy in Psychiatry, is completely inappropriate, and the general condemnation of megavitamin and orthomolecular therapy is unjustified.

Niacin
The report does my that it is possible that the other watersoluble vitamins will prove to be more effective than niacin but it adds;

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.
A failure to reject with statistical significance the nun hypothesis that the treatment and the placebo have equal value is not proof that the treatment has no value. The explicit statistical analysis of an alternative hypothesis should be carried out: for example, the hypothesis that there is a 10-percent or 20-percent greater improvement in the treated subjects than in the placebo subjects. No such analysis has been published.
In fact, some of the “negative” studies indicate that the treatment has value. The report states that “Greenbaum (33) reported a double-blind study of 57 schizophrenic children who received nicotinamide 1 gm. per 50 lbs of body weight or placebo for six months. No statistically significant differences were seen in the two groups as a result of the treatment” (P. 11). it is true that no statistically significant differences were wen, but that is not the whole truth, The principal criterion of improvement in this study was the increase in the score on a clinical scale of observable behavior categories. The average improvement in the score of the 17 children receiving niacinamide was 4.0 units and that of the 24 controls was 2.6 units (there was a third group of 16 children who were given a tranquilizer and niacinamide). The children who were given niacinamide showed a 54-percent greater improvement than the children who were given placebo. The groups were too small, however, for the difference to be significant at the 95-percent level of confidence. This study does not prove that niacinamide has no value. Rather, it indicates that niacinamide has greater value than the placebo, even though it fails to show this at the customary level of statistical significance.

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.

The Bias of the Task Force
The last sentence of the report reads as follows:

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.
I have written two popular books, No More War! (35) and Vitamin C and the Common Cold (24). I feel that each of them was worthwhile and that neither would have been easily replaced by a more technical book. The second book (24) was written because I had discovered in reading the medical literature that there was much evidence there about the value of ascorbic acid in decreasing both the incidence and the severity of the common cold and that this evidence had been suppressed or misrepresented by the medical and nutritional authorities. Since publication of the book, eight new studies have been reported. Every one of these has verified the value of ascorbic acid. The APA report shows the same sort of negative attitude as that shown by the authorities toward ascorbic acid in relation to the common cold. There seems to be a sort of professional inertia that hinders progress.

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. The APA task force report Megavitamin and Orthomolecular Therapy in Psychiatry discusses vitamins in a very limited way (niacin only) and deals with only one or two aspects of the theory. Its arguments are in part faulty and its conclusions are unjustified.

-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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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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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

27.Ananth, J.V., Ban, T.A., Lehmann, H.E.: Potentiation of therapeutic effects of nicotinic acid by pyridoxine in chronic schizophrenic& Can Psychiatr Assoc J 18:377-382, 1973

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30. Task Force Report 7: Megavitamin and Orthomolecular Therapy in Psychiatry. Washington, DC, American Psychiatric Association, 1973

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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